It’s a safe bet that all of us, at one time or another, has had the hiccups – involuntary contractions of the diaphragm that suddenly shuts the opening between the vocal cords, making the classic hiccup sound and causing mini-convulsions. Lovely, aren’t they? There are 1,001 cures for the hiccups: drinking water upside down, drinking water from the other side of the glass, eating a spoonful of sugar, having someone scare you, yanking on your tongue, holding your left ear with your right hand and your right ear with your left hand and having a friend help you drink a glass of water. It’s no surprise that none of these work. They were all devised by your sadistic friends and family to make you look stupid . . . and drench you with water.

The exact cause of hiccups is unclear, but the most common “triggers” for people are eating or drinking too much, swallowing air, and emotional stress. Long-term hiccups, lasting more than 48-hours, could be due to irritation of the vagus nerve, which networks our parasympathetic, unconscious actions, like breathing, digestion, and blood circulation. More severe disorders, like multiple sclerosis, encephalitis, stroke, and kidney failure are also associated with hiccups. Did I mention starfruit? Don’t forget about the starfruit.

Seriously? Really. Starfruit, or carambola, is the fruit of Averrhoa carambola, an evergreen tree native to Southeast Asia, which also grows well in tropical climates of North and South America. The entire (sometimes) sweet and juicy fruit is edible, including its waxy coating, and is not altogether bad, which explains why a billion people eat them. Though they aren’t that common in the United States, you can find them at your local Asian market or well stocked grocery store.* What we aren’t told, however, is that starfruit can be neurotoxic, nephrotoxic, and in some cases, fatal.

* When I was in elementary school we were asked to bring a fruit to class for a project. All the kids brought in apples and oranges. What did I bring? A starfruit. I was a weird kid.

Though the neurotoxic and kidney damaging effects of starfruit have been known for quite some time, it wasn’t until recently that the chemical agent behind the hiccupping hi-jinx was elucidated, when a group of chemists and pharmacologists from Brazil isolated caramboxin (1). A non-proteinogenic amino acid analog similar to phenylalanine, caramboxin is an excitatory neurotoxin with glutamatergic activity, coupled with convulsant and neurodegenerative properties. Glutamate receptors play a key role in excitotoxicity – the process of damaging and destroying nerve cells by over-stimulation – which leads to neurodegeneration. But this is nothing new, because you read all about domoic acid and amnesic shellfish poisoning, right? Or maybe you just forgot . . . please forgive the horrible pun. Also of interest is that aqueous solutions of caramboxin lose their biological activity after a few hours, something that other researchers have observed with starfruit extracts. What our Brazilians discovered is that caramboxin undergoes an intramolecular cyclization (condensation) to an inactive compound. But this is supposed to be about hiccups, right?

1. Caramboxin, 2. Inactive cyclic caramboxin analog.
Photo by DeusXFlorida (CC BY 2.0) and modified with caramboxin structures.

Starfruit poisoning in 32 uraemic patients (that’s urea in your blood, and a bad, bad sign of renal failure) manifested with intractable hiccups in 30 patients (2). Other symptoms included mental confusion, vomiting, paresthesias, and seizures. In another set of case studies, 5 of 6 dialysis patients (so also in renal failure) experienced persistent hiccups after consuming starfruit (3). Sensing a pattern? Me, too.

The starfruit neurotoxin caramboxin is metabolized and excreted by the kidneys. In healthy individuals caromboxin is readily flushed from the body, but in compromised individuals with renal disease or failure, it accumulates and signs of neurotoxicity, such as the dreaded hiccups, begins. I’ve seen starfruit consumption discouraged, or forbidden, for those with kidney failure or on dialysis, but not nearly frequently enough.**

** In the U.S., for those with kidney disorders, The National Institute of Diabetes and Digestive and Kidney Diseases fails to mention starfruit, while the National Kidney Foundation exclaims “Always AVOID star fruit.” It’s also hit-or-miss with clinicians working with renal patients, though that could just be a factor of starfruit not being popular here in the States. What I’ve learned from Mrs. Natures Poisons, a clinical pediatric Registered Dietitian, is to not assume that people eat like you or your other patients, and to ask a lot of questions and learn what other populations eat. I see starfruit in peoples’ baskets at my Asian market every weekend, and with growing Asian populations in the U.S., clinical toxicology fellows should take note.

But don’t think that starfruit poisoning is just for the kidney impaired, it can also manifest itself in those with (supposedly) normal renal function. In Brazil – they’re on top of this – five previously healthy patients were diagnosed with acute renal failure associated with starfruit consumption (4). Four ate large amount of starfruit, while the fifth drank 300 mL (10 oz.) of pure starfruit juice. All five exhibited signs of neurotoxicity: intractable hiccups, vomiting, and insomnia, 3-8 hours after consumption. They also exhibited signs of acute renal failure, such as high creatinine concentrations. Interestingly, two of the patients were biopsied which revealed – drum roll please – oxalate crystals. Oxalic acid is present in many foods, like rhubarb and spinach, and can accumulate as its calcium salt to form kidney stones. In our starfruit cases, oxalate crystals formed, giving rise to acute tubular necrosis and renal failure. This is the same pathology involved with ethylene glycol (antifreeze) poisoning and death (5).

So what comes first, hiccups or renal failure? Though not quite on par with the classic chicken and egg conundrum, the most likely order of operations is: consumption of large amounts of starfruit induces oxalate crystal nephropathology and acute renal failure (or exacerbates an existing disorder), preventing the clearance of caramboxin, leading to neurotoxicity in the form of hiccups. Once renal dysfunction clears up, the hiccups go away.

So should you stop eating starfruit? Nah, you’ll be fine. But if you happen to get the hiccups, lay off the starfruit. As my Mom used to say “It’s all fun and games until someone loses a kidney.”

References:
1. Garcia-Cairasco, Norberto, Miguel Moyses-Neto, Flavio Del Vecchio, José A. C. Oliveira, Francisco L. Dos Santos, Olagide W. Castro, Gabriel M. Arisi, Márcio Dantas, Ruither O. G. Carolino, Joaquim Coutinho-Netto, Andre L. A. Dagostin, Marcelo C. A. Rodrigues, Ricardo M. Leão, Samir A. P. Quintiliano, Luiz F. Silva, Leonardo Gobbo-Neto, and Norberto P. Lopes. “Elucidating the Neurotoxicity of the Star Fruit.” Angewandte Chemie Angew. Chem. 125.49 (2013): 13305-3308.
2. Neto, M. M. “Intoxication by Star Fruit (Averrhoa Carambola) in 32 Uraemic Patients: Treatment and Outcome.” Nephrology Dialysis Transplantation 18.1 (2003): 120-25.
3. Neto, M., F. Robl, and J. Netto. “Intoxication by Star Fruit (Averrhoa Carambola) in Six Dialysis Patients? (Preliminary Report).“Nephrology Dialysis Transplantation 13.3 (1998): 570-72.
4. Neto, M. M., G. E. B. Silva, R. S. Costa, O. M. Vieira Neto, N. Garcia-Cairasco, N. P. Lopes, P. F. C. Haendchen, C. Silveira, A. R. Mendes, R. R. Filho, and M. Dantas. “Star Fruit: Simultaneous Neurotoxic and Nephrotoxic Effects in People with Previously Normal Renal Function.” Clinical Kidney Journal 2.6 (2009): 485-88.
5. Mcmartin, Kenneth. “Are Calcium Oxalate Crystals Involved in the Mechanism of Acute Renal Failure in Ethylene Glycol Poisoning?” Clinical Toxicology 47.9 (2009): 859-69.