Continuing Education Activity

Niacin is a medication used in the management and treatment of hyperlipidemia. It is in the vitamin supplement class of drugs. This activity reviews the toxic reactions commonly associated with nicotinic acid use. It will highlight the pathological mechanisms of action, along with the evaluation and treatment of poisoning from this drug, that the health care team will need to understand when managing this condition.

Objectives:

• Identify the etiology of niacin toxicity in its different formulations.
• Review the evaluation of niacin toxicity.
• Outline the treatment and management options available for niacin toxicity.
• Describe interprofessional team strategies for improving care coordination and communication to advance and improve outcomes.

Introduction

At a time when so many people are taking large amounts of supplements, niacin toxicity is something of which to be aware. Niacin, also known as vitamin B3, is required in regular amounts, usually acquired through diet. Niacin, in its forms of nicotinic acid and nicotinamide, is mainly metabolized in the liver. The primary use of nicotinamide today is to treat nutritional niacin deficiency. For many years, the main clinical use of nicotinic acid was the treatment of hyperlipidemia. This approach changed as statin drugs became the mainstay therapy. Recent trials suggest no significant improvement by adding niacin to statin treatments.[1][2] This review will focus on the various clinical manifestations and complications of niacin toxicity.  

Etiology

Much less common now than in the past, niacin deficiency was the cause of pellagra. Other observed reactions of niacin deficiency are an increased risk of developing diabetes in non-diabetic patients and increased fasting glycemic levels in people with diabetes.[3][4][5] However, at higher doses, niacin can cause more serious reactions. These include but are not limited to, hypotension, hepatotoxicity, and multiple organ failure.[6] 

Energy drinks can contain large quantities of vitamins, including niacin. There have been isolated reports of acute hepatitis involving ingestion, which appear to be the result of high amounts of niacin from energy drinks.[7] Another trend that has resulted in toxicity is using niacin to help pass a pre-employment drug test, following the online theory that niacin speeds up metabolism to help eliminate toxins. 

Epidemiology

The incidence of niacin poisoning is reflected in the most recent report (2018) of the American Association of Poison Control Center’s National Poison Data System.  Of the approximately 792 single exposures, there were no documented gender differences, and the most common age groups fell into a bimodal distribution, with 248 patients aged five years or less, and 397 patients aged 20 years or older. There were 405 unintentional exposures and 150 intentional exposures; 232 adverse reactions were documented, and 227 cases received treatment in the hospital. The morbidity breakdown of the outcomes was as follows: 71 individuals experienced no problems, 255 had minor toxicity, 61 sustained moderate toxicity, one had a significant reaction, and no one died.[8]

Pathophysiology

The well-known side effect related to niacin is flushing, most commonly in the face, arms, and chest, which typically occurs within 30 minutes of ingestion and abates after 60 minutes.[9] This vasodilation from niacin appears to be caused by niacin interacting with a G-protein-coupled receptor 109A on Langerhans cells in the epidermis, which results in activation of prostaglandins.[10][11] This effect can occur at prescribed doses of immediate-release (IR) niacin and is known to affect patient compliance negatively.

Niacin can also cause serious hepatoxicity that ranges from a mild elevation of liver enzymes to acute liver failure. The hepatocellular injury pattern is more common than the cholestatic damage pattern. Clinical manifestations are jaundice, itching, fatigue, nausea, and vomiting. Early in the course of liver injury, transaminase levels can elevate significantly but may normalize with the removal of the offending agent. The thought is that there is a direct toxic effect similar to acute hepatic necrosis. Biopsy has revealed centrilobular necrosis. The severity of toxicity seems to be dose-dependent and more commonly involves sustained-release (SR) preparations.[12]  

Niacin associated hepatotoxicity is generally related to ingestions of around 3 grams per day.  In contrast, the more common symptom of flushing can occur at doses as low as 30 mg per day. Niacin is broken down in the liver via two pathways. One pathway has a low binding capability but can handle a lot of nicotinic acid substrate as it conjugates it with lysine into nicotinuric acid, which triggers the prostaglandin mediated flushing. The other pathway binds stronger to the substrate that it encounters. It is easily overwhelmed, and its by-products build up to damage the liver. This route processes the sustained release form.[13] The observed microvascular steatosis of liver damage is probably a reflection of mitochondrial injury with a resulting prothrombin time elevation, increased ammonia level, and normal bilirubin value.

History and Physical

Common complaints include flushing, itching, nausea, headache, vomiting, light-headedness, and epigastric pain.  The patient may or may not volunteer that they are taking supplemental products containing niacin, and the clinician should specifically query the patient about these substances. The patient may be hypotensive on the exam; the skin may or may not be flushed, they may have hepatomegaly and/or be jaundice, and they can have altered mentation. The presentation could lead the provider to assess that the patient is having anaphylaxis or an allergic reaction.[14]

Evaluation

A 12-lead electrocardiogram should be performed to look for QT-prolongation, QRS-widening, or any arrhythmias. Blood gas and a chemistry panel should be ordered, in addition to a complete blood count, liver panel, and prothrombin time.  As with any other potentially toxic ingestion, the physician should screen for co-ingested substances. While a specific nicotinic acid level can be ordered, the results will not come back in time to alter management, and should not be relied on to make the diagnosis. There is rarely an imaging study that would have any utility in the diagnosis of niacin toxicity. Finally, it is important to remember that a diagnosis of niacin toxicity should be one of exclusion.  

Treatment / Management

The emergency department assessment begins with rapid assessment and stabilization of the airway, breathing, and circulation, in addition to finger-stick glucose, oxygen saturation, and core temperature. Re-warming for hypothermia, dextrose infusion for hypoglycemia, in addition to intravenous crystalloid volume replacement may be necessary.  In rare cases, a bicarbonate drip may be indicated, or vasopressor support. Some severe cases have required transfusion of fresh frozen plasma or packed red blood cells. In patients who develop severe hepatotoxicity, consultation with gastroenterology is necessary for consideration of N-acetylcysteine (NAC) therapy and possible liver transplant. While the flushing can be alarming to the patient, it is self-limiting and does not require medication, although it would be responsive to the anti-prostaglandin properties of non-steroidal anti-inflammatory drugs such as aspirin or ketorolac. Nevertheless, in most cases, discontinuation of the niacin product, along with reassurance and follow-up, will be the only treatment indicated. 

Differential Diagnosis

The approach to the consideration of other possibilities when screening for niacin toxicity is to consider other conditions that present with flushing, with or without associated gastrointestinal symptoms[15]:  

• If the flushing is associated with angioedema, the clinician should consider anaphylaxis. This response is triggered by an Ig mediated effect on mast cells, basophils, and eosinophils, which releases inflammatory mediators.  Epinephrine counteracts this cascade.  
• Panic attack, dumping syndrome, rosacea, thyroid storm, or hyperthyroidism
• Food or preservative allergies
• Medications, like metronidazole, can precipitate disulfiram reactions.  
• Scombroid poisoning, which is histamine-mediated
• Cardiac medications (adenosine, beta-blockers, calcium-channel blockers)
• Parenteral antimicrobials (ceftriaxone, vancomycin, amphotericin-B)
• Phosphodiesterase inhibitors (erectile dysfunction drugs)
• Black widow envenomation
• Anticholinergic medications and plants (e.g., jimsonweed and deadly nightshade) can cause anticholinergic toxicity, which can present with flushing as one of its symptoms.  Through its mechanism of action, physostigmine acts to reverse the poisoning by promoting cholinergic stimulation.  
• Seratonin syndrome can present with flushing, in addition to delirium, hyperreflexia, hyperthermia, and tachycardia. This reaction is due to excessive stimulation of 5-HT2A/5HT1A receptors. A nonselective serotonin antagonist like cyproheptadine may help treat this, along with benzodiazepines.

In cases involving liver damage, the extensive differential for elevated liver function tests would be applicable. The clinician must consider:

• Drugs like amiodarone, isoniazid, and methotrexate
• Over-the-counter medications like acetaminophen
• Hepatotoxic species of mushrooms like Amanita phalloides (i.e., "death cap")
• Alcohol misuse

Prognosis

Flushing is self-limited and usually requires no treatment.  Most patients, even those who sustain significant elevations of liver function tests, do very well so long as they discontinue the niacin, especially the SR formulations.

Complications

The flushing, headache, lightheadedness, itching, nausea, and vomiting are self-limited as long as the patient stops the supplement. Hypotension, coagulopathy, and metabolic acidosis improve with supportive therapy. Complications of niacin toxicity are limited to liver injury in rare cases. Occasionally, this can progress to fulminant hepatic failure necessitating transplantation or resulting in death.[16]

Deterrence and Patient Education

It is essential to ask the patient about over-the-counter medications and supplements. One would use the history to explore the specific type of vitamin compounds, especially if there is a slow-release preparation. It is important to find out what is motivating the patient to take the supplement, especially if they found the information on the internet. 

Pearls and Other Issues

The clinician must keep in mind that niacin toxicity is a diagnosis of exclusion. Many other conditions can cause liver damage, including other dangerous ingestions. The current clinical context is such that niacin is now less common in the treatment of hyperlipidemia, so it would less likely appear as prescribed patient medication. It would more likely be a supplement. 

Enhancing Healthcare Team Outcomes

The clinician has many resources available to help detect potentially dangerous supplements that patients are taking. Consult a toxicologist when needed, or Poison Control Centers are available around the clock to provide support.