Gastrointestinal Poisoning

Gastrointestinal Poisoning2009 Edition

Forensic Medicine & ToxicologyDr. Willis Ochieng

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Poisoning depends very much on the structure of the organ. The gastrointestinal tract is an external tube passing through

the body and is the major route of exposure to many poisons.◦ It contains a big fraction of metabolic enzymes required for its

protection against poisons especially xenobiotics on contact and for the purpose of digestion.

Due to the presence of these enzymes, it is sensitive to rapid autolysis and post-mortem alterations.

Exposure pattern of poisons may be acute such as in suicide or subchronic or chronic. ◦ Exposure pattern produces different types of lesions. The chronic

exposure may cause thickening of the muscular layer or result in tumour depending on the duration of the toxic insult.

Because of the high proliferative and metabolic activities of mucosa, the gastrointestinal tract is very sensitive to poison mediated injury than are other most organ systems.

Different portions of the gastrointestinal tract respond differently to toxic insults due to structural differences.

Poisoning SusceptibilityIntroduction-1

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Oesophagus relatively has a marginal blood supply and does not heal quickly following traumatic injury as other portions of the gastrointestinal tract.

Cardia is the first glandular portion of stomach, followed by fundus and pylorus distally. ◦ Fundic mucosa contains parietal (oxyntic), chief (zymogen) and enteroendoctrine

cells which may be activated by the presence of xenobiotics, vagal nerve stimulation, gastric distension or by gastrin release.

The morphology of small intestine characterised by the presence of absorptive villi and crypt enzymes with specific functions facilitate the absorption of poisons.

Apical membranes are membrane-bound ATPases, alkaline phosphatases and loosely bound lactases, maltases and other digestive enzymes. ◦ Toxicological damage to membrane bound proteins can influence the viability of the

mucosal epithelial cells and nutritional status and cause a functional disorder. Lymphocytes, many IgA-producing plasma cells, mucosal mast cells

and eosinophils are present throughout the villi and around the crypts. The large intestine. The presence of bacteria in large intestine is of

toxicological significance because they may lead to activation of poisons.

Poisoning SusceptibilityIntroduction-2

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The intraluminal contents move down the tract due to intestinal motility and peristalsis.

Cholinergic mechanism plays a major role and can be affected by cholinomimetic xenobiotics such as drugs and chemicals in food. ◦ The nervous input includes both stimulatory and inhibitory

fibres. Sympathetics, endogenous or exogenous through the

effects on sympathetic nerves can reduce blood flow and motility of the tract and cause reduction or cessation of muscle motor activity (ileus). ◦ Spasm is another functional disorder which is due to over

muscular stimulation. ◦ Intoxications by various cholinergic and sympathomimetic

agents will thus cause gastrointestinal tract functional disorders.

Poisoning Susceptibility Introduction-3

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Poisons may hasten or stagnate the gut content movement along it by nerve fibre interferences.

They can also interfere with the epithelial transport mechanisms and lead to malabsorption of nutrients with undesirable consequences like malnutrition or diarrhoea.

Poisons which damage junctional complexes between enterocytes, and interfere with hydrostatic pressure gradients may lead to increased water loss in stool. ◦ Some bacterial toxins and laxative preparations act in this

way. ◦ There are other poisons whose presence in the

gastrointestinal tract may lead to increased absorption of nutrients other than diarrhoea.

Mechanism Of Gastrointestinal Poisoning

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Toxic impact on the mucosa is followed by a response to maintain a functional homeostasis of the gut.

Mucosa is the first site exposed to ingested poisons directly. This would imply the greatest vulnerability to toxicosis.

This, noticeably, is not the case because the gastrointestinal tract has the capacity for metabolism of the poison and a large surface area that permits extensive contact between the toxic compound and the multiple toxin metabolising enzymes.

Furthermore, mixing the toxin with luminal contents dilutes the toxin and its effects.

Mucosal ability to produce mucus and the short half life of the mucosal epithelial cells effectively protects cells or removes those with molecular damage on time preventing the possible onset of carcinogenesis.

Furthermore, it has a rapid epithelial restructuring which is considered as the mucosal primary defence mechanisms throughout the gastrointestinal tract.

Membrane resealing is a key process in maintaining an intact epithelial layer if toxicosis has not caused a wide spread and severe loss of epithelial cells. Sub-lethal epithelial toxic injury can thus be easily resealed.

Mucosal Response

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 Mucosa is a site with a detoxification facility against exogenous poisons. ◦ It has high enzymic activities which can modify a high concentration of orally

ingested xenobiotics prior to their absorption into the blood stream. These exogenous substances may either be detoxified or toxified by the

intestinal P-450 enzyme activities which is about 30% that of the liver. The dual properties of epithelial cells make them be able to absorb and

remove compounds from the circulating blood and the intestinal lumen, showing that absorption is a two way process. ◦ Vascular toxins can thus be secreted into the gut.

Ingested materials may also be metabolised by intestinal bacteria producing reductases, hydolases, demethylases, -glucuronidases and –glucosidases contributing mainly in detoxification processes but may also cause toxification in certain cases.

There are about 1010 bacteria per gram of human faeces. ◦ Antibiotics affect these microbes and must be used with caution. ◦ They cannot only modify bacterial populations in the gastrointestinal tract but can also

depress neuroeffector and neuromuscular transmission. ◦ This can impair mucosal motility with a possible facilitation of proliferation of some

bacteria such as Clostridium which is the cause of pseudomembranous colitis following a long exposure to some aminoglycoside antibiotics.

Mucosal Detoxification Metabolism

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Enterohepatic recycling of compounds is to a large extent made possible by the presence of the gut bacteria.

This is a condition when the orally ingested substances are absorbed in the gastrointestinal tract enter the portal circulation, go to the liver, and then return to the gastrointestinal tract via biliary excretion only to be reabsorbed back into the vascular system.

The amount of compound that is excreted in the faeces is controlled by the lipophilicity of the compound and the extent of the metabolism that alters this lipophilicity.

It therefore means that the combined biotransformation of both the liver and intestine can substantially affect the toxicity of the ingested compound.

Enterohepatic Poison Recycling

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 Inflammation (gastritis, enteritis, colitis) is a toxic response in many lesions of the gastrointestinal tract regardless of the different underlying mode of toxicosis.

The consequence may manifest as ulceration, haemorrghage, hyperplasia and perforation in severe cases.

These may culminate into complications such as septicaemia, bacteremia and neoplasia which is life threatening.

Reaction to InjuryInflammatory Response

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 The exocrine pancreas is composed of two basic parenchymal types of cells namely acinar and ductal cells.

Acinar cells synthesise and secrete zymogen by exocytosis of granules into the acinar lumen in response to various stimuli. ◦ These exocrine cells synthesise and store digestive enzymes as inactive

proenzymes which are activated by cleavage in the intestinal lumen. Duct cells secrete water and bicarbonate, which buffer the

pancreatic secretion at about pH 8.3, a pH which favours the stability of the proenzymes.

Toxic exposure to pancreas occurs principally by oral route but can also occur by other conventional routes. ◦ Oral overdose often may lead to a reflux of the poison during bowel movement

and be absorbed into the pancreatic duct reaching duct cells. Both cell types contain a small amount of phase I and II

metabolic enzymes and participate in the detoxification processes. ◦ A toxification of exogenous substances is also possible.

A wide spectrum of environmental chemicals has been implicated in exocrine pancreas poisoning. ◦ Of great importance to us is alcohol. Alcohol appears to have direct cytotoxic

effects on the pancreas which alters pancreatic acinar function

Pancreatic Poisoning-1

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The endocrine pancreas is composed of alpha () secreting glucagon, beta () secreting insulin and delta () secreting somatostatin cell types. ◦ The cells are the most abundant and the most important toxicologically.

Chemicals and poisons may increase or decrease insulin secretion resulting in diabetes mellitus.

There are two types of this condition. Insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). ◦ There is evidence of environmental causes of IDDM. Several diabetogenic

environmental chemicals including alloxan (experimental diabetogenic agent), pose a potential threat to all mammals including humans, either through contamination of their environment or inadvertent exposure.

◦ Once in the organ, they may be transformed into toxic metabolic intermediates through metabolic reactions.

Rather than precipitate IDDM by destruction of cells, some of the environmental poisons may trigger the development of autoimmune processes after a long period of subchronic exposure, thereby hastening the onset of clinical manifestations of IDDM.

In NIDDM, the lesion is a functional defect in the glucose stimulated secretory mechanism for insulin. Even this may have environmental aetiology.

Pancreatic Poisoning-2

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The liver is regarded as the sewage treatment plant of the body and is the first organ to be exposed to ingested toxins due to its portal blood supply. ◦ For this reason, toxins may be partially removed from the circulation during the first pass. ◦ In this way, it provides the protection to other organs while increasing the likelihood of its toxicosis.

Hepatitis is a manifestation of liver disorder as a result of this and is associated with several chemical preparations, phytotoxins and some therapeutic drugs.

The parenchymal cell of the liver is the hepatocyte which represents 60% of the liver. The non-parenchymal cells consist of sinusoidal, perisinusoidal and biliary cells. ◦ All of these cells can respond to a toxic exposure resulting in their degeneration and necrosis in

extreme cases. Centrolobular injury is by far the most frequent form of hepatocellular necrosis which

is also easily and rapidly repaired.◦ Periportal hepatocytes might be expected to be more sensitive to poisoning since they receive

blood–borne toxin first and presumably in the highest concentration. ◦ Compared with the periportal hepatocytes, the central lobular hepatocytes have a much higher

concentration of cytochrome P-450 and associated enzymes that metabolise and thereby activate xenobiotics.

◦ It is this that accounts for occurrence as well as the frequency of centrolobular liver toxicity. The whole liver may be affected. Massive injury is characterised by necrosis involving the

entire liver lobule. Due to a massive reserve liver functional potential, destruction of a large portion of

the liver is still compatible with life. ◦ Hepatocytes remaining unaffected may effectively take over the function and can repair the

damaged liver by regeneration.

Liver Poisoning-1

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A common indicator of mild liver poisoning is lipidosis (steatosis).

Although lipidosis may be associated with hepatic necrosis in extreme cases, moderate lipidosis alone does not impair hepatic function.

The presence of hepatotoxin may result in the accumulation of triglycerides in the liver resulting in imbalance between uptake of fatty acids and their secretion as very low density lipoprotein (VLDL). ◦ Any poison which reduces the availability of apoprotein, a

component of VLDL, certainly will interfere with VLDL mobility and affect secretion.

Phospholipidosis is another form of lipidosis caused by the accumulation of phospholipids seen following chronic poisoning by some of the amphiphilic xenobiotics.

Liver Poisoning-2

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Many poisons cause cholestasis, stagnation of bile flow causing-◦ raised blood bilirubin, hence hyperbilirubinaemia,◦ bile academia with a consequence elevation of enzymes

such as alkaline phosphatase, and -glutamyl transpeptidase. Several environmental chemicals particularly chronic

alcohol ingestion may cause cirrhosis. ◦ This is a hepatic fibrosis and nodular regeneration which

occurs as a chronic exposure to various hepatotoxins. The regeneration and fibrosis result from a chronic

hepatocellular necrosis. Early cirrhosis may result in hepatomegaly, although

the progression of the disease may at times result in a reduction in liver size.

When advanced, cirrhosis may result in liver failure.

Liver Poisoning-3

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 The liver is the major metabolic organ of the body and has the competence of converting toxic materials into a form that can be eliminated from the body.

Metabolism is divided into two phases. Phase I produces a suitable site on the molecule to allow phase II reactions to take place.◦ Phase I prepares the xenobiotics to facilitate phase II reactions.◦ Phase II metabolic process is synthetic and involves conjugation or addition of xenobiotics

to endogenous molecules. Phase I metabolic reaction is mainly catalysed by the activities of

Cytochrome P-450 which is a family of isozymes involved in the oxidation and reduction of lipid soluble compounds. ◦ It is in the highest concentration in the liver and is non-specific.

The purpose is to reduce lipid solubility, decrease lipid storage and promote urinary excretion.

Oxidation attack occurs at N, S, and C bonds, resulting in the insertion of one atom of oxygen producing relatively less toxic products through unstable intermediate toxic epoxides.

Of the many mechanisms of insertions, N-hydroxylation and aromatic C-oxidations are the most commonly associated with toxifications.

Epoxide hydrase or hydrolases convert these intermediate toxic epoxides to non-toxic hydrodiols. ◦ Epoxide hydration serves as a detoxification process because it increases water

solubility and excretion.

Detoxification of Poisons by the Liver-1

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Phase II conjugation reactions involve the addition of endogenous compounds like glucose, glutathione, sulphate and amino acids notably glycine.

Glucuronidation is the major conjugation reaction.

Glutathione regarded as endogenous antidote, either spontaneously or with the aid of transferases, conjugates toxic electrophiles, neutralising their cellular potential toxicity.

Detoxification of Poisons by the Liver-2

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 Did you know that you could eat to kill yourself unknowingly with foods we normally eat daily by causing stress to your body systems?

Did you know that you could help reduce this stress on your body just by making sure that most of the carbohydrates you eat are the types that keep your blood sugar from rising too fast?

All carbohydrates are broken down into simple sugars which enter into blood circulation. Unless you are exercising at the time, when you eat carbohydrates, your body requires insulin to get that sugar from the blood into the cells.

A rapid rise in blood sugar triggers a rapid more insulin release.  Sugars leave the blood and enter the cells (unless you have developed insulin resistance).  ◦ Blood sugar drops rapidly as well.

One way to reduce the rate of release of sugar into the bloodstream is by eating foods that lead to sugar entering the bloodstream more gradually -- over a longer period of time.  ◦ The Glycemic Index (GI) is a powerful tool for selecting these types of foods. ◦ (www.glycemicindex.com/). Here you can find the GI of just about any food (the lower the

better for our purposes, especially if you are not engaging in strenuous activity). 

Toxicological Implications of Foods and how to prevent them-1

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When you are looking up the GI of a particular food, lower is "better" with respect to helping keep blood sugar stable.  Below 55 is best.

If you are going to eat a food higher on the GI, eat another food at the same time that is low in carbohydrates and higher in protein and good fats. ◦ For example, add an egg or drink milk after eating.  The fat will slow down the release of

sugars into the bloodstream, and the protein will trigger the release of the hormone glucagon that counteracts the effect of insulin release and helps to keep blood sugar levels more stable.

 Select and eat foods that keep your blood sugar more stable. ◦ If you scavenge on everything with low GI, you need to know that even a lower GI food can

lead to a significant blood sugar rise, so use Glycemic Load (GL) to help you choose the correct foods.

Just because a food is low on the GI, does not mean it is necessarily good for you.  ◦ A couple of examples: Peanuts have a low GI, but you could have an allergy to them, or

they could have too much salt for you, or the oils they were roasted in may not be good for you.

Milk is fairly low on the GI, but again, you could have sensitivity to dairy, or be lactose intolerant. 

Most people drink pasteurized milk in which the enzymes have been destroyed by the heat involved in that process.  ◦ The lack of enzymes could place a stressful demand on your own enzymatic production

processes.

Toxicological Implications of Foods and how to prevent them-3

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Table sugar has both glucose and fructose and is toxicologically worse than glucose arising from carbohydrates alone. ◦ Table sugar is one of the worst nutritional poisons if not controlled.

Sugar is one part glucose and one part fructose (50/50). The more damaging half of this dastardly duo of glucose and fructose -- regardless of whether it occurs in table sugar or in other sources is clearly fructose.

Fructose raises insulin resistance, raises triglycerides in the bloodstream and contributes to fatty liver disease.

Pure refined fructose is the worst whether it comes from other sources or from sugar. Sugar with a greater fructose portion is sweeter than the ordinary sugar.

◦ These sweeter forms of sugars are now used to sweeten almost everything we eat and the result is that we now consume more fructose than we ever did

Natural white sugar accomplishes exactly nothing but relatively safer than sweetened sugar. ◦ Refined sugar is the worst due to the presence of refined fructose which is a

metabolic poison, Fructose is found naturally in fruits.

◦ Eating lots of fruits is good for you because fructose in fruits is surrounded by fibres, vitamins, protective phytochemicals and other good stuff

◦ You do not need to avoid fructose when it occurs (in small amounts) in natural whole foods.

Toxicological Implications of Foods and how to prevent them-4

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Physical ExaminationThe routine physical medical examination may be of help to evaluate the status of the liver. Whatever the opinion formed, it must be checked with other non-invasive toxic liver indicators.

Clinical ChemistryAn elevation of serum enzymes such as alanine and aspartate aminotransferases reflect damage to hepatic parenchyma, while elevated levels of alkaline phosphatase is an indicator of biliary injury. Bilirubin, bile salts, proteins especially albumin are serum indicators of liver toxicity.

HistopathologyLiver biopsy can be used to confirm the disorder of the liver. However, the histological appearance of the liver using either a light or electron microscopy remains the most definitive indicator of liver dysfunction. Organ body weight ratio is an additional indicator at autopsy.Organ Function Tests

Toxicity may be detected by the administration of dye such as indocynine green or antipyrine drug and clearance pattern analysed.

Methods For Detecting Hepatocellular Poisoning

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The End