BACKGROUND Human Tuberculosis, a known historical disease, as per genetic and archaeological data Mycobacterium tuberculosis complex (MTBC) may have co-existed with humans for 15,000 [1]years. It's etiology was discovered by sir Robert Koch in th [2]March 24 1882. Globally, estimated 10.0 million people (range, 9.0–11.1 million) developed TB disease in 2017: 5.8 [3]million men, 3.2 million women and 1.0 million children. Although witha running programmeto control tuberculosis for almost more than 50 years TB continues to be India's one of the leading health hazard. Almost 480,000 persons die per year and more than 1,400 every day due to tuberculosis in India. Many cases are lost to follow up or inadequately treated in [4]private sector. Side effects and toxicity of the rst line anti-tubercular drugs (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol and Streptomycin) are a hurdle to the physician and the patients [5]for continuation of treatment. The most severe side-effects leading to interruption of treatment were hepatotoxicity (11%), [5]skin rash (6%), and joint pain (2%). Drug induced injury to liver with rst line drugs is a serious challenge during the treatment as well as signicant hazard while re-introduction [6]of the same regimen. Incidence of hepatotoxicity in Indian population is around 11.5%, compared with 4.3% in western population, with mortality of 6-12% when continued even after the onset of symptoms. Some responsible factors for hepatotoxicity are older age, female population, poor nutritional status, high alcohol intake, existing liver disease, hepatitis B carriage, increased prevalence of viral hepatitis in developing countries, hypoalbuminemia and advanced [7,8]tuberculosis, and inappropriate use of drugs. Asymp tom [9,10]atic elevation of transaminases is common, around 20%. Clinical presentation of anti-tuberculosis drug induced hepatitis usually resembles acute viral hepatitis and resolves spontaneously following withdrawal of the anti-tuberculosis [9,10]drugs. Many mechanisms were suggested for drug- induced liver damage such asidiosyncratic damage, dose- dependent toxicity, induction of hepatic enzymes, drug- [9,10]induced acute hepatitis and allergic reactions. It takes around 16 weeks (Range 6 weeks-6 months) from treatment [10]initiation to development of clinical symptoms. Though there are controversies regarding hepatotoxicity with alternate day regimen and daily regimen. Some studies are of opinion that there is no difference in hepatotoxicity incidences [11]among daily and alternate day regimen. Therefore, monitoring should be done after starting of Anti-tuberculosis drugs every 2 weeks interval to get a chance to avoid undue disruption in treatment, fatal complications and better patient [12]counselling. Various studies have shown that Anti-TB drugs are common [13,14,15]cause of hepatotoxicity worldwide. The incidence of anti- TB drug induced hepatotoxicity varies with the characteristics of the populations, drug regimens involved, upper limit used to dene hepatotoxicity, monitoring and reporting pattern. Overall, hepatotoxicity due to anti-TB drugs has been reported [14]in 5%–28% of people treated with anti-TB drugs. Many of these may not t into a more recent international case denition of drug-induced liver injury (DILI). Majority of the reports have used an elevated alanine (ALT) or aspartate transaminase (AST) of 3 times upper limit of normal range (ULN) with symptoms (Abdominal pain, nausea, vomiting, unexplained fatigue or jaundice) attributable to liver injury or 5 times ULN of ALT or AST without symptoms to dene [16]hepatotoxicity. Combination therapy develop transient asymptomatic elevation in liver enzymes, which comes to [17,18]normal level with continuation of the drug. The median interval from treatment initiation of drug to development of [19,20]clinical symptoms is 16 weeks. Poor nutritional status has been considered to be one of the factors contributing to a higher incidence of DIH induced by short-course chemotherapy for TB in the developing countries. Drug metabolism pathways including acetylation pathways have been shown to be deranged in states of protein energy [29]malnutrition. A STUDY TO DETECT ASSOCIATION OF BODY MASS INDEX AND HYPERBILIRUBINEMIA AS WELL AS BODY MASS INDEX AND LIVER ENZYMES AMONG PATIENTS ON FIRST LINE ANTI-TUBERCULAR DRUGS FROM RNTCP DURING THE COURSE OF ANTI-TB TREATMENT Original Research Paper Dr. Rupam Kumar Ta Associate Professor. Department of Pulmonary Medicine. Burdwan Medical College, Burdwan Pulmonary Medicine BACKGROUND: Globally, estimated 10.0 million people developed Tuberculosis in 2017. Side effects and toxicity of the rst line anti-tubercular drugs were hepatotoxicity, skin rash, and joint pain. Poor nutritional status has been considered to be one of the factors contributing to a higher incidence of DIH induced by short-course chemotherapy for TB in the developing countries. Hence this study was conducted to nd out the association between Body Mass Index and hyperbilirubinemia as well as Body Mass Index and liver enzymes among patients on rst line anti-tubercular drugs from RNTCP during the course of Anti-TB treatment. METHODS: 116 patients who were diagnosed to have Pulmonary (PTB)/ Extrapulmonary (EPTB) tuberculosis at Outpatient & In-Patients of Department of Chest Medicine, Burdwan Medical College & Hospital for eleven months after fullling the inclusion and exclusion criteria. Treatment was given as per guidelines by Revised National TB Control Program. RESULTS: Signicant association was observed between BMI<18.5 kg/m2 and hyperbilirubinemia and BMI>=18.5 and elevation in SGPT level at 2nd week of treatment. CONCLUSION: Hyperbilirubinemia is a common occurrence during the course of anti-TB treatment in patients with low BMI. Most patients show tolerance to anti-TB drugs and get adjusted after transient rise in liver enzymes. Clinicians should be vigilant for occurrence of hyperbilirubinemia in this high-risk group. ABSTRACT KEYWORDS : Hyperbilirubinemia, Sgpt, Bmi, Tuberculosis. VOLUME-9, ISSUE-2, FEBRUARY-2020 • PRINT ISSN No. 2277 - 8160 • DOI : 10.36106/gjra Dr. Saugata Bhaumik* rd3 Year Junior Resident, Department of Pulmonary Medicine. Burdwan Medical College, Burdwan *Corresponding Author Dr. Pronoy Sen st1 year Junior Resident, Department of Pulmonary Medicine. Burdwan Medical College, Burdwan 8 X GJRA - GLOBAL JOURNAL FOR RESEARCH ANALYSIS Therefore, in a country like India where malnutrition is very common it is very important to consider the nutritional status of patients on Anti-TB drugs and provide nutritional care. Due to paucity of studies in this respect, this study was conducted to nd out the association between Body Mass Index and hyperbilirubinemia as well as BMI and Liver enzymes among patients on rst line anti-tubercular drugs from RNTCP during the course of Anti-TB treatment. METHODS Aprospective observational study after taking proper written consent from the patients wasconducted in Outpatient Department (OPD) & In-Patients of Department (IPD) of Burdwan Medical College, Department of Pulmonary Medicine after they were diagnosed with tuberculosis either clinically or microbiologically as pulmonary or extra- pulmonary during the period of 11months. Base line data were collected such as history, detailed clinical examination, body mass index, residence, occupation, smoking and alcoholic status, sputum microscopy and CBNAAT, pleural uid analysis ( in cases of pleural effusion), lymph node ne needle aspiration for cytology and CBNAAT ( in lymphadenopathy), Chest X-ray, and routine blood along with base line liver function test. All the patients were put on xed dose combination (FDC) daily regimen with Isoniazid, Rifampicin, Pyrazinamide and Ethambutol as per RNTCP guidelines and according to body weight. Blood samples were drawn for assessment of bilirubin, SGPT, SGOT and alkaline phosphatase (ALP) on follow-up at 2 weeks interval during the Intensive Phase (IP) and 1-month interval during Continuation Phase (CP). During each follow up visit detailed history and clinical check-ups were done and duly put down on preformed data sheet. Patients were educated about the signs and symptoms of hepatitis and hepatotoxicity such as nausea, vomiting, abdominal pain and yellowish discoloration of skin and eyes. If any of the mentioned features observed then they were tested for hepatitis (viral) prole, prothrombin time, bilirubin, SGPT, SGOT and alkaline phosphatase test. Also, patients were tested for other organ involvement such, urea and creatinine. Normal range taken as for liver function tests were as follow bilirubin <1.2mg/dl, SGPT<40 IU/L, SGOT<40 IU/L, ALP 40- 120 IU/L, GGT <60 IU/L, Albumin >3mg/dl. Hepatotoxicity was considered as per American Thoracic Society guidelines - as 1) rise in serum ALT above 5 times from baseline, 2) serum ALT above 3 times with symptoms like nausea, vomiting, pain abdomen and jaundice. In cases with hepatitis patients were admitted in our indoor department and symptomatic treatment given. ATD were stopped for 2 weeks or until SGPT and SGOT comes down to less than 2 times the upper normal limit in cases with hepatitis. Re-introduction with ATD were done with same regimen in full doses after 2 weeks. And patients were closely observed for any further hepatitis. If symptomatic hepatitis develops or liver enzymes start raise alarmingly then patient were planned for shift the current regimen to hepato-safe regimen. Serial increase or decrease in liver function were recorded and patients were counselled not to take any hepatotoxic drugs or alcohol during the treatment period. Every patient's sputum samples were tested as per RNTCP guidelines. Those who were not responding to ATD regimens were further investigated for drug resistance.If any of the patients found to be a case of DRTB (Drug Resistance Tuberculosis) then he/she was excluded from the study. Statistical analysis was done by SPSS version 20. Categorical variables are expressed as Number of patients and percentage of patients and compared across the groups using Pearson's Chi Square test for Independence of Attributes/ Fisher's Exact Test as appropriate. Continuous variables are expressed as Mean, Median and Standard Deviation and compared over time using Wilcoxon Signed Ranks Test. Association between continuous variables are captured using Spearman's Rank Correlation Coefcient. RESULTS Out of 114 treated cases 5 patients developed hepatitis and we re subjected to interruption in treatment, whereas rest of the patients continued treatment without any symptoms. Among the 5 patients 4 male and 1 female. 4 PTB and 1 EPTB. 2 patients developed hepatitis 4 weeks after treatment, 1 developed after 2 weeks, and other 2 patients developed after 4 months of treatment. 2 patients had BMI < 18.5 kg/m2 and other were >18.5 kg/m2. 3 patients were age below 40 years and 2 of the patients were above 40 years. All of them were newly diagnosed cases. Among the 5 cases 3 had SGPT and SGOT levels above 3 times but below 5 times and had symptoms like nausea vomiting and abdominal pain and jaundice. On the other hand, 2 cases had SGPT and SGOT above 5 times and they also presented with symptoms like VOLUME-9, ISSUE-2, FEBRUARY-2020 • PRINT ISSN No. 2277 - 8160 • DOI : 10.36106/gjra Table 1. Demographic Chart of TB Patients included in the Study Characteristics No(n) Percentage (%) Age (years) 11-20 yrs. 27 23.7 21-30 yrs. 39 34.2 31-40 yrs. 21 18.4 41-50 yrs. 4 3.5 51-60 yrs. 17 14.9 61-70 yrs. 6 5.3 Gender Male 59 51.8 Female 55 48.2 Patient registered at IPD 56 49.1 OPD 58 50.9 Address Rural 73 64 Urban 41 36 Marital Status Married 94 82.5 Unmarried 20 17.5 Smoking status Smoker 43 37.7 Non-smoker 71 62.3 Alcohol Intake Yes 42 36.8 No 72 63.2 Sputum smear Positive 41 36 Negative 73 74 Diagnosis Microbiologically 77 67.5 Clinically 37 32.5 CBNAAT MTB Detected 77 67.5 MTB not Detected 37 32.4 Family/Contact H/O PTB Present 64 56.1 Absent 50 43.9 Chest X-Ray Normal 57 50 Abnormal 57 50 Case Type Newly Diagnosed 94 82.5 Previously Treated 20 17.5 X 9GJRA - GLOBAL JOURNAL FOR RESEARCH ANALYSIS jaundice, nausea and vomiting. Serum hepatitis virology markers were negative for all the 5 cases and their serum urea and creatinine levels were within normal limit. Prothrombin time and INR was within normal range in all the hepatitis cases. All the case had raised serum bilirubin at the time of hepatitis and were between 3mg/dl and 5 mg/dl. ATT was on hold for an average 2 (10 to 15 days) weeks for all the patients and same regimen of ATT continued. No second episode of symptomatic hepatitis developed later, although 2 patients had SGPT and SGOT above normal range but were below 2 times of upper normal limit. No other symptoms were noted in ththese cases of DILI. At the end of 6 month all patients with ATT induced hepatitis had normal serum bilirubin, SGPT and SGOT level. Among the 114 patient's bilirubin levels were nd thabnormal in 13.2% after 2 week, 7.9% after 4 week, 6.1% th th rdafter 6 week, 5.3% after 8 week, 3.5% after 3 month, 6.1% th thafter 4 month, 6.1% after 5 month, but all patient had normal thbilirubin after 6 month. Mean, median and standard deviation in bilirubin levels during the treatment period were shown in table 2. Statistically signicant changes seen ndcompared to bilirubin level at the start of treatment and 2 th thweek [p-value <0.001], 4 week [p-value 0.020], 4 month [p- thvalue 0.026] and 5 month [p-value 0.016] [Table 2]. VOLUME-9, ISSUE-2, FEBRUARY-2020 • PRINT ISSN No. 2277 - 8160 • DOI : 10.36106/gjra Table 2. Statistical Signicance of Changes in Bilirubin Levels p Value Signicance Bilirubin (mg/dl) - 2nd Week - Bilirubin (mg/dl) - Day 0 <0.001 Signicant Bilirubin (mg/dl) - 4th Week - Bilirubin (mg/dl) - Day 0 0.020 Signicant Bilirubin (mg/dl) - 6th Week - Bilirubin (mg/dl) - Day 0 0.181 Not Signicant Bilirubin (mg/dl) - 8th Week - Bilirubin (mg/dl) - Day 0 0.426 Not Signicant Bilirubin (mg/dl) - 3rd month - Bilirubin (mg/dl) - Day 0 0.822 Not Signicant Table 3. Elevation of Liver Enzymes in Follow Up Characteristic No (n) Percentage (%) Serum SGPT Elevated 95 83.3 Not elevated 19 16.7 Serum SGOT Elevated 81 71.1 Not elevated 33 28.9 Serum SGPT&SGOT both Elevated 76 66.7 Not elevated 38 33.3 Serum SGPT&SGOT elevated >5 times 2 1.75 >3 times but <5 times 3 2.63 Serum SGPT&SGOT elevated > 3 times Symptomatic 5 4.38 Asymptomatic 0 0 SGPT Elevated in No Follow-up 19 16.7 1 follow-up 45 39.5 2 follow-ups 28 24.6 3 follow-ups 12 10.5 4 follow-ups 8 7 6 follow-ups 2 1.8 SGOT Elevated in No Follow-up 33 28.9 1 follow-up 38 33.3 2 follow-ups 29 25.4 3 follow-ups 10 8.8 4 follow-ups 1 0.9 5 follow-ups 1 0.9 6 follow-ups 2 1.8 Bilirubin (mg/dl) - 4th month - Bilirubin (mg/dl) - Day 0 0.026 Signicant Bilirubin (mg/dl) - 5th month - Bilirubin (mg/dl) - Day 0 0.016 Signicant Bilirubin (mg/dl) - 6th month - Bilirubin (mg/dl) - Day 0 0.065 Not Signicant Wilcoxon Signed Ranks Test Table 5: Association of BMI with SGPT BMI Kg/M2 Total <18.5 >=18.5 p Value Signicance SGPT (IU/L) - 2nd Week Normal 32(68.09) 31(46.27) 63(55.26) 0.021 Signicant Abnormal 15(31.91) 36(53.73) 51(44.74) Total 47(100) 67(100) 114(100) Table 6: Association of BMI with serum Bilirubin values in 2nd week BMI Kg/M2 Total <18.5 >=18.5 p Value Signicance Bilirubin (mg/dl) - 2nd Week Normal 18(40.91) 44(63.89) 62(54.38) 0.033 Signicant Abnormal 26(59.09) 26(36.11) 52(45.62) Total 44(100) 70(100) 114(100) Signicant association was observed between BMI>=18.5 kg/m2 and elevation in SGPT level at 2nd week of treatment compared to BMI < 18.5kg/m2 Statistically signicant number of patients having BMI <18.5have high bilirubin levels. In contrary to that liver adaptive response is higher among the patients with BMI >=18.5 which is also statistically signicant. DISCUSSION In the present study, transient hepatic function derangement was seen in patients initially more in the second week of treatment and the effect seems to fade of later subsequent follow up. All patients were closely monitored during treatment, counselling done to prevent use of any kind of hepatotoxic agents or alcohol. Those who developed hepatitis were also observed not report any kind of hepatic symptoms even after completion of treatment. And all patients completed their treatment successfully without further adverse reactions. So, from our study we can say that ATT can be reintroduced, even after hepatitis develop during treatment, safely after a gap and waiting for the patient to become asymptomatic with [21,22]normalization of enzymes. In a study by Gulati et al. it was observed that most cases of hepatic enzyme elevations occur in intensive phase of ATT, in our study we have seen that most number patients have abnormal liver enzymes in second and fourth week after [23]treatment. As most anti-TB drugs are metabolized by the liver, therefore, it is the central to detoxication of INH, Rif, and PZA. So poor compliance in the initial phase of treatment is more likely. In the study by Vijayalakshmi et al drug induced hepatitis cases were reintroduced with hepatosafe regimen of ATT to [24]complete the treatment, but in our case, we stay with the same regimen and started with the full dose in all the 5 cases of hepatitis and didn't observed any further hepatitis in all the cases. A study with full dose re-introduction of all antitu 10 X GJRA - GLOBAL JOURNAL FOR RESEARCH ANALYSIS VOLUME-9, ISSUE-2, FEBRUARY-2020 • PRINT ISSN No. 2277 - 8160 • DOI : 10.36106/gjra bercular drugs also had successful completion of ATT course [25]comparable to other safer regimen. Therefore, it can be said that though drug induced hepatitis can occur with the standard four drug regimen initially but on rechallenge same event may not happen. Incidence of drug induced hepatitis was 4.38% in our study which supporting the existing literature. As per the study by Surendra K Sharma et al ATT induced hepatitis was about 5% of all anti-TB treatment for [7]Indian population and only 2% for western populations. Asymptomatic elevation liver enzymes are noted in various [26,27,28]studies to be around 20%. But our study observes that this gure is much higher in our study population. Near about 76% patients in our study showing abnormal level of liver enzymes (Both SGPT and SGOT). Only 16.7% had no elevation in SGPT and 28.9% had no elevation in SGOT. So adaptive response to Anti-TB medications are much more common in our study population than previous study suggests. [29]In the study by Singla et al poor nutritional status has been considered to beone of the factors contributing to a higher incidenceof drug induced hepatotoxicity induced by short- course chemotherapy for TBin the developing countries. Similarly, in our study we have found statistically signicant association between low BMI and serum hyperbilirubinemia ndin the 2 week of receiving ATT. CONCLUSION Drug induced liver function abnormality is a common occurrence during the course of anti-TB treatment. Most patients show tolerance to anti-TB drugs and get adjusted after transient rise in liver enzymes. Some patients may develop serious hepatitis and need treatment interruption, but we should always try to stay with the present regimen and see whether reintroduction leads to any further derangement or hepatitis. Asymptomatic rise may be upto 3 times from the baseline value, but that does not need any intervention unless patients develop symptoms. Serum Bilirubin values show statistically signicant rise in patients with low BMI on ATT compared to those patients having higher BMI. Hence serum Bilirubin values along with Liver enzymes have to be measured in low BMI group of patients.Abdominal symptoms like pain, nausea, vomiting and jaundice should always be taken seriously and needs intervention by holding the ATT. Risk factors like, age, gender, smoking habits, alcohol intake, tuberculosis disease severity, along with BMI must be studied further to have better understanding in relation to liver function changes. 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