Continuing Education Activity
Aflatoxins are metabolites produced by toxigenic strains of molds, mainly Aspergillus flavus and A. parasiticus which grow in soil, hay, decaying vegetation, and grains. Aflatoxin is produced by fungal action during production, harvest, storage, and processing of food. Aflatoxin toxicity may result in nausea, vomiting, abdominal pain, convulsions, and other signs of acute liver injury. Long-term exposure also leads to various complications like growth retardation, cirrhosis, and hepatocellular carcinoma. This activity describes the evaluation and management of aflatoxin toxicity and reviews the role of the interprofessional team in managing patients with this condition.
- Describe the epidemiology of aflatoxin toxicity.
- Outline the typical presentation of a patient with aflatoxin toxicity.
- Explain the treatment considerations for patients with aflatoxin toxicity.
- Review the importance of improving care coordination among the interprofessional team to enhance care coordination for patients affected by aflatoxin toxicity.
Aflatoxins are metabolites produced by toxigenic strains of molds, mainly Aspergillus flavus and A. parasiticus, which grow in soil, hay, decaying vegetation, and grains. Aflatoxin toxicity occurs due to acute or chronic exposure to aflatoxin.
The term "aflatoxin" is derived from the name of Aspergillus flavus. It was named around 1960 after its discovery as the source of a disease in turkey called "turkey X disease" in turkeys fed rations of peanuts and cottonseed.
Aflatoxins form one of the major groupings of mycotoxins. Aflatoxin is produced by fungal action during production, harvest, storage, and processing of food and feed. The U.S. Food and Drug Administration (FDA) considers it to be an unavoidable contaminant of foods. Aflatoxin toxicity has been well established in both humans and animals. Aflatoxin exposure can cause nausea, vomiting, abdominal pain, convulsions acutely, and its chronic exposure can also lead to various complications like hepatotoxicity, immunotoxicity, and teratogenicity. Aflatoxin is one of the major causes of hepatocellular carcinoma in developing countries.
There are different types of aflatoxin. Aflatoxin B1(AFB1) and aflatoxin B2(AFB2) are produced by both A. flavus and A. parasiticus, and AFB1 is believed to be the most potent among all aflatoxins. Aflatoxin M1(AFM1) is found in the fermentation broth of A parasiticus, but it and aflatoxin M2 are also developed when an infected liver metabolizes AFB1 and AFB2. AFM1 can be transmitted by milk.
AFB1 and AFM1 have been classified as group 1 and group 2B human carcinogens by the International Agency for Research on Cancer (IARC).
Around 25% of worlds crop is affected by mycotoxin, and the vast majority of that is aflatoxin. They are regularly found in improperly stored cassava, cottonseed, chili pepper, maize, wheat, millet, peanut, rice, sesame, sunflower seed, and many spices. Crops can be contaminated in two phases:
- Aspergillus species infect crops during growth and development.
- Contamination can build during storage or transport when exposed to warm, humid conditions or severe drought.
Animals fed on contaminated feed can pass aflatoxin metabolism products into eggs, milk products, and meat, and thus humans can be exposed.
Around 4.5 billion people living mostly in developing countries are exposed to largely uncontrolled amounts of aflatoxin. Children are particularly affected by aflatoxin exposure. It is associated with growth stunting, development delays, and liver damage ultimately leading to liver cancer. Many reports show an association between growth stunting and aflatoxin exposure in children. Also, epidemiological studies to establish a causal relationship between growth stunting and aflatoxin exposure are underway. Adults have a higher tolerance for Aflatoxin exposure than children, though still remain at risk. Hepatocellular carcinoma(HCC) is a well-established sequela of Aflatoxin exposure and 4.6 to 28.2% of all global cases of HCC can be caused by Aflatoxin. Around 25% of all high dose acute exposures may cause death.
There is evidence that the dose and duration of aflatoxin exposure has a major effect on the toxicology. Exposure to large doses, known as acute aflatoxicosis can lead to acute illness and death. High-level exposure produces acute hepatic necrosis, resulting in sequelae of cirrhosis or HCC afterward. Acute liver failure manifests as fever, nausea, vomiting, abdominal pain, bleeding, digestion problems, edema, malabsorption, mental changes, and coma.
Exposure to chronic sublethal dose has nutritional and immunologic effects, which is largely contributed to DNA Alkylation by aflatoxin B1.
Irrespective of the dose, all exposures have a cumulative effect on the risk of cancer. The carcinogenic effect of aflatoxin metabolites is via intercalation into DNA and alkylation of the bases by epoxide moiety. This results in mutations in the p53 gene, an important gene in preventing cell cycle progression in instances of DNA mutations or signaling of the programmed cell death(apoptosis).
The liver is the main organ affected by the toxic effects of Aflatoxin. Histopathologic changes seen in acute hepatotoxicity due to aflatoxin toxicity are fatty changes in hepatocytes, acute hemorrhagic necrosis, and bile duct proliferation.
Also, chronic Aflatoxin exposure may present with histopathologic features of cirrhosis - nodular degeneration and fibrosis leading to distortion of the hepatic architecture and HCC- well-vascularized tumors with wide trabeculae, small cell changes, vascular invasion, prominent acinar pattern, atypia, mitotic activity, and absence of Kupffer cells.
The most common route of entry of Aflatoxin into the human body is ingestion. After entry, it is metabolized by microsomal mixed-function oxidase (MFO) enzymes in the liver to reactive epoxide intermediate. MFO is an enzyme of CYP450 superfamily. This epoxide intermediate(8,9-epoxide) is responsible for DNA mutation. The predominant mutation has been identified as the G→T transversion in codon 249 of the p53 tumor suppressor gene. This epoxide can also bind to other macromolecules like RNA and proteins, causing cellular dysregulation. It is also responsible for the inhibition of proteins, RNA, and DNA synthesis. Another pathway leading to toxicity is depletion of Glutathione and subsequent toxicity from Reactive Oxygen Species. Other pathways of carcinogenesis, catalyzed by Prostaglandin H (PGH) synthase and lipid peroxidase (LPO) is under study.
Another pathway of Aflatoxin metabolism is by Microsomal biotransformation of AFB1 by hydroxylation. It leads to the formation of less toxic and non-polar metabolites like AFM1 and Aflatoxin Q1 (AFQ1). Also, enzymatic and non-enzymatic action on AFB1 can produce a dialdehyde form. Aflatoxin dialdehyde is acted by aflatoxin aldehyde reductase (AFAR) and excreted through urine as dialcohol. It can also bind proteins, mostly albumin.
History and Physical
Whenever aflatoxin toxicity is suspected, a careful history regarding the dietary habits of the patient, similar features in family and community, patient occupation, and environmental exposure should be carefully assessed. Health implications from aflatoxin exposure depend on various factors ranging from dose and duration of exposure to a person's age, gender, health, immunity, diet, and environmental factors. Patients with aflatoxin toxicity may have a range of non-specific signs and symptoms, but the predominant features are of hepatotoxicity.
Acute toxicity results when someone takes in a high amount of aflatoxins in a very short time. Most common signs and symptoms are:
- Yellowing of skin and sclera (icterus)
- Abdominal pain
Adults usually have a good tolerance to aflatoxin, and, in the reported deaths due to acute poisonings, it is the children who usually die.
Chronic toxicity occurs by consuming small amounts of aflatoxins at a time but over a prolonged period. Chronic exposure to aflatoxin can cause:
- Impaired growth and development especially in children
- Hepatocellular carcinoma presenting as weight loss, abdominal mass, anorexia, nausea, vomiting, bleeding, psychosis, etc.
An evaluation of a suspected case of aflatoxin toxicity can be done by measuring the aflatoxin level in food consumed by the patient, or the aflatoxin metabolites in the patient's body.
Some popular methods to detect aflatoxin exposure in food and feed are:
- Thin-layer chromatography (TLC)
- High-performance liquid chromatography (HPLC)
- Liquid chromatography-mass spectroscopy (LCMS)
- Enzyme-linked immune-sorbent assay (ELISA)
ELISA using AfB1-lysine (metabolite of AFB1) concentration in the patient blood can help detect aflatoxin.
There are other techniques used to detect levels of aflatoxin in the human body. One method is the measurement of the AFB-guanine adduct in the urine of patients. This technique measures only recent exposure during the past 24 hours. Due to the varying half-life of this product, its level may vary from time to time based on diet. Therefore it is not ideal for assessment of long term exposure. Measurement of AFB-albumin adduct level in the blood serum is another method to detect Aflatoxin exposure over a long period.
Additionally, the assessment of liver function test to include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, aspartate transaminase, alanine transaminase) is done. Imaging of the liver using ultrasonography and CT-scan may help to study liver involvement further.
Other tests include the basic metabolic panel, complete blood count, and renal function depending upon the patient presentation and features.
Treatment / Management
Acute aflatoxicosis has no known antidote. The management is mainly focused on symptomatic and supportive care. Management options may include suitable intravenous fluids, vitamin B, and vitamin K administration. A high-quality protein-restricted diet with adequate carbohydrates is suggested. Also, fever, nausea, vomiting, and other patient complaints should be carefully addressed. If signs and symptoms are suggestive of acute liver failure, it must be recognized early, and subsequent care should follow in a critical care setting.
Aflatoxin toxicity is characterized by its toxic effects in the liver. So the presenting symptoms are similar to other causes of liver injury.
Differential diagnosis of acute aflatoxicosis is as follows:
- Drug intoxication (acetaminophen, tetracycline, halothane, isoniazid, ecstasy)
- Amanita species poisoning
- Infection (Hepatitis-A/B/C/D/E, Cytomegalovirus, Ebstein Barr virus)
- Immunological (autoimmune hepatitis)
- Metabolic (alpha-1 antitrypsin deficiency, Wilson disease)
- Venoocclusive diseases
Prognosis of aflatoxin toxicity depends upon the dosage and duration of exposure, nutritional status, immunity, and health. Acute exposure may cause nausea, vomiting, and abdominal pain, which may warrant symptomatic treatment only. Acute high dose intoxication can be fatal in children. Chronic exposure to low dose aflatoxin can lead to cirrhosis and hepatocellular carcinoma, which are irreversible disease conditions with high morbidity and mortality.
Acute intoxication of a high dose of aflatoxin may result in fulminant hepatic failure and rhabdomyolysis. Chronic exposure to aflatoxin may result in cirrhosis of the liver and ultimately lead to hepatocellular carcinoma. Also, gall bladder carcinoma is associated with chronic toxicity.
In children, aflatoxin exposure is associated with growth stunting and impaired development.
Deterrence and Patient Education
Aflatoxin toxicity has important impacts on agriculture, livestock, and human health. Providing knowledge to the public about aflatoxin toxicity will help to ensure food safety and decrease the incidence of aflatoxin related health problems. Aflatoxins are found in various cereals, oilseeds, spices, nuts, and also animal products. Patients should be wise in the selection of food products. Farmers especially should keep an eye on possible aflatoxin contamination during growth, harvesting, storage, and transportation of crops.
The public should be informed about early signs of aflatoxin toxicity and encouraged to seek medical help without delay. Some studies have shown that a regular diet consisting of apiaceous vegetables, such as celery, carrots, parsley, and parsnips, may help reduce the carcinogenic effects of aflatoxin.
Enhancing Healthcare Team Outcomes
The management and mitigation of aflatoxin toxicity encompass a wide range of professionals from farmers, agriculture engineers, food technicians, veterinary physicians, and other health professionals. Protecting food from Aflatoxin is the major step in limiting the health impacts of Aflatoxin. Health professionals should be aware of the prevalence of Aflatoxin toxicity and food practices in the region in which they live. Exposure in a patient warrants a food checkup of the patient as well as the family and community. This process helps trace the source of exposure and limits its effect.
The majority of presenting cases of aflatoxin toxicity are late presentations after chronic exposures. Aflatoxin toxicity is one of the major causes of liver cirrhosis and hepatocellular carcinoma in developing countries. Acute high dose exposures are rare and most severe cases occur in children. Recognition of this condition throughout multiple contact points in the healthcare system is imperative. High dose acute intoxication may require admission and close monitoring as life-threatening fulminant hepatitis will need intensive care support. [Level 5]