Too much of a good thing – Toxicology Blog

Author: Kristen La, MD, Emergency Medicine Resident PGY1
Fellow: Richard Chen, MD, Medical Toxicology Fellow PGY5
Faculty: David Goldberger, MD, Medical Toxicology / Emergency Medicine Attending

The case:

You are working a night shift at the Emergency Department (ED) of a Philadelphia hospital. A 25 year old woman presents to the ED for nausea, vomiting, headache, and vision changes for the past 2 days. Upon speaking with her, she says that 2 days ago she started having some generalized malaise, nausea, a few episodes of non-bloody, non-biliary  emesis, and a gradually worsening headache. She initially thought she was having food poisoning from some fish that her boyfriend had caught on his fishing trip last week. Then this morning, she began having intermittent blurry vision. She states she has been having episodes of “dark cloudy” vision that last for a few seconds and then self resolve, which prompted her to come to the ED. 

On physical exam, her vitals are within normal limits, she is afebrile. Her pupils are equal in size and reactive, with full extraocular range of motion and intact visual acuity. She states that her last episode of “cloudy vision” occurred an hour ago. The rest of her neuro exam is nonfocal. Her skin appears dry, with some skin peeling. The remainder of the physical exam is normal.

Learning point 1: Clinical presentation of Vitamin A toxicity

First let’s talk about vitamin use:

The use of nutritional and herbal supplements is widespread. A 2015 report by the Council for Responsible Nutrition indicated that up to 68% of American adults take some sort of supplement, the vast majority of which are vitamins or minerals. While the standard diet should provide sufficient nutrition, many people take supplements for their purported health benefits, and often in excess of the recommended daily allowance. In recent years, social media has also popularized multivitamins among young adults. In terms of toxicity, according to 2018 data from the  Poison Control Center at The Children’s Hospital of Philadelphia vitamins rank among the top 10 most reported ingestions for children under five years old. Luckily, adverse outcomes are extremely rare and uncommon, and most cases have an unremarkable course.

Generally, fat-soluble vitamins have a larger potential for toxicity compared to water-soluble vitamins, because of the increased storage potential in body tissue. Fat soluble vitamins include A, D, E and K. 

Now let’s learn some more about hypervitaminosis A in particular:

Image credit to: Goldfrank’s Toxicologic Emergencies (11th ed)

Vitamin A is necessary for maintenance of the immune system, retina and epithelium. It occurs naturally in animal products such as liver, fish, and dairy, and is also found in fortified foods. There are two forms of Vitamin A: (1) Retinoids, primarily as retinol, which are typically found in animal products, and (2) Carotenoids, which are provitamins typically found in plants and vegetables, such as carrots. Toxicity is usually from excess retinoids, and less commonly from carotenoids. Synthetic retinoids also exist, a well known example being isotretinoin use in treatment of cystic acne. 

After vitamin A is absorbed in the gut, it is stored in the liver, where it is subsequently converted into retinal and retinoic acid. A normal serum retinol concentration is 30-70 mcg/dL, but because it is fat soluble and stored in the liver, there is a significant potential for it to bioaccumulate over time. As a result, most hypervitaminosis A is from chronic ingestion, rather than acute ingestion. The recommended daily allowance is 2,300 IU (700 mcg retinol activity equivalents) in adult women and 3,000 IU (900 mcg RAE) in adult males. However, there isn’t a well established toxic dose level for vitamin A, with case reports varying in the levels of toxic ingestions for acute toxicity. However, a randomized double-blind trial compared a one time dose of 400,000 IU of vitamin A to placebo, and indicated no significant effects from the Vitamin A. 

Chronic ingestion of high amounts of vitamin A can lead to a range of symptoms. Hepatotoxicity may be seen at doses of 50,000-100,000 IU/day when taken chronically for months. 

But there have been reports of damage at lower doses. Still, there appears to be a correlation between degree of liver injury and the dose and duration of vitamin A. Additional presentations include skeletal hyperostosis leading to bone and joint pain, and increased bone turnover resulting in osteoporosis, increased fracture risk and hypercalcemia.  Patients may also have hair thinning, xerosis, pruritus, and desquamation due to thinning of epithelial tissue. 

Acute ingestions are very uncommon, but could occur due to massive overdose. The most well known example is from historical ingestion of polar bear liver (contains 34,600 IU/g) by Inuits and Arctic explorers. While exceedingly rare, there continue to be case reports of acute toxicity presenting after ingestion of animal liver products, especially fish liver, most commonly in Europe and East Asia. Symptoms can present quickly, sometimes within hours of an acute ingestion. The clinical presentation may include gastrointestinal (GI) involvement (abdominal pain, nausea, vomiting), skin involvement (desquamation, xerosis, erythema), liver damage, neurologic symptoms (headache, papilledema, scotoma, photophobia, seizures), anorexia, and drowsiness.  For acute ingestion, hepatotoxicity may be seen at extremely high doses >600,000 IU. Vitamin A has also been implicated in idiopathic intracranial hypertension (IIH), although the exact etiology is unclear. It is possible that it is due to disruption of cell membranes, resulting in obstructed cerebrospinal fluid drainage.

Case continued:

You begin to formulate your differential. With her abdominal symptoms, you wonder about any acute abdominal pathology, however her physical exam is largely benign. She has no adnexal tenderness or gynecologic complaints. Her headache and vision changes are concerning, and you worry about acute pathology such as stroke, cerebral venous sinus thrombosis, etc. Luckily the rest of her neuro exam is nonfocal. She is afebrile, and has no nuchal rigidity to make you suspect meningitis. Malignant hypertension is also low on your list because of her normal vitals. You wonder if maybe it’s a migraine, or elevated intracranial pressure. You decide to get a urine pregnancy test, abdominal labs, measure intraocular pressure, and perform a bedside ocular ultrasound to check for intraocular abnormalities. 

Lab workup is remarkable for a mild transaminitis and moderate hypercalcemia of 11.7 mg/dL. Otherwise all other labs are within normal limits. You decide to check her intraocular pressures, which are normal bilaterally. You then perform an ocular ultrasound. It is significant for increased optic nerve sheath diameter bilaterally, with OD measuring 6.5 and OS 6.8 mm (normal <6 mm), suggestive of elevated intracranial pressure. You obtain neuroimaging that is unremarkable for any acute intracranial pathology, space-occupying lesion/mass, or cerebral sinus thrombosis. You then perform a lumbar puncture, which results in an elevated opening pressure of 28 cm H2O (normal range of 7-18 cm H2O). 

You then remember a story you heard about people who got sick from vitamin A poisoning after eating animal liver, and go back to your patient to ask her about her recent fish ingestion. She says that her boyfriend went deep sea fishing with some friends last week, and brought back a large fish. She had recently read about fish-paté online. She loves to cook and tried to experiment with making her own paté from fish livers a few days ago. You wonder if she could have hypervitaminosis A from fish liver ingestion, and discuss the case with the Toxicology team. You decide to order a serum retinol level. Since it may take some time for the retinol level results to return, you continue supportive management and also consult Neurology.. 

Learning point 2: Management of hypervitaminosis A

For acute overdoses of vitamin A, you can consider GI decontamination with activated charcoal (50g) vs gastric lavage. With this patient, ingestion occurred a few days ago, making GI decontamination a low yield intervention. The rest of management consists of stopping vitamin A and continuing supportive care.

Because of the increased bone turnover, patients can be hypercalcemic. If it is severe (>14 mg/dL) or symptomatic, consider isotonic fluids to maintain a urine output of 100-150 cc/hr. You can also give calcitonin (4 IU/kg q12h) in more severe cases. Alternative treatments include loop diuretics, bisphosphonates, and glucocorticoids. 

Vitamin A is also associated with Idiopathic Intracranial Hypertension, as has occurred in this case. Be sure to consider other causes of headache and vision changes, as well as any secondary causes of intracranial hypertension (malignant hypertension, cerebral venous sinus thrombosis, etc). When treating elevated ICP secondary to hypervitaminosis A, follow standard IIH management. Acetazolamide is typically first line, beginning with about 500 mg twice daily.Continue to monitor the patient’s neurological and visual symptoms. Pursue additional neuroimaging such as MRI/MRV as indicated to further evaluate the etiology behind the elevated ICP/IIH. Symptoms should typically resolve with discontinuation of the vitamin A source and supportive treatment.

Vitamin A is metabolized into retinal and retinoic acid, which possess teratogenic properties. Therefore, it is important to check a urine pregnancy test in the setting of vitamin A use. Isotretinoin is an acne medication that is notorious for its teratogenicity. Prescriptions for this medication require a documented negative pregnancy test as well as a birth control regimen to limit occurence of pregnancy and is distributed through an FDA approved program called iPledge (https://www.ipledgeprogram.com/iPledgeUI/home.u).. 

Finally, vitamin A can result in hepatotoxicity (Figure 1). This occurs because it accumulates in the fat storing Ito cells, leading to cell hypertrophy and hyperplasia. With chronic excessive ingestion the cellular architecture may become disrupted leading to portal hypertension, further liver damage, eventually causing fibrosis and cirrhosis. Liver biopsy may be helpful in diagnosis.

Figure 1: Schematic demonstrating hepatotoxicity from excessive deposition of vitamin A in Ito cells of the Liver. Image credit to Goldfrank’s Toxicologic Emergencies (11th ed)

Case continued:

In conjunction with Toxicology and Neurology, you continue to monitor her and initiate acetazolamide for her elevated ICP and IV fluids for her hypercalcemia. You go back to reassess the patient and she states her headache has improved after the LP. You tell her she will be admitted for further monitoring, and that you are treating her for elevated intracranial pressure, possibly due to acute vitamin A toxicity. She is then transferred to the floor for further management.

A few days later you follow up and note that her serum retinol level has resulted with an elevated level of 110 mcg/dL (normal <95-100). With continued supportive care, her symptoms are improving. 

Takeaway points:

  • Herbal and Vitamin supplement use is common in the USA, with people often taking more than the recommended daily value.
  • Most hypervitaminosis ingestions do not have any serious sequelae, and it is exceedingly rare for there to be a poor outcome. 
  • The most common presentation of hypervitaminosis A is due to chronic ingestion of supratherapeutic amounts of vitamin A in supplements, however acute cases have been reported, particularly with ingestion of animal liver. 
  • Vitamin A toxicity is associated with fatigue, changes in hair, skin and bone, hepatotoxicity, increased ICP, and hypercalcemia.
  • Management is largely supportive, with symptom resolution after discontinuation of the offending agent. 

Resources

Chisholm, J. T., Abou-Jaoude, M. M., Hessler, A. B., & Sudhakar, P. (2017). Pseudotumor Cerebri Syndrome with Resolution After Discontinuing High Vitamin A Containing Dietary Supplement: Case Report and Review. Neuro-ophthalmology (Aeolus Press), 42(3), 169–175. https://doi.org/10.1080/01658107.2017.1367931

Dewailly E, Rouja P, Schultz E, et al. Vitamin A Intoxication from Reef Fish Liver Consumption in Bermuda. J Food Prot 1 September 2011; 74 (9): 1581–1583. doi: https://doi.org/10.4315/0362-028X.JFP-10-566

Farkas J. PulmCrit: Algorithm for diagnosing ICP elevation with ocular sonography. October 2017. https://emcrit.org/pulmcrit/pulmcrit-algorithm-diagnosing-icp-elevation-ocular-sonography/ 

Homma Y, Otani N, Ishimatsu S. A case report of acute vitamin A intoxication due to ocean perch liver ingestion. The Journal of Emergency Medicine, 2015; 49(1), 15-17. https://doi.org/10.1016/j.jemermed.2014.12.056

Lee AG, Wall M. Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis. https://www.uptodate.com/contents/idiopathic-intracranial-hypertension-pseudotumor-cerebri-clinical-features-and-diagnosis?search=idiopathic%20intracranial%20hypertension&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H20

Lee AG, Wall M. Idiopathic intracranial hypertension (pseudotumor cerebri):Prognosis and treatment. https://www.uptodate.com/contents/idiopathic-intracranial-hypertension-pseudotumor-cerebri-prognosis-and-treatment?search=idiopathic%20intracranial%20hypertension&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H1 

Nelson L, Howland M, et al. (2019). Goldfrank’s Toxicologic Emergencies (11th ed.). New York: McGraw-Hill Medical. 654-658.

Olson JM, Ameer MA, Goyal A. Vitamin A Toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532916/ 

Poison Control Center: 2018 Call Center Report. Children’s Hospital of PHiladelphia: PCC https://media.chop.edu/data/files/pdfs/poison-control-center-reports-2018.pdf

Sassan P, Burns D. Overview of vitamin A. https://www.uptodate.com/contents/overview-of-vitamin-a?search=vitamin%20A%20toxicity&source=search_result&selectedTitle=2~148&usage_type=default&display_rank=1#H16 

Schmitt C, Domangé B, Torrents R, de Haro L, Simon N. Hypervitaminosis A Following the Ingestion of Fish Liver: Report on 3 Cases from the Poison Control Center in Marseille. Wilderness Environ Med. 2020 Aug 26:S1080-6032(20)30113-7. doi: 10.1016/j.wem.2020.06.003. Epub ahead of print. PMID: 32861618.

Shane E, Berenson J.Treatment of hypercalcemia. https://www.uptodate.com/contents/treatment-of-hypercalcemia?search=hypercalcemia&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H13 

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s