EPISODE 1➡️THE 1950s.
“My son’s jaundice is relentless,” told the elderly man. At two hospitals that he took him to, the doctors were baffled, unable to find a cause for Nitin’s sudden onset jaundice. “They say he may need a liver transplant, but it’s a burden we can scarcely bear,” the old man continued, his silent sobs conspicuous.
Nitin’s clinical history was so complicated, convulated, it was like I was dragged inside a thrilling movie, its ending waiting to be written.
Nitin’s ordeal began two weeks prior with jaundice and relentless itching. His liver tests were alarmingly high, but the itching tormented him the most, gnawing at his mental well-being. In a condition known as cholestatic hepatitis, the liver cells as well cells that form the bile ducts (called cholangiocytes) get injured. The resulting inflammation leads to stagnation of bile and a congested liver which results in jaundice and severe itching. Something was attacking Nitin’s liver and killing both his liver cells and damaging his bile ducts and no one could discern the culprit.
The detailed anatomical view of bile system in the liver (Source: MedlinePlus)
“No one wants to listen to me,” he pleaded.
“Will you please hear me out? Our story? My son is of bad character, I understand that, but his jaundice is because of something else, I am certain,” he asserted.
“I like stories,” I told him. And he told me things wild, so wild, that I knew why the other doctors could not figure anything out.
Nitin had spent the last four years in a quaint town in Tamil Nadu, completing his studies in laboratory medicine and awaiting his internship. He stayed in a hostel while his best friend Shane lived in a paying guest facility. But Nitin never attended his internship. Instead, he moved out of the hostel, finding a room on the town’s outskirts. Six months later, he returned home, demanding a bike, claiming he needed it for his external postings. His father, wary but doting, bought him the bike at his mother’s behest. Nitin vanished again, only to return a month later, now wanting a car. He had some money to contribute and sold the bike. Alarmed, his father still helped him get the car, also paying a burdening monthly EMI – it was, after all, for his son.
Four months go by and Nitin’s contact with his family withers. The parents call him from time to time, but he does not pick up. He calls back every few days later and assures them he was alright and things were fine. One evening on a latee evening video call, Nitin’s mother sees a Persian cat in his room. He spent close to INR 20,000 for the animal. A few months later, even the occassional voice calls, as well as video calls stopped.
One day, Nitin’s father received a call from home telling him that Nitin had called and he claimed that he was in danger, but he was taking care of it. His mother was sure that Nitin, an adult would take care of things. But something was amiss. The father called Nitin to confirm his whereabouts. He was still inside his room, but delirious and fearful. A group of men, some with their faces covered, barged into his room, threatened him at knife point and asked him to gather all the recreational and psychedelic drugs he was peddling to other students. Nitin denied. But they searched his room, found a lot of “hidden things” which Nitin claimed they “planted” and forcefully shot a video of him, claiming all “goods” were his and he was selling them. Then they took his car and his wallet, and got away, asking Nitin to disappear or they would come back to kill him.
Panicked, Nitin’s father called Shane, who was out of touch with Nitin but responded to the urgent plea. Shane rescued Nitin late at night, taking two bags and him to his place. Nitin’s father then booked a cab to bring him home. Nitin got into the cab and his father, in and out of sleep, tracked his journey, only to see that halfway through, the cab had stopped. He called Nitin who was verbally fighting with the cab driver. Nitin had his Persian cat in one of the bags and he did not disclose it to the driver and he was unwilling to carry an animal in his vehicle. He asked Nitin to get out and travel by other means. Nitin’s father begged the cab driver him to take his son home and he agreeg, only after he transfered another INR 6000 to his account. By late afternoon, Nitin was home.
“You should have seen him,” the father said, his voice breaking. “He wasn’t my son. He looked primal, unbathed for days, reeking of neglect.” He had not change his underwear in a week. He stank and it looked as if he was lost.
“What happened then?” I asked him. Medically relevant information that would help me find out the cause of Nitin’s liver injury had not come in yet, and I was stuck inside a thriller of a story that the father needed to tell, to ease his burden. I decided, I was going to hear him all the way.
“We got him warm bath, cleaned him up and called the local barber to cut his knotty hair and gave him a clean shave. Only then, I knew that this was really my son.”
Nitin’s father asked him about the recreational drugs. He denied it. He said that many people were jealous of his good lifestyle and they were trying to destroy the life he built there. But his father knew he was lying. He asked, if he wanted to file a case with the police to nab the people who took his car and threatened him and Nitin nodded.
And so, his father took him to a police officer, who was a friend, but retired, and also someone who had worked with the narcotics division. The police officer dwelled deep into Nitin’s story and through mellow, but imposing tactics, make Nitin confess about his drug-peddling and through empathy, convinces him to take a tox screen test. The tests came back positive for heavy marijuana and MDMA and Nitin was, as per regulatory directive, sent to a de-addiction program.
On that night, only Nitin’s father returned home and his mother was devastated. She never lost hope in her son and never believed the drug stories, even after she saw him in his primal state. Bad people were trying to frame him. But the police involvement and the tox screen results numbed her. Not only was Nitin selling recreational drugs, but he was deep into using them for more than year, so much that he never started internship. He used to travel in the car, that his father got him through burdening EMIs, to sell drugs outskirts.
At the de-addiction center, Nitin became delirious, delusional and aggressive. The doctors found it difficult to manage him and so they restrained and sedated him over few days. His father knew about the bad days Nitin had to overcome, to get to the sunny ones. Nitin was allowed few home calls in a couple days. After three weeks of treatment, during one such call, Nitin told his father that he felt “itchy” all over. A few days later, his urine turned dark and his eyes were a deep yellow. Blood tests revealed jaundice and increased liver enzymes (called SGOT or AST & SGPT or ALT, the latter more specific for liver injury).
Referred out to a government hospital and further to a specialist department at a multispecialty center, tests for viral, parasitic and bacterial infections were negative and blocks, tumors or stones in the bile system on advanced imaging also turned out non-contributory. The doctors were in a fix. Nitin’s liver tests worsened rapidly and his itching took a toll on his quality of life and he lost sleep. The doctors looked at all medications that the de-addiction center physicians prescribed at discharge. None were directly liver toxic.
Except one, a drug called oxcarbazepine. Oxcarbazepine was rarely, but still, documented to be associated with liver injury and severe hepatitis. This was it. And they withdrew that drug and put Nitin on supportive care. But he did not improve and the jaundice and itching increased exponentially.
Distressed, they referred Nitin to our center. Nitin arrived on a weekend, late evening. My colleagues in the department reviewed all investigations and the drug charts from previous hospitals as well as the de-addiction center. Oxcarbazepine was likely the only culprit. Nitin had used MDMA (also called Ecstasy) three weeks before his admission to the center and cannabis one week before. His alcohol consumption was not significant.
The drug 3,4-methylenedioxymethamphetamine (MDMA), otherwise known as “ecstasy,” is a synthetic amphetamine that produces euphoria, increases sociability and energy, and is often used as a “weekend” recreational drug by young adults. Severe hepatitis, that too of cholestatic variety is quite rare with MDMA use and reports are sparse in medical literature. Nitin had not used the drug in more than a month too. A temporal association to conclude that the drug caused the event was lacking. The identification of drug-induced liver injury rests on exclusion of other causes for acute liver injury and a timeline of use that fits with start of treatment and development of liver injury. This was not so in Nitin. MDMA related liver injury affected mostly the liver cells (hepatocellular type of injury), and not bile duct cells (cholestatic injury).
Effects associated with MDMA or Ecstasy use (from:
https://positivechoices.org.au/teachers/ecstasy-and-mdma-factsheet
)
Now cannabis. Marijuana, is not known to cause severe liver injury, especially of the cholestatic variety and is generally considered non-liver toxic. Cannabidiol use may lead to abnormal liver tests and increase suseptibility of the liver towards increased damage from other insults (alcohol, chronic viral hepatitis), but it has not been shown to cause severe liver injury. Marijuana was an unlikely cause of clinically apparent liver injury in Nitin.
Source:
https://bhudiscount.nowara.org/category?name=what%20does%20thc%20do%20to%20your%20body
See here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202751/
&
https://onlinelibrary.wiley.com/doi/10.1111/joim.13627
&
https://www.ncbi.nlm.nih.gov/books/NBK548890/
&
https://www.ncbi.nlm.nih.gov/books/NBK590051/
So it must be the oxcarbazepine. Oxcarbazepine, is a medication used to treat epilepsy. For epilepsy, it is used for both focal seizures and generalized seizures. Side effects are dose-dependent, which means increasing doses beyond a specific threshold only promoted adverse events from the medication. Chronic therapy with oxcarbazepine was associated with elevations in liver enzyme levels in a small proportion of patients. Very rarely, oxcarbazepine use can cause an acute hepatitis like illness – like in Nitin – but then there was a peculiar pattern of associated symptoms and signs. Patients usually present with fever, followed by rash, facial swelling, enlarged lymph nodes and increased eosinophils around two weeks after starting therapy. The liver invovlement was usually mild – with modest elevation in liver enzymes and bilirubin and without major “itching-cholestatic” type of symptoms. These peculiarities were absent in Nitin and he had only received five days of oxcarbazepine.
See here:
https://www.ncbi.nlm.nih.gov/books/NBK548414/
Oxcarbazepine was a Red Herring here. Something else was injuring Nitin’s liver and time was running out.
Red Herring: diverting attention from the real issue by focusing instead on an issue having only a surface relevance to the first.
Nitin’s liver injury was rapidly progressing and his father was drowning into a void of depression. Because he thought it was all his fault that the son was now dragged out from a “life and dealth” situation into a “worse life and death situation.” Every document was searched again for clues, every treatment summary re-assessed and every investigation double checked. There was no hope.
But then, something was amiss. And it came to me, during a sleepless night, when I was deep in thought about completing this responsibility that was given to me. A father devastated for his son and a liver injury that played hide-and-seek in the most torturous way. Nitin was at the de-addiction facility for almost three weeks before development of jaundice. What did he receive there while he was admitted? Most of the notes provided details of medications he was continued on at discharge. None of the notes revealed the whole inpatient treatment details.
But the hospital bills did.
And I saw something there, which other physicians missed, but physicians in the 1950s saw. A cause for liver injury, that history had swallowed whole and modern physicians never considered because…
…And here it was, hiding in plain sight.
On December 11, 1951 Paul Charpentier, in the laboratories of Rhône-Poulenc, a French pharmaceutical company, synthesized a chemical which was released for clinical investigation in May 1952 as a possible potentiator of general anesthesia. In 1952, Henri Laborit, a surgeon and physiologist in the French army, in the course of his research with “artificial hibernation” in the prevention of surgical shock found that this chemical produced disinterest without loss of consciousness in persons and with only a slight tendency to sleep.
Hydrotherapy was a popular method of treatment for mental illness at the beginning of the twentieth century, and was used at many institutions, including the London Asylum for the Insane. Water was thought to be an effective treatment because it could be heated or cooled to different temperatures, which, when applied to the skin, could produce various reactions throughout the rest of the body. Source:
At the time, cooling with water was used in France to control agitation in patients and with the discovery of this chemical, its treatment of agitation in psychiatric patients became a new area of interest. Jacques Lh., a 24-year-old severely agitated psychotic (manic) male was the first psychiatric patient to receive this chemical, and he was administered 50 mg of the drug, intravenously, at 10 am, on January 19, 1952. The calming effect was immediate but lasted only a few hours and several treatments were required before the patient’s agitation was controlled. Subsequently, over the years, the drug was tested in large numbers of psychiatric patients and its value in clinical use emerged. In 1952, Dr. Delay and his associates first reported the clinical use of this drug in the management of psychoses. But in 1955, another side of this drug also came into light. One of the side-effects observed with the use of the chemical or drug was a cholestatic or bile duct injuring type of jaundice that developed insidiously or with an abrupt onset of mild grippe-like symptoms.
They called it thorazine hepatitis and the drug, was chlorpromazine. Reports of multiple patients developing thorazine hepatitis came to light in 1950s and the decade that followed its introduction as a valuable drug in psychiatric practice.
Nitin was given this drug for the intial few weeks in multiple doses at the de-addiction center while the doctors struggled with controlling his agitation, delirium and aggressiveness. They thereafter discontinued it because of abnormal movements and high heart rate during its use in Nitin.
Chlorpromazine (Thorazine) drug card. Source:
Liver cell and bile duct cell damage due to thorazine hepatitis was further confirmed on Nitin’s liver biopsy. We started Nitin on low dose steroids and targeted his cholestatic symptoms especially the itching (medically called pruritus) with medications.
Treatment of cholestatic symptoms. Source:
During the course in hospital, Nitin showed an improvement in his appetite, reduction in itching and better sleep. His jaundice stabilized and we all await a decreasing trend, for us to discharge Nitin home and to continue his de-addiction program. This time, with prudence and letting things in the past, be in the past.
We had dragged this young man, out of hell.
And the “masked” individuals who stormed into Nitin’s room, forcing him to confess to his involvement in the drug trade and warning him to cease this dangerous path, were none other than his own college friends. They sought to frighten him away from the brink of disaster, desperate to save him and others from the devastating consequences of his addiction, despite their repeated pleas for him to seek help. Once they knew Nitin was safely back home, they contacted his parents to assure them that his car, wallet, and other valuables were secure and would soon be returned. Though they would miss Nitin dearly, they found solace in knowing he would no longer be consumed by the darkness that had transformed their dear friend into someone or something, unrecognizable.
Knock nock 
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