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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 food production, harvest, storage, and processing. Dietary exposure to aflatoxins may result in severe toxic and carcinogenic outcomes in humans and animals. 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. Objectives: Describe the epidemiology of aflatoxin toxicity. Outline the typical presentation of a patient with aflatoxin toxicity. Explain the treatment options 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. Access free multiple choice questions on this topic.

Aflatoxins are metabolites produced by toxigenic strains of molds, mainly Aspergillus flavus and Aspergillus parasiticus, which grow in soil, hay, decaying vegetation, and grains. Aflatoxin toxicity results from acute or chronic exposure to aflatoxin. The term "aflatoxin" is derived from the genus Aspergillus and the species Aspergillus flavus. It was named around 1960 after its discovery as the source of a disease in turkey called turkey X disease.[1] It was also observed to be a cause of cancer in rainbow trout fed peanut and cottonseed meals. Dietary exposure to aflatoxins may result in severe toxic and carcinogenic outcomes in humans and animals. The symptoms and biomarkers of exposure, production, and metabolism of aflatoxin, as well as methods to reduce aflatoxin toxicity, have been widely investigated over the last 50 years.[2] Studies have mostly focused on humans, agricultural animals, or laboratory model species and have identified species-specific aspects of aflatoxin toxicity.[3][4][3] Aflatoxins are among the major groups of mycotoxins. Aflatoxin is produced by fungal action during the production, harvest, storage, and processing of food and feed. The U.S. Food and Drug Administration (FDA) considers it an unavoidable contaminant in food. Aflatoxin exposure can cause nausea, vomiting, abdominal pain, and convulsions acutely, and its chronic exposure can also lead to complications like hepatotoxicity, immunotoxicity, and teratogenicity. Aflatoxin is 1 of the major causes of hepatocellular carcinoma in developing countries.[5] Different types of aflatoxin, such as aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2), are produced by both A. flavus and A. parasiticus. AFB1 is considered the most potent of the 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.[6] AFB1 and AFM1 have been classified as Group 1 and Group 2B human carcinogens, respectively, by the International Agency for Research on Cancer (IARC).[7][8]

Approximately 25% of the world's crop is affected by mycotoxins, most of which are aflatoxins. 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 2 phases: Aspergillus species infect crops during growth and development. Contamination can accumulate during storage or transport under warm, humid conditions or severe drought. Animals fed contaminated feed can pass aflatoxin metabolites into eggs, milk, and meat, thereby exposing humans.[8] Structural derivatives of difurocoumarin and aflatoxins are commonly produced by strains of A. flavus, A. parasiticus, and A. minus. Furthermore, many other Aspergilli, such as Emericella teleomorphs, are aflatoxigenic. Named according to their green or blue color under UV light, there are 4 primary aflatoxins. Of these, AFB is the most mutagenic, hepatotoxic, and prevalent worldwide.[9] The following is a concise list of all the risk factors that can lead to aflatoxin exposure in humans and livestock: Contaminated feed (corn, cottonseed, peanuts, sorghum, figs, tree nuts, and spices) [10] Stress from drought or insect damage [11] Warm and humid conditions Temperatures near 30 C (86 F) Substrate, CO levels, time, and other environmental factors

Approximately 4.5 billion people in developing countries are exposed to substantial levels of aflatoxin.[8] Children are particularly affected by aflatoxin exposure. It is associated with growth stunting, development delays, and liver damage, ultimately leading to liver cancer. Numerous studies have reported an association between growth stunting and aflatoxin exposure in children.[12][13] Also, epidemiological studies are underway to establish a causal relationship between growth stunting and aflatoxin exposure. Adults have a higher tolerance for aflatoxin exposure than children, though they remain at risk. Hepatocellular carcinoma (HCC) is a well-established sequelae of aflatoxin exposure, and 4.6% to 28.2% of global HCC cases are attributable to aflatoxin. Around 25% of all high-dose acute exposures may cause death.[14][15][16]

Evidence shows that the dose and duration of aflatoxin exposure significantly affect toxicology. Exposure to large doses, known as acute aflatoxicosis, can lead to critical 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, digestive problems, edema, malabsorption, mental changes, and coma. Exposure to chronic sublethal doses has nutritional and immunologic effects, mainly contributing to DNA alkylation by aflatoxin B1. Irrespective of the dose, all exposures have a cumulative effect on cancer risk. The carcinogenic effect of aflatoxin metabolites is mediated by intercalation into DNA and by alkylation of the bases via the epoxide moiety. This results in mutations in the p53 gene, an essential gene that prevents cell cycle progression in response to DNA damage or signaling for programmed cell death (apoptosis).[16][17][18] Evaluating the results of human exposure to aflatoxin requires consideration of multiple factors. Firstly, not all ingested aflatoxin is biologically significant; a proportion of consumed aflatoxin is detoxified. The relationship between DNA-relevant exposure and carcinogenesis is well understood enough to estimate the effects of changes in aflatoxin concentrations in food on human risk.[19] Secondly, other aspects of the diet could significantly define the consequences of aflatoxin ingestion. Dietary intake of antioxidant vitamins (vitamins A, C, and E) can influence aflatoxin toxicity.[20] Thirdly, the extent of biological exposure is influenced by infections with the hepatitis B and hepatitis C viruses.

The liver is the primary organ affected by aflatoxin toxicity. Histopathologic changes in acute aflatoxin hepatotoxicity include hepatocellular fatty change, acute hemorrhagic necrosis, and bile duct proliferation. Also, chronic aflatoxin exposure may present with histopathologic features of cirrhosis, such as nodular degeneration and fibrosis, leading to distortion of the hepatic architecture and HCC, which are well-vascularized tumors with wide trabeculae, small cell changes, vascular invasion, prominent acinar pattern, atypia, mitotic activity, and absence of Kupffer cells.[10][16][21] See Image. Hepatocellular Carcinoma.

Whenever aflatoxin toxicity is suspected, a thorough history of the patient's dietary habits, similar complaints in family and community members, occupation, and environmental exposures should be obtained. Health implications of aflatoxin toxicity depend on several factors, including the dose and duration of exposure, a person's gender, age, health, immunity, environmental factors, and diet. Patients with aflatoxin toxicity can have a range of non-specific signs and symptoms; however, the most prominent features are those of hepatotoxicity. Adults generally have a good tolerance to aflatoxin, and children have higher mortality. Children tend to have severe malnutrition secondary to aflatoxin toxicity.[23] Acute toxicity results when someone consumes a high level of aflatoxins in a very short time. The most common signs and symptoms are: Nausea Yellowing of skin and sclera (icterus) Itching Vomiting Bleeding Abdominal pain Lethargy Edema Convulsions Coma Death Chronic toxicity occurs through consuming small amounts of aflatoxins over a prolonged period. Chronic exposure to aflatoxin can result in the following: Impaired growth and development, especially in children Immunosuppression Hepatocellular carcinoma (weight loss, abdominal mass, anorexia, vomiting, nausea, bleeding, psychosis) [8][10] Maternal exposure to aflatoxin is associated with a higher occurrence of preterm birth and late-term miscarriage.[24]

An evaluation of a suspected case of aflatoxin toxicity can be performed by measuring aflatoxin levels in the patient's consumed food or aflatoxin metabolites in the patient's body. Some popular methods to detect aflatoxin exposure in food and feed are: Thin-layer chromatography [25] High-performance liquid chromatography Liquid chromatography-mass spectroscopy Enzyme-linked immune-sorbent assay [26] Enzyme-linked immune-sorbent assay for AFB1-lysine (a metabolite of AFB1) in the patient's blood can aid in detecting aflatoxin. Other techniques are used to detect aflatoxin levels in the human body. One method is to measure the AFB-guanine adduct in patients' urine.[27] This technique measures only recent exposure during the past 24 hours. Due to the product's variable half-life, its level may fluctuate with diet. Therefore, it is not ideal for assessing long-term exposure. Measuring AFB-albumin adduct levels in serum is another method for detecting aflatoxin exposure over extended periods. Additionally, liver function tests include prothrombin time, international normalized ratio (INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Imaging the liver with ultrasonography and computed tomography may help further assess liver involvement. Other tests include a basic metabolic panel, a complete blood count, and renal function tests, depending on the patient's presentation and clinical features.[8][28][29]

Acute aflatoxicosis has no known antidote, and removing contaminated food and replacing it with an uncontaminated food source may help prevent further poisoning. Management is primarily focused on symptomatic and supportive care. Meeting optimal dietary requirements through supplementation may aid recovery. Largely, the focus of management should be on symptomatic control. Acute symptoms, such as fever, nausea, vomiting, and convulsions, should be carefully addressed. If signs and symptoms suggest acute liver failure, it must be recognized early, and subsequent care should follow in a critical care setting.[30][31] Once hepatocellular carcinoma develops, several treatment options are available, including: Surgical resection Resection + ablation Orthotopic liver transplantation Thermal ablation Percutaneous alcohol (ethanol) injection Transarterial embolization Chemoembolization Radiotherapy Systemic chemotherapy + radioembolization [32]

Aflatoxin toxicity is characterized by its toxic effects on the liver. So the presenting symptoms are similar to those of other causes of liver injury. Differential diagnoses of acute aflatoxicosis include the following: Drug intoxication (acetaminophen, tetracycline, halothane, isoniazid, ecstasy) Amanita species poisoning Infection (hepatitis-A/B/C/D/E, cytomegalovirus, Epstein-Barr virus) Immunological (autoimmune hepatitis) Metabolic (alpha-1 antitrypsin deficiency, Wilson disease) Veno-occlusive diseases [30][31]

The prognosis of aflatoxin toxicity depends on the dose and duration of exposure, nutritional status, immune status, and overall 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 with a high dose of aflatoxin may result in fulminant hepatic failure and rhabdomyolysis. Chronic exposure to aflatoxin may result in liver cirrhosis and ultimately lead to hepatocellular carcinoma. Also, gall bladder carcinoma is associated with chronic toxicity. In children, aflatoxin exposure is associated with growth stunting, nutrition deficiencies, and impaired development.[16][30]

Aflatoxin toxicity has important impacts on agriculture, livestock, and human health. Providing the public with knowledge about aflatoxin toxicity helps ensure food safety and reduce the incidence of aflatoxin-related health problems. Aflatoxins are found in various kinds of cereal, oilseeds, spices, nuts, and animal products. Therefore, patients should be wise in their selection of food products. In addition, farmers should keep an eye on possible aflatoxin contamination during crops' growth, harvesting, storage, and transportation. 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.[33]

The management and mitigation of aflatoxin toxicity encompasses a wide range of professionals, such as farmers, agricultural engineers, food technicians, veterinary physicians, and other health professionals. Protecting food from aflatoxin contamination is a significant step toward limiting its health impacts. Health professionals should be aware of the prevalence of aflatoxin toxicity and of food practices in the region where they live. Exposure in a patient warrants a food checkup of the patient, the family, and the 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 1 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 across multiple points of contact within the healthcare system is imperative. An interprofessional healthcare team is critical to the successful identification and management of these toxicities. High-dose acute intoxication may require admission and close monitoring, as life-threatening fulminant hepatitis requires intensive care support.[8][16]