In late June, I came across an article from the BBC that raised the question posed in the title of this post. Protein powder consumed by a teenager in London in order to bulk up was believed to have contributed to his death, and medical professionals involved in the case were calling for labels to warn consumers of the risk in people unable to safely metabolize large amounts of protein. But is this reasonable? Would it have actually saved this child’s life?
The case of Rohan Godhalia
On August 16, 2020, 16-year-old Rohan began drinking protein shakes made from powder purchased at a grocery store in West London. Three days later, after suffering from altered mental status, seizures, cerebral edema, and ultimately irreversible brain damage, he died. At the time, and even after an autopsy ten days later, the cause of his death was unable to be determined.
Rohan’s family had made the heroic choice to donate his organs, in this case his liver and kidneys, in the hopes that some good would come from the tragic loss of their child. Because of this, and completely unbeknownst to them of course, the discovery of what happened to their son would be delayed for several months until the recipient of his liver required hospitalization for similar mysterious symptoms. A simple lab test, but one that unfortunately wasn’t ordered during Rohan’s hospitalization, was the break in the case that lead to the diagnosis.
Doctors caring for the patient with Rohan’s liver discovered that they were suffering from dangerously elevated levels of ammonia. Not only is this potentially treatable with dialysis to remove the offending chemical from the bloodstream, though not always in time to prevent permanent injury to the brain, it was an important clue that the patient’s liver was the root of the problem. The liver, among many other important functions, is the organ where this highly neurotoxic byproduct of protein metabolism is converted into urea. Urea is then safely excreted in the urine.
Most adults who present with elevated ammonia levels have cirrhosis, a chronic scarring of the liver that occurs after years of injury from a variety of potential conditions, but most commonly excessive alcohol intake, viral hepatitis, or non-alcoholic fatty liver disease. None of these common causes made sense in this case, so a biopsy was performed which revealed the problem and also answered the question of Rohan’s untimely demise. It turns out that he had a rare genetic disorder, specifically a urea cycle disorder known as ornithine transcarbamylase (OTC) deficiency, that impaired his liver’s ability to convert ammonia into urea.
OTC deficiency: a brief primer
OTC deficiency is a rare condition that is passed down genetically on the X chromosome. So-called “X-linked” conditions generally occur more frequently, or present with more severe disease, in people with only one X chromosome. The additional X chromosome carried by most people assigned female at birth is usually protective and they are rarely significantly affected by elevated levels of ammonia in the bloodstream, with only 10-20% of them ever developing any symptoms at all.
Patients with one X chromosome carrying a defective OTC gene and another that is fully functional are known as carriers of the disease, and there is a 50% chance that their biological child would receive the dysfunctional gene. If that child has another X chromosome, they are a carrier as well. If they don’t, with the vast majority of these cases being diagnosed in patients assigned male at birth, they are significantly more likely to have severe disease that presents in the newborn period. There are exceptions, of course, such as in the case of Rohan Godhalia. Had Rohan lived long enough to have children, he would have pass his one defective X chromosome to each of them.
Symptoms from OTC deficiency are most likely to present in the newborn period once feeds start to pick up after the typical sleepy first day. By a few days of age, patients with early-onset disease, which is seen in roughly 1 in every 14,000 to 77,000 infants, will develop feeding difficulty and become excessively sleepy. This is often accompanied by abnormal breathing and problems maintaining a normal body temperature, and as ammonia level continue to increase unabated the brain will begin to swell, leading to seizures, coma, and even death over a period of hours to days if not treated with emergent dialysis. Surviving infants are still at risk of developing intellectual impairments and cerebral palsy over time, particularly if there are multiple episodes of severe hyperammonemia in childhood.
Some patients have a partial OTC deficiency and present later in adolescence or young adulthood. This usually occurs in carriers of the disease and is mild, but can rarely occur in patients assigned male at birth and even result in severe or fatal disease. Rohan is an example of this. OTC deficiency occurs in roughly 1 in every 35,000 people, but this likely underestimates the true incidence given how it likely misdiagnosed or undiagnosed in many people with a partial deficiency.
The most common clue that an older patient has a urea cycle defect such as OTC deficiency is when unusual symptoms such as headaches, nausea, and confusion are linked to high protein meals. It is not uncommon for these patients to have learned to reduce meat consumption, or even to have become vegan/vegetarian in response to their symptoms for years prior to being diagnosed. Some patients will also develop symptoms unrelated to protein intake, such as during stressful periods like pregnancy, intense exercise, illness, etc.
In the United States, only 8 states and territories have included OTC deficiency in their standard newborn screening programs. This involves the detection of decreased levels of citrulline in a newborn’s blood, which is an amino acid that is produced early in the urea cycle from ornithine and carbamoyl phosphate with assistance from OTC. Deficiency can also be detected indirectly by newborn screening in three additional states. Many babies with the condition will develop symptoms days prior to screening results being available, however, so pediatricians and family doctors who care for newborns need to be up to speed and to know when to check an ammonia level. England does not screen universally for the condition.
The plot thickens…..
I don’t have access to Rohan’s full medical or family history, so I don’t know if he or any of his relatives had episodes of recurrent symptoms consistent with OTC deficiency. That isn’t required, however. Some patients will go years, even decades, in apparent good health before a significant protein load or physical stress tips them over. And clearly, as with poor Rohan, not all cases are mild.
I found one interesting case report involving a healthy 34-year-old man who had developed acute mental status changes at age 30 that was initially diagnosed as psychosis. He subsequently had seizures that were misdiagnosed as epilepsy as well, but that was ultimately found to have partial OTC deficiency. He had apparently started an intense exercise program and increased his protein intake just prior to the onset of his odd symptoms. The authors of this report mention at least 10 other similar cases found in their literature search.
So it makes sense that, although this is a very rare scenario, Rohan’s liver was unable to handle a large protein load that was perhaps accompanied by exercise. What doesn’t appear to make sense to Rohan’s family, and honestly to me as well, is why an ammonia level wasn’t checked when he presented to care suffering from altered mental status without a clear etiology. He may have survived had emergent dialysis been provided.
An inquiry is underway looking into this issue as well as the question of why his organs were approved for transplant. I’m not an expert in these things, but I think it’s pretty unusual to clear organs without a known cause of death. Finally, and more pertinent to Rohan’s potential for surviving his condition, his family is asking why he wasn’t seen by a neurologist or transferred to a tertiary care center. It turns out that he was essentially listed as an adult and his transfer to a pediatric facility was rejected.
About those warning labels…..
According to the articles written about Rohan’s case, the coroner and at least one pediatric specialist have called for new regulations:
Coroner Tom Osborne said: “Concerning these protein drinks, my preliminary view about them is that I ought to write to one of the regulatory authorities that some sort of warning ought to be put on the packaging of these drinks because, although OTC is a rare condition, it can have harmful effects if someone drinks [one] and it causes a protein spike.”
Finbar O’Callaghan, professor of paediatric neurology at the Institute of Child Health, University College London, agreed intervention was needed, describing it as “potentially life-saving” at the hearing.
I’m skeptical that warning labels would make a difference. People who have a sense that they don’t tolerate meat, because of an undiagnosed partial OTC deficiency for example, aren’t going to know that it’s the protein that is the problem. So they wouldn’t think that the label applies to them. And if they have made that connection, they aren’t going to buy protein powder. For Rohan, I just can’t imagine how a label would have prevented his deterioration because it doesn’t look like he or his family had any concerns regarding protein consumption.
Patients with a known urea cycle defect are educated extensively on adhering to a low protein diet. They just wouldn’t pick up protein powder or drink protein shakes, and it’s important to point out that lots of people buy protein shakes from dining establishments without ever looking at a jug of powder. Are these businesses supposed to put up warnings or screen customers as well?
Protein powders and drinks might deserve some kind of warning for other reasons, however. And in fact some do when sold in California thanks to Proposition 65, which is also known as the Safe Drinking Water and Toxic Enforcement Act of 1986. Because of Prop 65, California maintains a list of chemicals linked with cancer or reproductive toxicity and products containing levels of such chemicals above a certain threshold must be labeled with a warning.
What is that threshold? For chemicals believed to cause cancer, it is the level of exposure that would result in not more than one excess case of cancer in 100,000 individuals over a 70-year lifetime. For reproductive toxicity, it is 1/1000th of the “no observable effect level” deemed safe by most relevant organizations such as the FDA and WHO. I can’t help but assume that there is a large amount of alarm fatigue that occurs in California and that these labels do little to influence use of these products.
There are definitely reasons to avoid protein powders and drinks. There are serious concerns regarding the presence of toxins in protein powders, for example. One 2018 study found that many protein powders contain heavy metals like lead and arsenic, bisphenol-A, pesticides, and other potential contaminants.
In addition, they are dietary supplements and thus regulation is weak and largely left up to the foxes to guard the hen house when it comes to safety. Consumers should approach labels skeptically with these and similar products because they may not provide accurate information. (Check out Scott’s post from yesterday for a nice discussion on this very problem.) There are also often large amounts of added sugar and excessive calories in these products. Essentially, there are better and likely safer ways to increase protein intake, which isn’t even necessary for most people.