 OK, hi everyone. So today we are going to discuss about hepatitis, hepatitis B, management in adults. So myself, Dr. Lapey Shanan, I'm a consultant gastroenterology and hepatopulmonary sciences at Mani Hospital, Dharaka. And with me, Dr. Sufla, we'll be discussing about neonatal hepatitis subsequently. So to begin with, my talk will cover the following topics. First is the natural history, epidemiology, goals, and indication of therapy. How are we currently managing hepatitis B? How do we monitor the therapy? What are the stopping rules? And how do we do the surveillance for liver cancer? What are the various treatment guidelines and certain clinical case business? So globally, just chronic hepatitis is a health problem. It is the most common chronic viral infection in the world. And there are certain, according to the prevalence, various cases are divided. And our country is somewhere in the intermediate group. And China comes in the high group. Overall, in Asia, it is very high prevalence group. And estimated around 240 million people worldwide are living with chronic hepatitis B. As regards India, chronic hepatitis B, again, is a public health problem. And around 40 million HPV carriers are there. 10% to 15% of all the pool in the world is in India. And there are 43 to 45 million new cases per year. One lakh deaths annually are attributable to hepatitis B. And of the 25 million newborns, annually one million run lifetime risk for hepatitis B. So let's discuss briefly about the roots of transmission. So there are broadly two roots of transmission. One is the horizontal transmission. And another is the vertical transmission. Horizontal transmission, it is by the sexual contact exposure to bladder, body fluids, immunalysis, organ blood and semen donors, IV drug use and prolonged close contact. Whereas the vertical transmission is from the infected mother to the child. Approximately 25 to 50% of acute infection in the children aged one to five years and less than 5% in older children and adults progress to chronic hepatitis B. And 90% of the infants born to positive mothers develop chronic hepatitis B. So if we discuss only in India, then the mother baby transmission is the commonest. And there are various studies which have shown around 80 to 90% rate of transmission. This was one study way back in 1987, another study in 2011, which have shown that patients who have a high DNA, they have 100% risk of transmission. 3 fourth of the hepatitis B in India is through the mother baby transmission and thus the role of pediatrician is paramount. So this another study in 2006, in which 116 hepatitis B positive children were studied and it was seen that 74% mother had evidence of hepatitis B virus infection. And thus they postulated that any adult who come to us with hepatitis B, their mother and their siblings should be checked for anti-hepatitis B E titer, anti-HB code total and anti-HBS. And if we do this screening, it is found that 18% family members are found to be hepatitis B positive. Therefore the message is that we should screen all patients and the screening should mean not only HBS AG, it should mean these four tests before vaccinating anyone. And if any patient come to you with hepatitis B positive, HBS AG positive to all the family members, these four tests should be advised by you. Now, when does HBV transmission occur during pregnancy? The one is during gestation. So now the studies initially it was thought that it is the delivery when the transmission is there during delivery, which is called the perinatal transmission. But now it is seen that the transmission occurs throughout the gestation, that is intra-eutrine transmission. And it is now considered more important route of transmission than only the delivery. And even in the postnatal period, the transmission can occur, which is considered important. And this transmission is prevented by immunoprophylaxis. We give hepatitis B vaccination to the newborn and also HB, that is hepatitis B immunoglobulin at the time of birth. But what happens during transmission during gestation? To prevent that, we need to give antivirals to the pregnant female during pregnancy itself. Now we come to the natural history of hepatitis B. Now, natural history very much depends on the postimmune response. So if we see that if the patient has a very good immune response, vigorous immune response, it leads to acute hepatitis. In acute hepatitis, there will be high transaminitis, that is ELT will be more than 1400, and in most of these cases, around 95% of the cases, they will be full recovery. In few of these patients, they can also present to us with fulminant hepatitis or acute liver failure, which can lead to death or it can also recovery. But the rule is that if the patient has a good immune response, it will lead to either full recovery or in few cases death. But if there is a weak immune response, then it leads to persistent infection. Patient can come to us either in the carrier stage, chronic hepatitis, cirrhosis or liver cancer. There are two different stages in that. One is the immune tolerant stage in which the ELT is normal and one is the immune active stage in which the ELT will be high. And there is rotation between this ELT immune tolerant phase and immune active phase, which happens every 4.3 months. And the best example of this weak immune response is the infants in which the immunity is not well developed. Therefore they do not have immunity against this infection which is transmitted to them from the mother and thus they have chronic infections which persist throughout life in them and come to us many times incidentally. So this is termed as IDAHS, which is called Incidentally Detected Asymptomatic HBaseG Positive Subjects. Many a times you must have encountered that a patient says that he went for blood transfusion, blood donation and on screening he was found to be HBaseG positive, but he's asymptomatic. So such patients these instead of saying have HBaseG carriers or chronic hepatitis B, the term now is IDHS. This was one study in 2008 in which it was seen that HBV DNA in such patients of normal ELT can be very high in 60% and in patients who had intermittently normal ELT, it was 72% had a high HBV DNA. And even in these 40% of these IDHS patients had with normal ELT had a hepatic fibrosis ranging from F2 to F4. Even 3.7% had F4 fibrosis which means that they are either preserotic or serotic. So it is important to detect these patients to evaluate these patients because these patients may turn up directly into cirrhosis or liver cancer to you someday. Now chronic HBV carrier is a misleading term. It is now replaced by chronic hepatitis B virus infection. So what happens in this chronic hepatitis B? Around 8 to 40% of the patients, they go to cirrhotic state. Cirrhosis means there's a irreversible damage. How do we define chronic infection? It is defined as the persistence of positive test result for HBaseG or HBV DNA for at least six months. Of these, cirrhotic patients 10 to 17% can cause hepatic cancer. 15% can go to decompensated liver disease or liver failure. And both of these ultimately require liver transplantation. Otherwise, there is 70 to 80% chances of death. Now what are the various factors that lead to this hepatitis B progression? There are certain post factors, viral or disease factors and environmental factors. Most factors important is more than 40 years of age, male gender, family history of hepatocerebral cancer and African or Asian race. Thus, we are at a higher risk of this progression. Viral factors are the high DNA level, high HBaseG quantitative level, prolonged time to HBE antigen zero conversion. Zero conversion means conversion of HBE antigen to anti-HBE. Development of E negative chronic hepatitis B, genotype C or D, there are various genotypes for hepatitis B. So just genotype C or D has a higher risk of progression and in Indians have more of genotype D than a basal core promoter mutations, elevated ALT levels and presence of fibrosis or cirrhosis. There are certain environmental factors like co-infection with hepatitis C, hepatitis D or HIV, uncommitted alcohol consumption, cigarette smoking, aflatoxins, obesity and or diabetes. So in these risk factors, there are certain causes of HCC development also. And these include the high level of HBaseG, again genotype C or D, pre-core or basal core promoter mutations, increased alpha-phytoprotein, decreased baseline ALT and family history of HCC or alcohol consumption. Apart from that, there are certain non-HCC liver deaths and the cause for that are increased ALT and reduced albumin platelet count, which indicates CLD, acytis and enkephalopathy. And for both of these, there are certain common things like older age, as we have seen more than 40, male sex, cirrhosis, increased DNA load and HBE antigen status. Now we come to this course of HBV infection, many of them we are aware of this thing that there are various stages. Chronic hepatitis V, this follow a variable clinical course, but it is not necessary that all patients will go through each phase. So we have immune tolerant phase. In this immune tolerant phase, there will be a high DNA level and low ALT level. This is often seen in perinatally infected children and it may last for several decades. And in infection acquired during adults, put or in late childhood, this phase is short or absent. And as there is a high DNA, HBE antigen is positive in these cases and there is very low rate of HBE antigen, zero clearance. ALT will be normal. So when the patient will get this LFT done, it is normal, but it doesn't means that the patient is normal, but because the DNA level is very high in these patients. And as older age predict adverse outcomes, it is important to monitor older immune tolerant patients who may show minimally or intermittently elevated ALT. The next phase is immune clearance phase. Immune clearance phase, this occurs when there's a ALT starts increasing and the DNA starts decreasing. The patient again, maybe will have HBE CT positive and HBE antigen will start showing some zero conversion. And when there's a HBE antigen zero conversion, it's a serological marker of the end of the immune clearance phase. 10 to 20% will have annual spontaneous HBE antigen zero conversion. This typically occurs during the second or third decade of life and may last for years, leading to progressive liver damage. When we do a liver biopsy, it will show necro inflammation and varying degree of fibrosis as a result of immune mediated liver damage. And the patients with active liver disease in the immune clearance phase are potential candidates for treatment. Now the next stage is inactive carrier. In the inactive carrier, there will be E antigen zero conversion. That means E negative and anti positive. The HBE DNA will be suppressed to very low or undetectable level and ALT will also get normalized. On biopsy, there will be mild hepatitis on minimal fibrosis, but it may have severe liver damage also, including cirrhosis. And the term healthy carrier is an erroneous term because a significant proportion of patients may have high viral load, hepatic fibrosis and other liver-related complications such as liver cancer. And around 20 to 30% of these patients may experience reactivation after E seroconversion. The next stage is reactivation and resolution. Reactivation may occur spontaneously or due to immunosuppression. The reactivation, what happens? Again, there will be high ELT, there will be DNA will increase. And these patients with reactivation are usually older with more advanced liver disease. And these patients may have increased risk of liver cirrhosis or FCC. Treatment is recommended for E negative chronic hepatitis B who experience reactivation. HPSHE laws, which is called resolution, this occurs in just 0.5 to 2% of Western patients and 0.1 to 0.8% of Asian patients. Some patients may still have detected HVB DNA in serum and are vulnerable to reactivation even in the resolution stage. So this is the natural history of hepatitis B. There is a change in the nomenclature. The old terminology of immune tolerant hepatitis B in which there is a high DNA, normal ELT, normal liver disease and E positive. They is now called E positive chronic infection. The previously term immune reactive E positive patients they have DNA ranging from 10 to 4 to 10 to 7. There is the elevated ELT level liver disease will be more to severe E positive and HBSHE higher. These patients are now called HBE antigen positive chronic hepatitis. The inactive carrier term which was used earlier in it, there was a low DNA level, ELT normal, no liver disease, E negative and HBSHE was also low, is now called HBE antigen chronic infection. And there's a previously used HBE antigen negative chronic hepatitis in which E was negative but DNA was high, ELT was elevated and there was more to severe liver disease. They are now called HBE antigen negative chronic hepatitis. So now how do we evaluate this treatment for medical management? So the patient needs to have a thorough history and physical examination like the risk factors for hepatitis risk factor for HIV co-infection, duration of infection, route of transmission, history of alcohol use, comorbid disease, family history of liver cancer. And on evaluation apart from LFT we need to have test for antibodies for HIV, HIV, HIV, HBE antigen and anti-HBE status and the HBE DNA level that has to be done at six month period. Patient should also be screened for HCC in high-risk patients. He may or may not require liver biopsy and if liver biopsy there are certain non-investing markers also for liver fibrosis like fibroscan and urine analysis. And patient should be counseled on risk of transmission, screening of the family members, vaccination of at-risk household and sexual contact and the family plan. So that becomes a treatment since 1990 when the interferon was first used for hepatitis B. There is a remarkable change in the treatment and there is now new way of oral therapy in which interferons are not used. The landmark change came from the discovery of Antecavir and Tinofevir and now the latest in the basket is Tinofevir elephanomide which is more nephrosafe than the earlier Tinofevir diastroproxen fumarate. There is also improvement in the efficacy of the seroconversion with these newer anti-nucleoside analogs and nucleotide analogs. Now, which nucleotide to be used? It depends on the safety, the barrier to resistance because the earlier nucleosides like the lime avidine, edifovir, they're a high antiviral potency but they also had increased chances of resistance, also the efficacy. So among them, the best are the Tinofevir and Antecavir because they have a good antiviral potency, their pharmacological barrier is very high and genetic barrier for resistance is also high. Only the Tinofevir, the earlier one had nephrotoxicity which the new TAF had very less incidence. So these both, these are the preferred nucleotide analogs and should be used as a first line therapy. So the 2018, the American guidelines, they say there is not much difference in which to use but like in pregnancy, this Tinofevir is a category B. It is more commonly used than Antecavir. There is no human data for TAF now. Regional disease, of course Antecavir is better and TAF can be used but for the bony diseases, all are good. And if there is HIV co-infection, the TDF was in the co-formulated in the retroviral regime. TAF is also in the co-formulated in the retroviral regime but if we use Antecavir, it is in addition to the complete ART regimen. The dose that is commonly used is 0.5 milligram for Antecavir, TAF 25 milligram per day and PDF 300 milligram per day. Is there any role of interferon nowadays? So there are certain roles. What are the favorable predictors of response? If the DNA is low, there is high ART and the genotype is ARB. But there are certain patient demographics also like in young people, in young women who want the pregnancy and there is absence of comorbidities, patient preference and concomitant delta infection or HCV. So in these, a course of peg interferon will be the most appropriate first-line treatment strategy and because it is a finite treatment, it is for one year of course and there is a sustained response and this patients who have a high LT and low DNA, there is a chances of seroconversion are higher than the nucleoside analogs. But again, there should be a careful patient selection. We cannot use this in patients who have a very high transaminitis in patients who have cirrhosis, be it compensated or decompensated cirrhosis. So only in patients who have chronic hepatitis B with these parameters, it can be used. There is another way in which this interferon is used which is called a sequential regime. And in the sequential regime, the patient is first given tenofovir or any other nucleotide analog for 12 weeks, then combined tenofovir and interferon is used for 24 weeks and then again, a lone tenofovir is used till the end of one year and it has found in various studies that there is a very good response in such patients. Even the patient can have HBSHE conversion also. Now, the next is who should be treated? Now, this is a very confusing and topic because there are various guidelines from American Association, from the European Association and the Asia Pacific Association. All these three agree on this that a patient have a very high DNA level and a high ALT level. In E positive patients should be treated and in E negative patient who have more than 10 for four log DNA and high ALT should be treated. But in practical this scenario, majority of the patients do not fall in this category. So again, how to monitor this patients on treatment for hepatitis B DNA? So HVB DNA should be detected every three months until it is undetectable and every three to six months thereafter. ALT similarly should be monitored every three months until normalization and every three to six months thereafter. For E positive patients, HBE antigen should be monitored every six months until it is negative and NTHBE is achieved. And in E negative patients once sustained suppression of HVB DNA is achieved, HBS AG is monitored every 12 months. We call the treatment response by virological response. If there is a definition of non-responses, primary non-response, when there is a less than one log reduction of DNA at 12 weeks. Passion virological response when there is more than one log reduction but still it is detectable. And virological breakthrough when there is a confirmed increase of one log DNA from the NADIR on treatment. And similarly for the pegging interferon, virological response is when the DNA level is less than 2000 and evaluated at six months and at the end of therapy. And sustained off therapy virological response is when the DNA level is less than 2000 for at least 12 months after the end of therapy. The response again are divided into biochemical, histological and serological. Biochemical response is the minimal follow up of at least one year post-treatment with ALT determined every three months to confirm sustained off treatment biochemical response. Histological response is decreased in the necro-inflammatory activity by more than two points without worsening in fibrosis. And serological response is E-antigen loss and seroconversion and HBase HG loss and seroconversion. Usually HBase HG losses are the goal, the endpoint which we seek but there are very less chances of HBase HG loss. So what is the significance of the estimation of this quantitative HBase HG? We all know this HBVDNA is a marker of HVV replication. But what does HBase HG detect? They are various viral particles which indicates HBV replication. So this HBase HG is a marker of transcriptionally active CCCDNA which is the core of this HBase HG. So it may be that the DNA is negative but this virus still remains inside the DNA in the form of active CCCDNA. And it's very difficult to detect this CCCDNA so we detect this quantitative HBase HG for this. So another significance is that this HBase HG level provides the complementary information of triple CDNA. The true inactive carriers are those who have HBase HG have less than 1,000 HBV DNA, less than 2,000 a normal serum AFD. In the immune tolerance phase, HBase HG can be more than 1,000. An annual rate of HBase HG loss is approximately 0.4 to 2.3%. And HBase HG loss rate is lowest in E-positive patients followed by E-negative with the loss rate being highest in inactive carriers. So baseline HBase HG is usually a predictor of HBase HG loss. Both DNA and HBase HG levels positively correlate with HCC development. But in E-negative patients, HBase HG level more than 1,000 is an independent predictor for HCC development. Thus it's very important to measure this. And HBase HG level of more than 1,000 was noted to be consistently associated with a higher risk of E-negative hepatitis and cirrhosis. And thus combining both DNA and HBase HG level could be used to define minimal risk hepatitis with chronic HBV infection. So what are the rules for stopping this nucleotide after confirmed HBase HG loss with or without NPHBase seroconversion? This is the desired endpoint. But in non-serotic E-positive chronic hepatitis patients, even those who achieve E-seroconversion, that means conversion of HBE antigen into NPHBE and undetectable DNA and who complete at least 12 months of consolidation therapy. This consolidation therapy means followup after HBV DNA negative. That there also we can think of stopping. But again, there is a chance of recurrence in these patients. In HBE antigen negative patients, in selected non-serotic E-negative who have achieved long-term virological, at least three years of HBV DNA negative under a nucleotide envelope, we may consider of stopping it. But still we perhaps it is indefinite therapy that is usually given in E-negative chronic hepatitis B patients because it is considered unsafe to stop nucleotide analogs until we achieve HBase AG negativity. And recent evidence have shown, especially from Asian countries, that nucleotide envelope can be discontinued in E-negative chronic hepatitis B patients who achieve DNA undetectability on three separate occasions, six months apart. So either of the three we think, but the best of course, is when the HBase AG is negative and NPHBase is present. But it's very less chances of these. So this we have discussed that in E-negative, another thing to remember in serotic patients, we usually continue the antiviral treatment for life. So a word about HCC surveillance, the surveillance is done by AFP and by abdominal ultrasound. It should be done every six months. There are certain high risk patients like those who are serotic and there's a family history of HCC and low to moderate risk like in inactive carriers, immune tolerant patients, HBase AG positive means less than 40 and female less than 50 and patients with HBase AG loss. These are low risk. So let's see first to quickly the guideline. There are various guidelines, but what we follow usually is the Asian Pacific guidelines. The, there were another nice guidelines. In the nice guideline, they have divided according to the fibro scan, which we commonly use the fibro scan. There is a LSM value. If the LSM value is less than 11, that means it is either F1, F2, or F3 fibrosis. The patient has a low DNA. We monitor and measure the ALT and DNA level every 24 to 48 weeks. If the DNA is very high, that is more than 10 to the power five dog, we usually treat. And if the DNA is between 2000 to 20,000, then if the ALT is normal, we can monitor. The ALTs have normal and the patient age is more than 30, we treat. If the patient's age is less than 30, we go for biopsy. The biopsy is normal. Again, we monitor, but in the biopsy, which shows F2, F3 fibrosis or evidence of necro inflammation, we have to treat. If the fibrosis more than 11, which is usually indicative of cirrhosis and the DNA is detected, we have to treat. This is the nice guideline. The other appasal guidelines is for E positive and E negative. E positive patients, if the DNA is less than 2000 and ALTs less than upper limit of normal, we monitor the patient. If the patient has a 2000 to 20,000 DNA level in E positive, ALTs more than upper limit of normal, we monitor three to six months, assess fibrosis. If there is F2, F3 fibrosis or moderate to severe inflammation biopsy, we have to treat. And if the DNA is more than 20,000 and ALTs one to two times upper limit of normal, again, we monitor for three to six months by means of either fibroscan or apri. We assess the fibrosis and or we do a liver biopsy. If the ALT is persistently one to two times, age is more than 35, family history of HCCR cirrhosis, we should treat these patients. Or if the ALTs more than two times upper limit of normal, we should directly treat these patients. In case of E negative chronic hepatitis B infection patients, well, there are only two things. One is less than 2000, one is more than 2000. In less than 2000, if the ALT is normal, we assess the fibrosis noninvasively, monitor ALT and DNA individualized liver biopsy and treat if there is more to severe inflammation or significant fibrosis. Significant fibrosis means F2, F3 fibrosis. If the ALT is more than upper limit of normal, if elevated ALT, we have to exclude the other causes. We have to assess the fibrosis noninvasively and we have to monitor three monthly and individualized liver biopsy, like if the patient who has persistently elevated ALT aged more than 35 or family history of cirrhosis or HCC, we should do directly a liver biopsy and in case of moderate to severe inflammation or significant fibrosis, we have to treat. The DNA is more than 2000 and ALT is one to two times upper limit of normal or normal, again, the similar things we have to assess, individualized liver biopsy and treat if there is moderate to severe inflammation or significant fibrosis. If the ALT is more than two times upper limit of normal, we should treat these patients and we may initially observe for three months, but again, we have to individualize and we have to, we should have low threshold for treating, starting the treatment of these patients. For again, the chronic HVB infected, for the decompensated cirrhosis, any HVB DNA injectability we should treat and we should consider liver transplantation and there is no stabilization. For compensated cirrhosis, if there is a normal ALT, DNA more than 2000 or if elevated ALT, DNA detectable, we should treat. And if there is a reactivation, we should immediately treat. Now, let's see few case business. The first case is of a 45 years old male with HBCG positive in 2014, E-negative, anti-positive, ALT was 44, DNA was not detected. But now in 2020, again, the ALT is 100, AST is 88, E-negative, anti-positive. Serum albumin and total bilirubin still are normal and patient has overweight with BMI of 26.4. So what should we do? Should we, patient has most likely developed HCC or the patient has an E-negative immune reactivation chronic hepatitis B, which could be presentably diagnosed by obtaining a serum DNA level? Or do you think that the patient is likely infected with a pre-core mutant HPV or the patient's liver enzyme elevation is undetected to hepatitis B? So of this, the answer is that patient has an E-negative immune reactivation chronic hepatitis B and which could be diagnosed by obtaining a serum DNA level. The patient in 2004, he was in the inactive phase of chronic hepatitis B. 20% of these patients in the inactive phase will transition to the E-negative immune reactivation. This we have discussed in the previous slides. And this usually is by the mutation of pre-core or core promoter gene. So in this patient, obtaining a DNA level would provide valuable information and one would expect the DNA level to be elevated, which would be low in the inactive phase. Now the second case is a 34 years old injection drug users with HBCG DNA of N plus seven E positive and time negative. ELT is 135 and 96, three months apart. LSM is 12.5, which is indicative of F3, F4 fibrosis. NT-HCV-HIV is negative and liver ultrasound is normal. So what should we do in these cases? Should we do a liver biopsy or should we start directly with the treatment or we should continue to monitoring as ELT appears to be settling like in three months apart, it has come down or we should do a repeat E-antigen to check for clearance. So for this, we should see this algorithm proposed by ASLD, that is American Association. And this is very much similar to our appasal guideline which we have just discussed. So in this patient, the patient who has more than two times upper limit of normal to both all the three societies recommend that in patients with a high DNA level, with high ELT level, we should monitor for three to six months and we should treat if there is no spontaneous E-antigen loss. So we should do this in E-negative patients. Again, if there's a high DNA ELT more than two times, all the three societies recommend that treatment is required. And liver biopsy rather is optional in these cases. The third case is of a 55-year-old main with diabetes, BMI at 22, old history of blood transfusion in 1990, presented with jaundice followed by acitis in three weeks. His DNA is 10 to the power seven, E-positive and D-negative, AFP is 211 which is high, AST is 786, ELT is 822, and ITM and THB core is positive, which is of the range of one is to 200. So what is the diagnosis in this patient? Do we think because the patient has a high AFP, whether he has developed HCC or the patient has a HBV reactivation or the patient has acute hepatitis B or he should be advised directly liver transplantation. So I would say that the patient has a HBV reactivation and he should be started directly on antivirus. The reason for this is that how do we differentiate between acute hepatitis B and reactivation? In acute hepatitis B, the patient will have a very high IgM anti-coated, that is more than one is to 1,000. The HBV DNA is less than 10 to the power five. There is absence of an imitation. There's a recent history of exposure in this patient, the history of exposure over is 1990. And when treated as reactivation, 95% will show HBV sagy loss. Whereas in reactivation, this IgM anti-HBV tartar is low. These are very high HBV DNA more than 10 to the power of four, like in this patient, it is 10 to the power seven. There are presence of mutations. There's a previous history of hepatitis B in patient or in family members. And the patient is unlikely to clear HBV sagy even after therapy. Another case as of 45 years old businessman, prior policies tech to me a year ago, the patient will present with a fatigue and a routine health checkup shows HBV sagy positive, VMI is 28.6, E-positive, anti-negative, ALT is 45 and 48. DNA is 10 to the power seven docs. Fibro scan shows LSM of 8.9, which corresponds to F2 fibrosis. ASG, USG shows a mildly coarse and liver ecotexture. So what should we do in these patients? Important thing to remember is the age of this patient. Now, liver biopsy should be done in this patient. Why? Because the nasal guideline, easel guideline and American and a puzzle guideline all says that treatment is not required on the immune tolerance phase. But because there's a likelihood of response to available treatment is low. But liver biopsy should be considered in persistently borderline normal or slightly increased reality level like in this patient, particularly those older than age 40. And according to easel guideline that is your open guidelines age 30. And treatment should be recommended if the biopsy shows F2, F3 fibrosis or moderate to severe inflammation. Another case is of a pregnant lady, 32 years old with 24 weeks of pregnancy. HBase G is found positive. Patient has a normal ALT, but DNA is 10 to the power 5. So what should we do in this patient? Should the patient we ask to abort or we should ask to take nucleotide nods? So now the current guidelines says the patient should be given 10 off of it, which is safe, which is category B. And it can be done in all the three trimesters, but at least in the third trimester, that is after 28 weeks of pregnancy, irrespective of the DNA level. And the patient when a child is born, HBIC2 is to be given and three doses of vaccination will be given. And after the patient can, then after delivery, the nucleotide and lock can be stopped depending on the case to case. And then the breastfeeding can continue. And last case I think is the 28 years female. This is an interesting case. The patient presented with a history of being married 11 months back and the husband lived in Dubai. And four months back he consulted some infertility center in view of not being able to conceive in the first six months. And incidentally was found to have HBICG positive. She was complaining of weakness, easy fatigability and shortness of breath. And the patient's lab was done which showed a very low hemoglobin level. LFT was more or less okay and DNA was 10 to the power 5 log, E negative and USG was also normal. Our endoscopy was done which showed many erosions in the stomach. And a biopsy was taken from this which showed evidence of vesculitis. Our PNK was positive. So we thought what to do next because liver was normal, DNA was 10 to the power 5, but E negative, ALT is normal, no family history of CLB or HCC. So should hepatitis B treatment be started? Now these are the extra hepatic manifestations of hepatitis B, that is vesculitis. Skin manifestations, polyacroitis, neurosa, peripheral neuropathy and luminal fractus. And it is seen that this HBICG positive with extra hepatic manifestations and active HBV replication, they may respond to antiviral therapy. And in these patients, second typhanone should not be used. And we started on this treatment and it all the lesions improved within one month. There's one more case. This is 65 years old main patient diabetic on oral hypoglycemic. This is a known case of CLL, that is lymphoma on chemotherapy. The patient was diagnosed in 2014 and all the workup was done and patient received say five cycles of chemotherapy. And last cycle was in September 2014. And the baseline investigation showed a normal LFT. But in October, the patient developed jaundice, decreased appetite, generalized weakness. He was evaluated, found to have HBICG positive. Patient was then started on entechovir. His bilirubin, which on 17 was one, increased to 21 on 26th. ASTLT was very high. And his LFT started showing and his CT was done which showed neurosis and acitis and patient expired after a few months. So any patient undergoing chemotherapy or immunosuppressive therapy should be tested for HBV markers prior to immunosuppression and all HBV positive should receive the entechovir or tenofovir as treatment or profile access. And HBV negative patients should also be checked for co-total and positive subjects should receive anti-HBV profile access if they are at high risk of HBV reactivation. So I'll skip this one. So to summarize, in India, majority of chronic hepatitis patients are unaware of their infections. The clinical course of chronic hepatitis B consists of immune tolerant, immune clearance, inactive carrier reactivation and resolution phase. Not all patients will go through every phase of infections. However, chronic hepatitis B patients are at risk for severe liver damage. And HBV screening is important to identify chronically infected persons who may need treatment and to allow for interventions to reduce transmission to others. HBV screening consists of simple blood tests for physiological markers of infection. Screening vaccination and appropriate management of persons with chronic hepatitis B are important steps to help prevent hepatitis B and its liver complications. So gentlemen, hepatitis B is a treatable disease, but we need to know hepatitis B to prevent that. Thank you. Now I'll request Dr. Suflap to discuss of our new... Thank you, Dr. Lavkesh. So after a wonderful presentation by Dr. Lavkesh on hepatitis B, I'm going to speak through on the topic of immunative polystasis. Although it is a very elaborated topic, but I have tried to make it a bit concise with clinical pointers for easy diagnosis in day-to-day practice. So this is the most common cause of conjugated hypervillipinemia that you see in your practice. So I'm going to start with some cases that you see in your practice and how we should deal through with them. So usually these are the kind of cases that you see in your practice. A two-month-old baby who's a term normal channel delivery. The jaundice was noticed since her week of life with dark urine and intermittent clay-coloured stool. The birth rate of the child was normal, and he's gaining weight appropriately with all normal development signs and symptoms. There was no history of any consignments marriage with one healthy female sibling. And another, they could be in history of another male sibling who's expired with jaundice a couple months ago. So on examination, it's a well-looking active child with interest over the body and eyes with a discontented abdomen and a palpable liver and spleen. There was no murmur and all the other systemic examination is normal. So the pointers here are this was the colour of the stool initially and later on the stool colour changed to nearly clay-coloured. So it was a little bit pigmented initially to begin with and then it lost the pigment. So this is a very clear-cut pointer towards one of the possible diagnoses that is the lary trachea that you most commonly see. Then another presentation that could be a four-month-old child with a term baby born by cesarean, non-consignments marriage, no other sibling. Jaundice noticed since one month. The child is on examination and could be mildly intrigued with a pitocidino megalee. Rest of the systemic examination is normal. There's no itching marks on the body, no papyrus, no bruising. On investigation, you may see a raised enzyme with a normal gamma-GT level. So this level is very, very important whenever you are dealing with a child with conjugated hyperbilalobinemia. The child may have mildly raised serum-bilalobin levels with the range combination profile. A high-dose scan done was normal. So these are the kind of presentation that we get in clinical practice and then we have to decide about whether the neonatal polystasis is because of the intrahepatic causes or the extrahepatic causes. So let's proceed and see how we can diagnose and go about this truth. See, objective of my talk is when cholestatic liver disease should be suspected, how do we evaluate these infants with conjugated hyperbilalobinemia? What are the differential diagnosis and how do we manage them? So if you look by definition, there is a diminished bio-formation or extrusion in cholestasis. And Aspegan has given clear definition that neonates who are jaundiced beyond two weeks of age with a direct bilirubin of more than one milligram per deciliter, if the total bilirubin is less than five and if the total bilirubin is more than five, then it should be more than 20%. The IAP has given the guideline that the conjugated bilirubin of more than 1.5 or two milligram in a newborn infant with a high color duty with or without a colic stool. If you look at the incidence, cholestatic jaundice is fairly common. So in the Western world, one in every 2,500 line birth suffers from cholestatic jaundice. Biliriatrasia is one in 10,000 to 15,000 infants and idiopathic neonatal hepatitis is again fairly common, one in 5,000 to 10,000 line births. In India, however, neonatal cholestasis constitute around 19 to 30% of all the chronic liver disease in century. So it is quite common. If you look at the etiology, we just to simplify it, we divide it into two causes. So either it is liver related causes or it is violet or extra hepatic related causes. So it's very important when a child present whether on based on the presentation, then clinical findings and investigation you have to divide whether the child has got extra hepatic disease that is like biliriatrasia or polydopocyst or if it is an intra-hepatic disease, then because is it because of hepatocyte injury or bile duct injury? The hepatocyte injury can be because of multiple causes. They are roughly divided into metabolic, viral and adiopathy, whereas bile duct injury can be because of bile duct capacity. Now, if you look at the Western world literature, the most common causes of neonatal hepatitis and polystasis is extra hepatic biliriatrasia, which is around 25% followed by idiopathic neonatal hepatitis. Then they have the infectious causes followed by parental nutrition associated, then metabolic and then the rare syndromic causes that includes PFIC as well. If you look at the Indian data, which has been given by IP, again, the most common causes are from the hepatocellular causes, the neonatal hepatitis. The idiopathic one is the most common, whereas we cannot find out the cause of this disease, followed by torch infectious causes in which there is torch infections, sepsis, other causes. Then there are obstructive causes are quite common. So they are around 28% out of which 34% constitute is constituted by biliriatrasia. And then there are other causes which are metabolic miscellaneous and collidopal cysts in which they are bile salt transport disorder, bile acid synthetic disorders are also there, but they are quite rare. So if you look, this is the explanation for all the different causes and they're being categorized. So in extra hepatic biliria obstruction, it can be caused by biliriatrasia, collidopal cysts, insipid bile or mucus plug. It could be cause of polylithiasis or tumor or masses or neonatal sclerosis or meningitis. These are quite rare as compared to biliriatrasia. Then there are various infection, like viral infections, which is much more common. Then bacterial infection, sepsis, protozoal infection. Followed by this, there are metabolic and genetic causes which have been divided again into disorders of carbohydrate metabolism, amino acid metabolism and lipid metabolism. So you see, this is quite common, like galactosemia and fructosemia, tyrosinemia. Then you see a nemenpic disease in lipid metabolism. Then there are rare disorders which are quite rare in which there is disorders of bile acid synthesis because of deficiency of certain enzymes which are responsible for synthesis of bile. In that also we cover the Zellpeger syndrome and Slipp-Lemeli-Optin syndrome. Then there are inherited polystatic disorder which are much more common in the western world as compared to our side of the world. So there are allergies, there are ARC, there is cystic fibrosis. Then there is PFIC, which is quite common in India as well. Then there are mitochondrial disorders. And then again, other metabolic disorders in which there is alpha-1 antithesis and certain deficiency. Then it is also important to rule out endocrine disorders, hyperpetitism, and then the hepatitis or polystasis caused by drugs or parental nutrition. So children, especially preterm babies who are on parental nutrition on long time are quite prone to develop neonatal polystasis. They get better also once the parental nutrition has stopped. Then there are alloimmune disorders and miscellaneous disorders. So we have seen that idiopathic neonatal hepatitis in which no cause has been found of neonatal hepatitis is quite common as well. So let's see what are the pointers in the history. Usually in the obstructive parts, it is a rough type but it is not the rule of the book. Usually you will see a history of full-term baby with a normal birth rate, a calling stool growing well, feeding well with an uneventful antinatal history or there will be no family history. This is the pointer towards beliery atrasia or polytopansis or any other obstructive disease. And in non-obstructive causes or the hepatocellular causes, the baby is usually preterm or full-term with a low birth rate failure to thrive. Important thing is the baby will have pigmented stool with poor feeding. There could be other pointers in the diagnosis. For example, if it is a viral neonatal polystasis, then there could be history of fever, rash or lymphedinopathy. They may have family history of another sibling affected by the same. If the child on examination is dysmorphic in appearance, think of eligible or trisomers. Cataract is quite common in babies who have got galactosine. Similarly, in energies, you look up for posterior ambiotoxin in the lens. Then in torch anomalies or septuoptic dysplasia, retinal examination is very common because we know chorionetinitis is very, very common in torch infection. Sometimes beliery atrasia is associated with cytosine versus as well. Again, cardiac murmurs are seen in LHL and beliery atrasia. There could be a mass when there will be a presence of polygobal cyst. And then again, in septuoptic dysplasia, look out for microbinus. So these are rough clinical pointers which you can see on clinical examination and general examination of the child, which can points toward a certain diagnosis. Most of timely evaluation. The reason we want to timely evaluate these child is so that we can treat any medical or life-threatening condition. You know that the liver can get compromised very quickly. They can go into cirrhosis and acute liver failure. So they need to be diagnosed and treated on time. Obviously, we know that there is a crucial window for the surgery for beliery atrasia. So such disorders which are treatable by surgery should be diagnosed and treated in appropriate time frame. And very, very important, a lot of intrahepatic disease are referred for surgical intervention without knowing the underlying cause. So such errors should be avoided by doing the right diagnosis. So let's see what all can be helped in terms of investigations to diagnosis disorder. So if you look at the liver function test, I discussed earlier as well that gamma GT levels are very, very important. Usually you see a raised gamma GT levels in extrahepatic beliery atrasia or PFIC-3. That is primary familial intrahepatic polystasis type G, not in one and two. In the primary sclerosing colonitis and energy. So the GGT along with the other liver function test is a good pointer towards diagnosis of what kind of disorder it could be. In PFIC-2 and 1, it is usually normal, especially in biotubbed disorders and biosynthetic disorders as well, biosynthetic disorders, gamma GT could be normal. PT and ILR is severely, if it is severely abnormal, think about tyrosinemia, galactosinemia because it's hugely associated with sepsis. Then look out for urine for reducing substance, especially galactosinia, tors cleaning, thyroid status, cortisol screening. If there is evidence of hyperglycemia, think about galactosinia or hyperglycemia. AFP levels are very, very high in tyrosinemia. But for the conformation, it is very important that you do a urinary succinyl acetone levels because AFP can be high in enter condition as well. So that's why confirmatory diagnosis is always warranted before starting the treatment. So again, I'll go for the gamma GT levels. If it is normal or low, think about neonatal hepatitis could be associated with idiopathic or hypotheticalism or biosynthetic disorder or PFIC 1 and 2. But if it is high, then think about either obstructive disorders or neonatal hepatitis. So usually in related atresia, colidococyst, PFIC 3, allergis, and it can be high in alpha 1, and even alpha 1, anti-truxine deficiency as well. So let's see the ultrasound scan. Usually in all the babies, it is being told that you should do a fasting ultrasound scan followed by a post-perennial ultrasound scan. And this is the triangle, classical triangular chord sign that you see near the bifurcation of portal vein for conformation of diagnosis of really atresia. Now why it is done? Why it is very, very important? A good sonologist and a fasting scan, it can confirm if there is any other surgical treatable condition like colidococyst or insipid bilbacrisis. Triangular chord sign, as I said, is diagnostic. Then abnormal gallbladder morphology. For example, the gallbladder is not visualized on a fasting scan or the length is less than 1.9 centimeter or the lining is not complete or it's not smooth. The other thing is that no contraction of gallbladder happens after oral bleeding. So that's why it's very important that you do a fasting scan first and followed by that you do a post-perennial scan to look for the contraction of gallbladder and also non-visualization of the common bilbacrisis. So these are all the diagnostic signs for diagnosing bilader atresia. Now, afterwards, after this, we have to do the Hyda scan on the hepato- biladeris integrative scan. It has certain disadvantages. Although to confirm the diagnosis of bilader atresia, we always look for the excretion of the dye. So we give the child technician-labeled dyes. It depends on the hepatocellular function and patency of the biladerie trap. So if the child has got neonatal hepatitis, there will be delayed uptake, but there will be excretion. Whereas in bilader atresia, there will be a normal uptake, but there will be absent excretion. So it is 97% sensitive, but it is not specific for bilader atresia. It is very important to remember whenever you do a scintigraphy scan, you have to prime the baby for five days with pinovacetone. So as I was saying, that there are certain disadvantages of Hyda scan, especially when we have a time lag or we don't have enough time for the baby to wait for the surgery. So always, it's always better to go for a liver biopsy rather than waiting for five days to do a Hyda scan to confirm the diagnosis of bilader atresia. So because there is a new delay because of the priming and 40% cases of neonatal hepatitis will not show any excretion. And it has been shown that 20% cases, even with show excretion on Hyda scan, later provoked to be bilader atresia. So it's not a very specific test. So this is the clinical picture. The positive finding is when you give the dye, there is uptake in the liver and then there is excretion in the bald data in the early phase. And later on, you can see the tracer activity in the geodinum as well. Whereas when there is biladeria atresia, there will be no uptake and no excretion. And ultimately the dye will be seen in the bladder. There will be normal uptake in the liver, but there will be no excretion in the bowel. You can't visualize the biladerie tree and then you will see it in the bladder. So this is for biladerie atresia. So now we come to the next step of investigation which is liver biopsy and it is the gold standard and it is very, very useful, especially in defining the etiology in up to 95% of cases. You can also find out the extent of fibrosis. And it also gives a clue to the diagnosis. So you can avoid unnecessary surgery if the child is not suspected to have biladeria atresia then putting the child in the life is unnecessary. So it is very, very important in differentiating neonatal hepatitis and biladeria atresia. Acuracy is around 83% to 97%. The mandatory requirement is that the pro-common time should be normal. There should be no acytis or any other contraindication and the platelet count should be normal. Sometimes complication may occur, but it is extremely rare. It can lead to bleeding if adequate precautions are not being taken or peritonitis or pneumothonics. So this is the histological appearance. You can see biladuct proliferation in extraepatic biladerie atresia with bioplux. This is another picture in which you can see biladuct proliferation in biladeria atresia. Now in paucity of intraepatic biladucts, you can see that there are only few biladucts because of lack of it. This is the histological picture. This is giant cell formation in neonatal hepatitis. In PFIC, again, you can see that there is not only biladuct proliferation, but there is also fibrosis. So following all this, if we still don't get the diagnosis, then we go ahead and do the genetic and enzymatic study. It is very important to remember sometimes when you are investigating this child, you will get multiple diagnosis that you will find some amino acid to be raised in our DMS level. You will find that some of the IgM, especially the rubella IgM antibodies are raised. So you are always in a fix whether the child has got metabolic condition or viral condition or which treatment to start. So whenever you get this multiple kind of factors, it is always important to remember that for viral etiologies, the PCR should be done for confirmation in the diagnosis, unless clinically the child has got all the clinical condition which fits into a viral induced polystasis. Other than that, for genetic, you can do genetic and enzymatic studies which do take time to come to confirm the diagnosis of the cause. So alpha 190 trypsin deficiency, you have the PISZ gene, which is responsible. Then you can do the CFPR gene for CAF gallatin enzyme study for galactosemia. Then there are glycogen storage disorders. Then for hemopromatosis, usually you do the iron studies and then you look at the deposition of iron in the pancreas and iron. Then nemenpig disease, you do the nemenpig genetic studies. In citrin deficiency, you look for citrulline and raised alpha pitotopy with ferritin. Then in allergens, you see jag and non-chain. And then in PFI C123, you see the ABCB4 and ABCB1180P8B1 genes. These are very, very common. That's why I'm discussing because all these genetic and enzymatic studies are easily available and down nowadays to conclude the diagnosis of neonatal polystasis. So let's look at the diagnostic algorithm. If a child who's coming to you is sick has a positive septic spleen, treat the sepsis, but you need to exclude galpacemia. If the septic spleen is negative, then look out for other viral illness, like CMVHSV, to a ferritin level, a urinary succinyl acetone level to exclude tyrosinemia, valve level as well. If it is normal, then biopsy is optional. Sorry. If the child is not sick, look for pale stool. If there is pale stool, then do a fasting ultrasound scan and for gallbladder contractility. If it is normal, then biopsy is optional. If there is small gallbladder that you see on an ultrasound scan or epsom gallbladder, it's important to exclude biliary atresia. For that, you need to go ahead with either with the liver biopsy or do an introop cholangiogram. And if there is evidence of political cysts on ultrasound, then you have to do a surgery. If the stools are pigmented, then you do a sonography, look for any surgical cause. If there are not, then do not for metabolic cause as well. In biliary atresia, if the age is less than six weeks, do a Hyda scan after three days of priming. You look out for excretion. If there is no excretion, obviously you have to go ahead with the surgery. Again, no excretion, liver biopsy. If it is inconclusive, then introop cholangiogram with the site. If the age is more than six weeks, then directly go for liver biopsy. Don't wait for Hyda scan. If the child with biliary atresia present to you after three months of age with the site is, or maybe more than six months of age, then it should directly be delivered to the transplants and the child has developed cirrhosis in a site and it's a transplant. Now comes to the management. So we all know that liver needs a lot of nutrition and this is of prime importance in any child who has got chronic liver disease. So it's very important to ensure that the child gets adequate nutrition. It could be breastfeeding with supplemental feeds or you can give them a supplementary formula as well, but make sure that you provide all the adequate amount of carbohydrate, fats and protein. The energy intake should be adequate. With all the vitamins, fat-soluble vitamins, these are the recommended doses of ADEK, which needs to be given along with other minerals, calcium, phosphorus, vitamin zinc and iron. Now puritis is very, very common in polystasis so and it is very difficult to treat as well, especially in infants sometimes. Initially we start with the urso. If it doesn't get better, you can add the 1% of inobarbitone and if it doesn't get better, then you can give polystyramine as well in the dose of 428 gram per day. All these are good to be given in divided doses. So let's look, if there are associated common condition, then you need to treat. For example, if the child has got hyperthyroidism or hyperbacterialism, then you have to do hormone replacement. If the baby has got polystasis because of galactosinia, then obviously elimination of dietary galactose, elimination of dietary fructose for the fructose intolerance, tyrosine-free formula for tyrosinemia, and for bile acid synthetic defects, you have to supplement all your bile salts. Now finally, if the child doesn't get better with all this and the child has got progressive or chronic liver disease, then the child should be referred for liver transplantation. The indication is decompensated liver disease, psitis or encephalopathy, or failed auto-entry storming. Now, the survival rate for liver transplantation is very, very good. The one year survival rate is approximately 85 to 90%. Five to eight year survival rate is around 75 to 80%. And mostly the most common reason in child who undergo liver transplantation, half of them belong to biliretrizia. So, if the age of, I'm just going to skip this slide, it's not, so this was the study which was done in 1999, but the results are much better. Earlier the survivors used to be around 30 to 50% and 10 year survival was around 23 to 43%. This is now gone up to about, the five year survival has gone up to around 85 to 90% in the recent times. So, if you look at the long term outcome, the mean survival of biliretrizia patient who are untreated is around 90 months or maybe lesser. Three year survival is less than 10%. But all this kids' life can be saved if they are referred for an early liver transplant. Similarly, in neonatal hepatitis, 60% of the patient with idiopathic neonatal hepatitis will recover without any specific therapy. 10% die quickly because of bleeding or pulmonary hepatic failure and 30% of them can progress to progressive liver disease. So the key message I would like to give from my presentation is early diagnosis is the key to save the child with or maybe with chronic liver disease. Congenital infection is the most common cause of polystatic jaundice. Parputaneous liver biopsy is safe and most useful tool for diagnosing of any kind of chronic liver disease in babies. And surgery for biliretrizia and the CES should be done before two months of age. With that, I thank you for your patient listening and we're gonna take the questions from you.