Jaundice or yellowing of the skin in newborns is a widespread problem; globally. Newborns, in particular, often experience this. So much so, that the term Neonatal Jaundice or Jaundice of the newborn has been coined to describe it. It is estimated that Jaundice of the newborn occurs in up to 85% of all live births. In most cases, it resolves without complications within five days. But that should not be an excuse to take Jaundice in newborns lightly. Left untreated it can have tragic consequences and sometimes it spirals into neurological complications that can even lead to death.
Jaundice happens when there is an excess of the pigment Bilirubin in the blood. Bilirubin is a yellow coloured pigment that is naturally present in bile: a digestive liquid secreted by the liver. Treatment of Jaundice in adult is easy and most of the medicines target the liver, the Bilirubin-breakdown machine in the body, for the cure. Unfortunately, this strategy fails in case of neoborns because their tender young livers are not properly functional just yet. Some therapies to treat neonatal Jaundice do exist, but these are either costly or have severe side effects. Scientists from S. N. Bose National Centre for Basic Sciences, Kolkata, India, and their collaborators are now holding out the hope of more effective therapy (nanomedicine) based on Nano-technology.
To truly understand what makes the Indian findings so encouraging we need to understand what causes Jaundice and what exactly does Nano-technology mean. It is only when the facts are taken in context that the true significance of the research findings of these scientists will come to light.
To begin with, it may suffice that the science of Nanotechnology involves working with matter at the scale of 1 billionth of a meter. A nanoparticle usually ranges in size between 1- 100 nanometer (nm).
Nanoparticles have different physical and chemical properties from the properties of the mother material in bulk. Nanoparticle-based therapeutic systems have attracted tremendous attention, globally due to their novel properties.
Some nanoparticles used as therapeutic agents can even overcome biological barriers and even preferentially target the active sites for best results. Nano-carriers can be engineered to improve results. Worldwide there is growing interest in the medical applications of nano-particles and even nano-robots (nanobots) that are designed to carry out applications not possible using conventional treatment options. The future of medicine may well lie with the judicious use of Nano-technology.
Jaundice or Elevated Bilirubin levels
Bilirubin is also a natural component produced when red blood cells break down. Usually newborns have slightly elevated Bilirubin in their blood. The worry begins when the level crosses 5mg/dL in the blood. This is because of elevated Bilirubin levels:
- Can affect the central nervous system. Condition is called Acute Bilirubin Encephalopathy (ABE). It may even affect the brain.
- Kernicterus is a group of symptoms that presents if ABE has caused permanent damage to the brain. It is rare.
It would appear that measuring the Total Bilirubin in Blood serum (TSB) would provide a clue as to just how widespread Jaundice of the newborn is; globally. Unfortunately, reliable methods for TSB assay are not always readily available. This is more so in countries that are developing economies in the low- and middle-income bands. Thus the true incidence of severe neonatal jaundice may never have been quantified till date.
Physiological Jaundice/Neo-natal Jaundice/Neo-natal Hyper-bilirubinemia
The red pigment that gives blood its characteristic colour is called Hemoglobin. The hemoglobin contained in the red blood cell of the foetus is slightly different from the hemoglobin that is present in the red blood cells of the newborn/adult. Soon after birth, the foetal hemoglobin is replaced by the adult version of hemoglobin. This is usually when the problem starts for many infants.
Normally, the liver processes the Bilirubin released when the foetus’s red blood cells are destroyed. However, sometimes the newborn’s liver is unable to process the rapid break down of red blood cells and handle the amount of Bilirubin released. This excess Bilirubin circulating in the blood leads to jaundice. The good news is that, for most cases, intervention measures are limited because this jaundice is transient and eventually disappears as the baby’s liver matures. The number of cases of severe hyper-bilirubinemia in developed countries has decreased markedly since the 1990s.
Unfortunately, in some cases the Jaundice is markedly more severe. This is called Pathological Jaundice. When Bilirubin levels exceed a rise of 5mg/dL per day; peak levels reach higher than the expected normal range; and dark urine stains clothes, the situation requires swift intervention. It has been found that 5-10 per cent of the cases of neonatal Jaundice, progress to pathological Jaundice.
Other factors leading to Jaundice
Sometimes Jaundice arises because of incompatibility of blood-factors and blood groups between mother and foetus. Rh factor incompatibility/ABO blood group incompatibilities are the most common reasons. For example, if the newborn and mother have different blood types; SOMETIMES, maternal antibodies or protein molecules that under normal conditions carry out important immunological role(s), target and destroy the newborn’s red blood cells. This causes a sudden rise in the Bilirubin level of the infant’s blood.
Jaundice may be related to deficiency/defect of the enzyme Glucose-6-phosphate dehydrogenase. This is a genetic disorder that causes the red blood cells to break down prematurely leading to release of Bilirubin in the blood. In infants, Glucose-6-phosphate dehydrogenase deficiency/defect is a leading cause of Jaundice ranging from mild to severe.
Surprisingly, Jaundice may also develop when the baby does not get adequate maternal milk. This is because the poor nourishment leads to dehydration and fewer bowel movements that limit the excretion of Bilirubin in the stools.
Since Jaundice is quite a common symptom especially in new-borns, there is a set protocol for conventional therapy.
Photo-therapy means therapy by exposing to light. This is the commonest treatment for babies requiring treatment. The baby’s eyes are covered and the body is exposed to blue light. This exposure helps to convert Bilirubin into Lumirubin; a compound that is readily excreted. The Bilirubin levels are checked periodically and photo-therapy is resumed as and when needed. Photo-therapy is considered safe but may have minor side-effects such as skin rashes and loose stools etc. There is also chance of exposure to Ultra-Violet during the course of phototherapy, leading to complications.
- Injections of a blood protein (Immunoglobulin) may be needed if the Jaundice is because of antibody action. These injections act by decreasing the level of antibodies in the baby’s blood. But this is a costly therapeutic strategy.
- Extremely severe Jaundice may need blood transfusion. Blood transfusions in such cases carry with it the risk of morbidity and even, death.
Unfortunately, despite the high incidence of cases with elevated levels of Bilirubin (Hyper-bilirubinemia) there is currently NO MEDICINE available which can degrade Bilirubin directly in the living body (in-vivo). This is where the nano-technological research work carried out by Dr. Samir K. Pal of the S. N. Bose National Centre for Basic Sciences, Kolkata and his team members plus the contributions of his international collaborators is considered to be path-breaking.
Nanoparticles for treating elevated Bilirubin levels
As early as in 2012, Dr. Samir K. Pal and his research collaborators initially investigated the role of Zinc oxide nano-particles in degrading Bilirubin under simulated conditions that mimicked the way Bilirubin was found in blood. They found that Zinc oxide nano-particles measuring 5 nm were best suited for breaking down Bilirubin.
The experiment involved setting up two glass plates separated by a spacer. Thin films of Zinc oxide nanoparticles were placed on one of the glass plates. Bilirubin solution was slowly passed through the channel. The results were encouraging. The presence of Zinc oxide nano-particles raised the rate of Bilirubin degradation from 4% (absence of Zinc Oxide nano particles) to 37%. (Link: )
Now, in the body, Bilirubin is usually attached to a blood protein called Albumin. The next experimental stage therefore was to simulate or mimic the natural condition inside a living body. A solution of Bilirubin and human serum Albumin was passed through the channel under Ultra-violet light. This time too, the degradation of Bilirubin when Zinc oxide nano-particles were present was significantly higher. It was 51% when Zinc nano particles were present and a mere 6 % in its absence.
An elated Dr. Samir K. Pal went on record saying that Zinc oxide nano-particles represented a promising nano-therapy for Jaundice. Interestingly, researchers who presented this work came not just from the S. N. Bose National Centre for Basic Sciences, Kolkata, India, but from Centre of Excellence in Nanotechnology, Asian Institute of Technology, Klong Luang, Thailand; and Water Research Center, Sultan Qaboos University, Al-Khoudh, Sultanate of Oman, which shows the global interest in the topic. This finding was published in Journal of Physical Chemistry and highlighted in the prestigious research journal NatureAsia.
Although ZnO nanoparticles were able to degrade Bilirubin efficiently, these required light to be activated; the process is called photo-activation. This motivated the team to find out a newer solution independent of any photo-activation. Thus, Dr. Pal and his team started to work on Manganese-based nano particles as therapeutic agent to combat elevated levels of Bilirubin. They used a complex of citrus extract along with Manganese-based nano particles (Citrate capped manganese oxide nanoparticle). Interestingly, Manganese (Mn) is often a cofactor that is associated with enzymes. Cofactors help the enzymes to effectively carry out the catalytic process. The team found that Mn in the citrate-capped Manganese oxide nano-particles was active in the selective degradation of Bilirubin. A bonus was that it did not need photo-activation or the action of light to do so!
In 2016, they reported that the citrate functionalized Manganese Oxide nano-particles worked marvellously in cases of liver damage (hepatic fibrosis) and associated chronic liver diseases.
Just the previous year the team had reported encouraging results from their experimental work on mice. They found that injected citrate-functionalized Manganese Oxide nano-particles degraded Bilirubin extremely swiftly and in a specific manner. Interestingly, the citrate moiety is a derivative of citric acid found in citrus fruits such as lemons. Dr. Nabarun Polley, of S. N. Bose National Centre for Basic Sciences, Kolkata, a co-researcher pointed out, “It is actually like nimbupaani administered through nanoparticles!” The media was quick to point out that traditional knowledge in India had for millennia recommended the use of lemon juice in cases of Jaundice.
Once injected, the citrate-functionalized Manganese Oxide nano-particles is able to degrade Bilirubin to near-normal levels within two-and-a-half hours compared to a much longer time taken by conventional drugs in a mouse model. For example, Silymarin, the commercially available drug takes more than a day to control the levels for the equivalent dose.
The efficacy of the nano-particles in symptomatic treatment of elevated levels of Bilirubin was found to be “ultra-high.” There were no toxicological issues. That indicated that these nano-particles could be safely used for rapid reduction of Bilirubin. This study on mice paved for practical clinical use of the nano-particles to address issued related to elevated levels of Bilirubin in humans.
Team Member Aniruddha Adhikari points out that currently, this is the only medicine that can directly and safely degrade Bilirubin inside the body. He emphasises that, this nanoparticle can show dual action to treat two different diseases depending upon the route of administration. If you treat it through injection it will treat jaundice. If you take it as tablet (oral) it can treat chronic liver diseases like liver fibrosis. Dr.Soumendra Darbar, the animal expert from Dey’s Medical Stores Pvt. Ltd. and an integral part of the team working on the problem, added that the nano drug is completely safe and has no side effect.
The Next Step
Success in science is often the result of sustained work that advances by degrees. Perseverance is the name of the game. The team behind this piece of research has been at it for five long years and more.
Today they stand at the threshold which divides animal model research from human trials. This is the first step towards actualizing the dream of launching a new and unique drug that will benefit newborns almost from the time they draw their first breath to older adults battling severe liver damage.
The success in mouse model has raised the hope that this technique will work on humans as well. Prof. Samir K. Pal, lead researcher is now looking for sponsors to take this study forward and initiate stringent human clinical trials.
What is a Win-win scenario for this treatment is that when injected it brings down elevated Bilirubin levels. When given orally, it works wonders in the treatment of liver damage (hepatic fibrosis) and damage due to exposure to Mercury, Arsenic and Cadmium etc. Heavy metals such as Mercury, Arsenic and Cadmium are often associated with industrial pollution. As such, there can be no debate about the importance of this study.
It is a matter of national pride that from India comes the news of a brand new therapy that has the potential to revolutionize the treatment of Jaundice; globally plus maybe have implications in the treatment of hepatic damage too.