Chapter 5

Man-made Mischief and Malfunctioning Metabolism

Man-made mischief: signs and symptoms

YOU KNOW THE SAYING that man is his own worst enemy? In the world of poisoning, this is proven: many of the potentially lethal chemicals, including drugs that we use today, no longer come from the natural world but are man-made.

In August 2008, as soon as the Beijing Olympics had celebrated the closing ceremonies, a food scandal involving powdered milk laced with melamine surfaced. Melamine is used to make plastic cups and saucers and is also used in glues. It had been added to milk powder to give the illusion of an increased protein content. Melamine contains nitrogen in its chemical formula, and the protein content of foodstuffs is measured by checking the quantity of nitrogen present. This had first come to light about six months earlier but had probably been going on for years.

The Chinese authorities managed to keep it hushed up until babies who had been fed with it started dying. Thousands of babies and young children had fallen sick with kidney stones and other complications. The most seriously ill were admitted to hospital with kidney failure. Six babies died and almost 300,000 more were sick as a result. This scandal had worldwide repercussions as so many other food products also use milk powder as an ingredient. Many of these products sourced from China were found to contain melamine and have now been recalled. Melamine was even found in sweets and chocolate.

The signs and symptoms of poisoning indicate what is happening to the body as a result of its contact with a noxious substance and seem rather like clues in a puzzle to discover the exact cause.

In the case of poisoning, while some victims may be able to say what has poisoned them, some may not know the cause or, if attempting suicide, may not tell the truth about what was taken. Consequently accurate observation and interpretation of the signs and symptoms by those treating the victim are paramount.

The signs are those indications, of disease or disorder, which are observed by the doctor during his or her examination of the patient. The patient usually describes the symptoms they are suffering from, with a presenting symptom being the one that finally made the patient decide to see the doctor. With babies and children, their parents must describe the symptoms. These signs and symptoms together help the doctor to make a diagnosis.

Some signs and symptoms are useful indicators of specific drugs that may be the cause of poisoning. For example, respiratory depression, which causes abnormally slow and shallow breathing, can lead to an increased level of carbon dioxide in the blood, and suggests that the cause could be opioid or benzodiazepine toxicity. A fast or irregular pulse, which means that the heart rate is also fast and irregular, may be due to salbutamol, atropine and hyoscine, tricyclic antidepressants, quinine or tranquilliser poisoning. A reduced body temperature may be due to drugs such as barbiturates while an increased temperature may be due to different types of drugs such as amphetamines or cocaine. Kidney failure may result from salicylate, paracetamol or ethylene glycol (antifreeze) poisoning, and can also affect the acid/base balance in the body. This latter effect can be due to poisoning by alcohol, antifreeze, paracetamol or carbon monoxide.

Medicines gone wrong

Medicines themselves, meant to be treatments in their own right, can sometimes become a problem rather than a solution.

Sometimes even a small change in the manufacturing process of a medicine can have catastrophic consequences. This happened with one medicine, called tryptophan, about 20 years ago. In late 1989, a stream of reports began to emerge, initially in the USA, but then also from Europe and Japan, of patients developing a particular set of symptoms. Painful muscles that made movement difficult and abnormal white cell counts were side effects normally associated with some other drugs, but never before with tryptophan.

It was called the Eosinophilia Myalgia Syndrome by the doctors. The symptoms developed over a period of several weeks, and some patients developed multi-system organ problems as well as inflammatory involvement affecting the joints, skin, connective tissue, lungs, heart and liver. Some of these affected patients had been taking tryptophan for many years previously, as a treatment for depression, either alone or in conjunction with other types of antidepressants, without any problem.

Withdrawal of the tryptophan led to improvement in most patients, but not all of them. In some patients the disease progressed, and there were even some fatalities. A worldwide withdrawal of all products containing tryptophan (or in some cases a set of very severe restrictions on its use) was imposed in 1990.

Investigations revealed that the whole of the world’s supply of tryptophan was manufactured by a single manufacturer in Japan, and was then exported in bulk to other countries, where it was used to make pharmaceutical products.

It appeared that changes to the manufacturing process had been made prior to the reports. The strain of bacteria involved in the fermentation process had been changed and the amount of charcoal used in the purification stage of manufacture had been reduced. These production changes had led to a number of new contaminants being present in the tryptophan now produced.

Despite much testing and investigation, no single contaminant has yet been found to be responsible; however, refinements to the manufacturing process have been made and production improved. In 1994, tryptophan was reintroduced in the UK, for restricted use, under carefully controlled conditions. In February 2005, the restrictions imposed were finally lifted as no further cases of this syndrome had been reported for many years.

All new drugs need to undergo trials. Initially, these are studies on tissue samples in vitro (outside the body) before then testing on animals. Only when a drug has been shown to work in these in vitro and animal tests, and only when its safety has been assessed, will the drug be considered for an initial clinical trial in human volunteers – normally a small group of fit, young, healthy people. Then, only if this initial human testing is successful will the new drug be tried out in a second phase of clinical trial, where the drug is tested on a few patients to see if it treats the condition for which it is designed, without significant side effects. A larger third-phase trial would then follow.

New drugs are always tested against placebos in clinical trials. A placebo is a medicine that is clinically ineffective, but may help to relieve a condition because the patient has faith in its powers. Placebos are made to have the same appearance as the drug on trial, and all supplies are coded so that neither the doctor nor the patient knows who is receiving the active drug and who the placebo. The code is only broken at the end of the trial to avoid any bias in the results. However, sometimes the results are so clear that a trial is stopped early, so that more patients can take advantage of a marked advance in the treatment of their condition.

These trials are very important, and only after a successful outcome on a larger group of patients can the drug company apply for a marketing authorisation, and only once that is granted are doctors allowed to prescribe it. Every patient, at every stage of the clinical trial, is carefully monitored for safety and efficacy. This topic appears again in Chapter 18.

It is not uncommon for a new drug to be launched on to an unsuspecting world, having been only tried out on a thousand patients or so – and sometimes a lot fewer – during the clinical trials.

Sometimes things go wrong, as they did on the 13th March 2006, when eight men entered a clinical trials unit at Northwick Park Hospital in North London. They were each being paid £2,000 to take part in a phase one clinical trial of a substance code-named TGN1412, which it was hoped could be used to treat Rheumatoid Arthritis, Multiple Sclerosis and Leukaemia.

Two patients received a placebo and came to no harm, but the other six suffered what the doctors described as a cytokine storm. Their bodies’ immune response systems went into overdrive, with a massive systemic inflammatory response, quickly causing extreme pain and massive swelling, with high temperature and heart rate, but falling blood pressure. They had respiratory distress, kidney problems and even blood coagulating within their blood vessels. Initial treatment in the clinical research unit was followed by transfer of all six to the intensive care unit of the hospital.

Injections of high doses of steroids were used, together with other treatments, and all six men survived. The men were affected to varying degrees, with the one most severely affected losing his toes and parts of several fingers. Investigation by the MHRA considered the most likely cause of the adverse reaction was an unpredicted biological action of the drug in humans. The conduct of the trial on that day exacerbated the situation. If the injections had been given at timed intervals, rather than one immediately after the other, then once any of the men became ill, the trial could have been stopped, so saving the rest from being affected.

Aspirin and Ibuprofen are both commonly used painkillers that are very useful in reducing fever, pain and inflammation, but are also commonly misused. The symptoms of overdosage seen with salicylates, like aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, include gastro-intestinal and haematological effects. There may also be kidney damage, as well as effects on the central nervous system. Nausea, vomiting, dehydration, hyperventilation and sometimes gastric pain are seen. Headache, drowsiness, dizziness, blurred vision, tinnitus, vertigo and sweating can occur. Rarely there may be lethargy or even coma, together with seizures. There may be a drop in blood pressure and heart block, with pulmonary oedema and hyperthermia. Other problems such as hyperventilation can occur and cause disturbances of the body’s acid/base balance. The effects are dose-related and potentially fatal. Fortunately the average lethal dose of aspirin is well in excess of 100 tablets.

There are rather different problems with paracetamol poisoning. Paracetamol is, like digoxin, another example of a drug where there is a relatively small margin between the therapeutic and the toxic dose.

Please note that paracetamol is called acetaminophen

in the USA and in Ireland.

Both names refer to the same substance.

Paracetamol poisoning is very serious, and a fatal dose can be as little as 20 tablets. However, prompt treatment with methionine or acetylcysteine can prevent liver failure and subsequent death. Paracetamol overdose initially shows no symptoms or perhaps just a little vomiting. It is only later that the liver damage caused by the overdose shows up as jaundice and brain damage – encephalopathy. Sometimes there may be kidney failure as well.

Occasionally, patients can die because of lack of treatment, even when they are in hospital. In 2003, a 26-year-old man took an overdose of painkillers, intending to commit suicide. He had taken 70 tablets but then changed his mind and went to hospital for treatment, telling a nurse in the Accident and Emergency Department what he had done. However, he died some eight hours later, still waiting to see a doctor. This unfortunate case came to light at the inquest on the poor man, which had happened at the University Hospital in Cardiff.

Early signs of overdose include nausea, vomiting, sweating and lethargy, and usually settle within 24 hours. Abdominal pain may be the first sign of liver damage but may not appear until at least a day later, and sometimes may be delayed even four to six days after the overdose was taken. Following liver failure, a whole catalogue of complications set in over the ensuing days and weeks, until death finally occurs.

As a rule of thumb, if treatment can be started within 12 hours of a paracetamol overdose, then the liver can be saved, but after that time it is likely to be too late, and only a liver transplant will save the patient’s life.

That said, paracetamol is a very effective painkiller if used properly. The maximum dose is two tablets at a time and the frequency is every four to six hours up to four times a day. This means that no more than eight tablets should be taken in any 24-hour period.

Carbon monoxide poisoning is another very lethal type of poisoning. It can occur accidentally when gas-fired central heating boilers, water heaters and fires are not regularly serviced. The colourless and odourless gas displaces oxygen from its binding sites on the haemoglobin molecules in red blood cells, forming carboxyhaemoglobin instead of the normal oxyhaemoglobin.

The symptoms of carbon monoxide poisoning include headache and vomiting with an increased pulse and respiration rate. Once more than half of the haemoglobin is bound with carbon monoxide, the patient has convulsions, lapses into a coma and then dies of cardiac arrest. Despite the resulting hypoxia (low oxygen level), the skin and flesh do not look cyanosed (blue) but are a bright cherry pink because of the carboxyhaemoglobin. The treatment is simple, if diagnosed in time – give the patient oxygen to breathe.

The introduction of catalytic converters to the exhaust system of cars has greatly reduced the number of attempted suicides made using exhaust fumes, which used to result in death from deliberate carbon monoxide poisoning in the past.

Organic solvents, such as alcohol, acetone and benzene, are widely used throughout industry, where acute or chronic exposure, resulting from inadequate ventilation of the workplace, may lead to toxicity. Adverse effects may result from inhalation of the vapour, ingestion or even absorption through the skin. Organic solvents are irritant to both the mucous membranes and to the skin, and commonly affect the central nervous system. They may also affect the heart, causing arrhythmias, ectopic (extra) heart beats, tachycardias, fibrillation and heart block.

Continued chronic exposure can then lead on to liver and kidney damage, as well as to both peripheral and central effects on the nervous system. Carbon tetrachloride, for example, which is used in many industrial processes, causes vomiting, abdominal pain, diarrhoea, seizures, coma, kidney failure and an enlarged liver with jaundice and liver failure. Intoxication leads to symptoms similar to those of alcohol intoxication, initially causing stimulation of the central nervous system, and then later depression, leading on to delirium, convulsions, coma and death.

Many different solvents have been the subject of abuse, as have been commonly seen in glue-sniffing. Many other products also containing solvents have also been subject to abuse, including lighter fuel, liquid paper solvents, dry cleaning fluids and nail polish removers.

Organophosphates, such as pesticides, like malathion, affect the nervous system and cause restlessness, anxiety, dizziness, confusion, hypersalivation, watering eyes and urination. Abdominal cramps, with nausea, vomiting and diarrhoea can also occur. There may also be sweating, constricted pupils, muscle twitching leading on from muscle weakness to flaccid paralysis, convulsions, coma, respiratory distress and cardiac depression causing a decline in blood pressure and a slow heart beat. All organophosphates are absorbed through the bronchi and intact skin as well as through the gut; toxicity varies between different compounds and the onset of symptoms after skin exposure may be delayed. Repeated exposure can lead to accumulation and ongoing symptoms.

In the summer of 2008, tainted rice was found in Japan in massive quantities. Thousands of bottles of shoshu and saké (rice wine) were recalled along with many other products made from rice contaminated with pesticides or the mould aflatoxin (mentioned in the last chapter). This contaminated rice should have been used as animal feed, glue or other low-grade uses, but for five years it had been diverted, relabelled and resold many times, to make huge profits for an Osaka-based milling company, which had imported it from elsewhere in Asia.

Paraquat the weedkiller, in concentrated solution, can irritate, inflame and blister the skin. Prolonged skin contact with it results in delayed healing of cuts and wounds. Paraquat may also cause cracking of the skin and shedding of the nails.

Those paraquat preparations available to domestic gardeners are now considered to be safe, as they are only available in a reduced strength. However, products available for agricultural or horticultural use are far more concentrated and, if swallowed, can cause death, although this may be delayed for two or three weeks. Drinking paraquat causes oesophageal ulceration and gastro-intestinal effects, resulting in widespread organ damage, particularly to the kidneys and lungs – and there is no antidote. The main danger is the lung damage it causes. In an attempt to deter ingestion, some preparations now contain an emetic or a laxative, or a malodorous agent, to try to dissuade or deter people from drinking it.

On 7th May 2007, the fashion icon Isabella Blow died. She ended her life by drinking paraquat, the deadly weedkiller. She died in hospital, several days after drinking it, having recently had ovarian cancer diagnosed. She was 48 years old. It is interesting to note that in the past both her grandfather and her father had killed themselves, and Isabella used the same method as her father.

Recreational drugs, such as ecstasy and amphetamines (stimulants), can cause serious poisoning, sometimes from as little as a single tablet. The acute effects of ecstasy are generally similar to those of amphetamines. The toxicity caused can be severe, affecting many organs or body systems. The symptoms associated with fatalities are due to overstimulation of the central nervous system, and can lead to insomnia, night terrors, nervousness and euphoria.

Other symptoms experienced include cardiac arrhythmias, hyperthermia, convulsions, cardiovascular collapse, muscle pain, water intoxication and acute renal failure. Repeated use can cause personality changes and problems with long-term memory, as well as liver damage. Lesser symptoms include nausea, blurred vision, confusion and ataxia. Psychiatric effects, including psychosis, depression and brain damage from the accumulation of fluid – cerebral oedema – have all been reported.

In 1995 Leah Betts died during her 18th birthday party. She had taken a single ecstasy tablet and her death was caused by water intoxication. She drank glass after glass of water, so much that, in conjunction with the tablet, it caused her brain to swell and she collapsed in a coma. Within two hours of taking that single tablet she was in her local hospital, in Chelmsford, Essex, on life support, until her death five days later, when they switched off the life support machine.

Many deaths from recreational drugs have occurred, some even from taking a single ecstasy tablet, as shown in the case of Leah Betts where water intoxication was the ultimate killer. Many deaths from stroke, heart attack and kidney failure have also resulted from the use of these recreational drugs. There is no antidote, so the only treatment that can be offered must be both supportive and symptomatic.

In November 2008 a woman died of water intoxication, but no ecstasy tablet was involved this time. Jacqueline Henson, a forty-year-old mother of five, died after drinking too much water only three weeks after beginning a water-based diet. She was trying to lose weight using the LighterLife method, part of which recommended drinking four litres of water daily, in small amounts over the course of each day. But Henson drank four litres in less than two hours, which caused her brain to swell. She collapsed and was pronounced dead the following day, leaving her husband and children devastated.

One young man developed the symptoms of Parkinson’s disease at the age of only 19. Before the onset of his symptoms, he had taken ecstasy about twice a month for six months. There was a family history of Parkinson’s disease, and it was considered that he had a genetic predisposition to this condition. By taking the ecstasy tablets, he made himself even more susceptible at an unusually early age.

Recreational drugs, or even some conventionally prescribed drugs, can cause convulsions when taken in overdose, whereas benzodiazepines, alcohol, opioids, tricyclic antidepressants and barbiturates all cause the patient to fall into a coma. Examination of the pupils can be an important clue to a doctor examining a patient: constricted or pinpoint pupils, caused by the stimulation to nerves of the parasympathetic nervous system, would suggest opioid or organophosphate poisoning; the opposite effect, dilated pupils, would suggest a cause by drugs such as amphetamines, cocaine, quinine or tricyclic antidepressants.

Those pinpoint pupils will appear again in Chapter 15, where a couple of murdering doctors were both caught out by this important clue.

Malfunctioning metabolism

The human body is a very complex machine, needing the right sort of fuel to function properly. It needs vitamins, minerals and essential trace elements; water and dietary fibre; carbohydrates and fats to provide energy; together with proteins for growth and maintenance. The correct proportions of each of these nutrients form a balanced diet.

Too much or too little of one or more of these ingredients can lead to illness. Any problems in the body’s use of nutrients can also result in toxicity. Such problems may be inherited or acquired during life as a result of infections or because of the malfunction of one or more body systems. Even one such problem can wreak havoc with the body’s normal metabolism. Too little of something vital, such as insulin to the diabetic, can be every bit as harmful as too much. All such conditions, whether caused by too much or too little, can be regarded as yet another sort of poisoning. Further details and explanation relating to vitamins, minerals and trace elements are given in Appendix V.

The way the body works can differ widely from person to person, depending on genetic variations, sex, weight, age and other factors such as diet, any medicines being taken and even gut bacteria. All these factors have important implications for toxicity and effectiveness.

Take your vitamins and minerals – but not too many

These substances, needed in very small amounts for healthy growth and development, cannot be made by the body, and so must be obtained from diet. A healthy, varied diet will supply all the vitamins and minerals you need to stay healthy. vitamins generally act as co-enzymes, and without them certain enzymes would not function properly.

However, you can have too much of a good thing and hypervitaminosis is the name given to excessive consumption of vitamins, which has become fashionable with some groups of people, particularly in the USA. This is not usually serious with water-soluble vitamins such as vitamin C, where any excess is simply excreted in the urine, but occasionally even here things can go awry, as shown by a report of traces of blood in the urine of a patient who took large amounts of vitamin C in a soft drink. However, if fat-soluble vitamins are taken to excess, it is usually very serious: the body will store them in the body fat, resulting in a toxic build-up, as with the polar bear’s liver, mentioned below.

Polar bears, because of their exclusively fishy diet, have evolved so that they can tolerate very high levels of vitamin A, which they store away in their liver. In 1596, the Dutch explorer William Barents and his men nearly died after eating some polar bear liver. Apparently this delicacy, previously known only to the Inuit, was so potent that a mere mouthful was sufficient to cause abdominal pain, headache, nausea, dizziness and general ill health that lasted for several days. A larger quantity would cause the skin to peel off and might even be fatal. It was not until the 1940s that this toxic ingredient found in liver was identified as vitamin A. It is interesting to note that drinking a glass of wine with your meal of polar bear liver will further intensify the toxic effects of the vitamin A overdose.

A more modern tale shows that vitamins can’t work miracles. vitamin E has been hailed as a wonder vitamin because it is an antioxidant. It was claimed that a daily supplement of vitamin E would reduce the risk of coronary thrombosis in those with heart disease. However, in the USA, after seven years of follow-up, a long-term trial has shown no evidence for this claim. Indeed, patients with vascular disease or diabetes who took vitamin E supplements appeared to be at even greater risk of heart failure, not less.

Certain minerals are essential to the human diet: calcium, phosphorus, potassium, sodium, iron, chlorine, sulphur and magnesium, as well as trace elements including manganese, zinc, copper, iodine, cobalt, selenium, molybdenum, chromium and silicon. Minerals frequently act as cofactors in enzyme systems or as part of other complex molecules. Frequently, it is the interplay of both vitamins and minerals that can prevent deficiency diseases, such as rickets and osteomalacia.

Rickets is a disease of childhood, once very common, in which the bones do not harden due to lack of vitamin D. Without this vitamin, insufficient calcium is deposited in the bones, so they are soft and liable to bend as a result. This is particularly noticeable in the long bones of the legs, resulting in bowed or ‘bandy’ legs, and also in misshapen ribcages.

Osteomalacia is the adult equivalent to rickets, with softening of the bones leading to progressive decalcification of the bones and bone pain. In the United Kingdom, rickets and osteomalacia are far more common in Asian immigrant families than in native British people. This is particularly true of the women and girls who continue to swathe themselves in their traditional all-enveloping mode of dress, which allows very little sunlight on to their skin. This would be fine if they were in Asia, but in the UK, even in a heatwave, our sunlight is nowhere near as intense, resulting in problems for these women. Other conditions involving calcium, which is the major component of our skeleton, include Paget’s disease and osteoporosis. Paget’s disease, otherwise known as the medical condition osteitis deformans, is a chronic disease of the bones occurring in the elderly. This disease was named after the British surgeon Sir James Paget (1814-1899). It usually affects the skull, backbone, pelvis and long bones. The affected bones become thickened and their structure becomes disorganised. There are often no specific symptoms, but pain, deformity and fractures can occur. If the skull is affected, blindness and deafness can also occur due to bone thickening. Nowadays treatment is readily available using medicines such as the bisphosphonates or calcitonin. Osteoporosis – the loss of bony tissue which causes bones to become brittle and liable to fracture – is also common in the elderly, and particularly in women after menopause. This is also treated with the bisphosphonates, together with calcium and vitamin D tablets.

Anaemia is a well-known iron deficiency disease, but not many people know that all the iron in each of our bodies would only amount to enough to make a small nail. The absorption and loss of iron by the body are finely controlled. Too little iron results in anaemia, of which there are a number of different types. Treatment of anaemia depends on the cause and in many cases is symptomatic. Too much iron can also cause problems; details of both anaemia and excess iron are given in Appendix V.

Some doctors have suggested that ME, myalgic encephalomyelitis, otherwise known as chronic fatigue syndrome, is a form of magnesium deficiency as it appears to clear up when sufferers are injected with magnesium in saline solution. When oral supplements were tried as a treatment they were found to be poorly absorbed and thus far less effective than injections. It may be that this is due to the absence or a vastly reduced level of some substance, as yet unknown, which is needed to effect absorption of magnesium from the gut, as is the case with the intrinsic factor that is needed for the absorption of vitamin B₁₂ . This is also explained in Appendix V.

Water is a vital part of the human diet; without a continuous supply, death will occur within days. Clean drinking water is taken for granted in the Western world today, but in the developing world it is estimated that a billion people still face daily problems in obtaining clean, uncontaminated drinking water. Despite walking many miles every day to reach their nearest water source, regardless of its purity, many women (for this is women’s work) spend most of their days simply fetching water for their family. The World Health Organisation (WHO) has, for decades, spent millions annually (in dollars or pounds) providing wells and pumps to communities in the developing world.

In Britain and other parts of the developed world, chlorine has been used to disinfect water for more than a century and is the main means of disinfecting drinking water, preventing outbreaks of water-borne diseases such as typhoid, cholera and meningitis. It is also used to disinfect swimming pools.

But even today, infected water is still a problem, and many millions of people in Bangladesh and Thailand are suffering from arsenic poisoning because the tube wells which were sunk to give them clean, safe drinking water, as part of a World Health Organisation initiative, were sunk into arsenic-bearing rock strata. We will return to this unsettling topic again in Chapter 10.

Dietary fibre, more commonly known as roughage, is the indigestible component of our food, but nonetheless an essential part of our diet. Dietary fibre is helpful in the prevention of a number of digestive problems such as diverticulitis and constipation. This plant material falls into four groups: the lignins, the pectic compounds, the hemicelluloses and cellulose itself, which is the largest component of dietary fibre. The lignins help strengthen the cellulose, which is the main structural material in plant cell walls; the hemicelluloses act as food reserves in seeds; and the pectic compounds form gels and are the basis of fruit jellies. Highly refined foods such as sugar contain no dietary fibre at all, while wholemeal cereals such as oats, wheat and barley have a high fibre content, as do many fruits and vegetables.

Carbohydrates are important as an energy source, being broken down in the body to the simple sugar glucose, which can then take part in energy-producing metabolic processes. Excess carbohydrate is stored in the liver and muscles as glycogen, which is composed of branched chains of glucose molecules. These can be readily broken down to glucose whenever our body needs some extra energy.

Milk and other dairy products are essential to our health, although humans are the only species known to continue to include these products in our diet after weaning.

Lactose is the sugar found in milk, and consists of glucose joined to galactose – one molecule of each is joined together to make one molecule of lactose. An intolerance to lactose occurs when there is a deficiency of the enzyme lactase, which is needed to break down the lactose present in milk into glucose and galactose. More than 90 per cent of Asians and Africans are lactase deficient, to varying degrees, and only those of northern European descent seem to retain the ability to produce lactase into adulthood. Other racial groups possess a partial ability to a greater or lesser extent. Abdominal pain, diarrhoea, distension and flatulence in the intestines result from this deficiency. These symptoms can also occur in those who ingest excessive amounts of lactose. An alternative to cow’s milk, such as soya milk, should be drunk by sufferers of lactase deficiency, as lactose-containing foods are contra-indicated and so should be avoided.

Infants born with the rare inherited metabolic disease galactosaemia lack the enzyme required to convert the galactose in milk sugar to glucose in their liver. If left untreated the galactose builds up to a toxic level in the blood. The baby then fails to thrive and becomes mentally retarded. Fortunately the elimination of galactose from the diet of such babies can result in normal growth and development, if the condition is diagnosed early enough.

Fats contain fatty acids, in the form of triglycerides, and these are the main form of energy storage in the body. Fats are needed in our diet as a source of the three essential fatty acids: linoleic, linolenic and arachidonic acids. They are all unsaturated fatty acids, which are necessary for growth, but which cannot be made by the body. However, as long as we get a supply of linoleic acid in our diet, we can make the other two essential fatty acids from it. Corn oil and soya bean oil are both rich sources of linoleic acid.

Proteins are essential constituents of the body, forming the muscles, tissues and organs as well as enzymes and hormones. They are complex structures made up of one or more chains of amino acids, linked together by peptide bonds. Proteins are manufactured in the body from their constituent amino acids, which are obtained from the diet.

Amino acids are the basic building blocks of all proteins, but of the 22we need to make our proteins, only nine of them are classed as essential. These essential amino acids are just that: they are amino acids that we must obtain from our diet because we are unable to make them ourselves. They are tryptophan, lysine, phenylalanine, histidine, threonine, methionine, valine, leucine and isoleucine. The rest can be synthesised by the body. We obtain the nine essential amino acids from protein-rich foods such as meat, liver, eggs and dairy products.

Hormonal disorders

Hormones are another form of protein. There are a number of hormonal disorders which, whether congenital or acquired, can result in poisoning. The best known of these is diabetes. This disorder can be either inherited or acquired, and long-term complications can lead to circulatory problems, including thickening of the arteries, which can lead to eye problems and blindness. Circulatory problems may also affect the lower limbs, which could ultimately need amputation. Regular visits to the optician and the chiropodist are a must for all diabetics.

Insulin is the hormone that regulates our blood sugar level. Diabetics with Type 1 diabetes need injections of extra insulin, as their pancreas cannot produce sufficient amounts for them. Without insulin, diabetics would lapse into a coma and die. Those who develop diabetes later in life, now called Type 2 diabetes, can usually be managed with tablets, as there are a number of drugs, called hypoglycaemics, that can act to reduce the blood sugar levels, although some Type 2 patients will eventually progress onto insulin injections after a period of some years.

As insulin is a protein, it must be injected – swallowing it would lead to it being digested like any other protein in our diet. However, a nasal spray formulation of insulin has recently been launched, but this will not totally replace injections, which will still be needed even by those using the spray.

The blood sugar level regulated by the insulin hormone is normally maintained within the range 3.5 to 5.5 mmol/l (millimoles per litre). Measuring the blood sugar level several times a day is a vital part of treatment for all diabetics. Low blood sugar – hypoglycaemia – where the level falls well below 3.5mmol/l, can be caused by too much insulin, or by taking oral hypoglycaemics, alcohol or salicylates. The opposite effect – hyperglycaemia – where the level is far in excess of 5.5mmol/l, can be caused by too much insulin, organophosphate pesticides or some drugs, such as theophylline.

Kenneth Barlow was a nurse who worked at Bradford Royal Infirmary. One evening in May 1957, his wife Elizabeth felt unwell and went to lie down in the bedroom. Later she decided to have a bath, and some time later Kenneth said he found her drowned there. He said that he then pulled the plug to drain the water and went for help. A neighbour called the doctor, who examined the dead woman and noticed that her pupils were widely dilated. However, the doctor could see no signs of violence, although before drowning Elizabeth had obviously vomited while in the bath.

The doctor called the police, who in turn called in the forensic experts. It was noticed that Barlow’s pyjamas were completely dry, despite him saying he had tried to get his wife out of the bath and had tried artificial respiration in an attempt to revive her. A search of the house revealed two syringes found in the kitchen, which Barlow said he had used to inject penicillin for himself when he had a carbuncle. He pointed out that, as a nurse, he used syringes at work every day, but he denied giving his wife any injections.

The post-mortem examination revealed that Mrs Barlow had been two months pregnant, but the doctors could find neither cause of death nor any sign of injection marks on her body. The syringes were tested and did indeed show traces of penicillin as the husband had told them. The doctors were puzzled, and made an even more thorough search of the body for needle marks. They eventually found two on the right buttock and another two more recent ones in a fold of skin under the left buttock – but what had been injected?

Barlow had said that her symptoms were vomiting, sweating and weakness. The doctors also needed to consider the cause of the dilated pupils. They decided that such symptoms could be caused by hypoglycaemia, that is, low blood sugar. Mrs Barlow was not a diabetic but blood taken from her heart during the post-mortem had a higher than normal level of blood sugar.

This finding was later found to be a natural reaction of the liver, only happening in circumstances where a violent death is imminent. This reaction was an automatic survival mechanism that came into play, resulting in a surge of blood sugar being released by the liver, but it only got as far as the heart before death occurred.

The police then discovered that on every working day Nurse Barlow gave many patients their insulin injections at the hospital where he worked. The police spoke to another nurse who told them that Barlow had once suggested that injecting insulin could be a way to commit the perfect murder.

Further investigation by the police revealed that Barlow’s first wife had died at the age of 33 and that no cause of death had ever been found. Experiments with mice injected with tissue extracts taken from the injection sites found on the body of Elizabeth caused the mice to go into a diabetic coma, as they would do when they were injected with insulin. In July 1957, Kenneth Barlow was arrested and charged with murder by the use of insulin; he was found guilty and sentenced to life imprisonment.

Another hormonal disorder, Addison’s disease, named after the British physician Thomas Addison (1793-1860), is a syndrome caused by inadequate secretion of corticosteroid hormones by the adrenal glands. The symptoms include weakness, loss of energy, low blood pressure and dark pigmentation of the skin. This, like diabetes, used to be fatal but today can be treated by replacement hormone therapy.

Hypothyroidism, due to too little thyroid hormone, is caused by a deficiency of iodine, makes a person feel listless and cold and tends to cause weight gain. Any deficiency is easily treated with daily thyroxine tablets.At the opposite extreme, too much thyroid hormone can cause hyperthyroidism, resulting in restlessness and hyperactivity. Hyperthyroidism, also called Graves disease, after the Irish physician Dr R. J. Graves (1850-1932), is also referred to as thyrotoxicosis. Further details of symptoms and treatment are given in Appendix V.

Inborn errors of metabolism

Unfortunately, there are sometimes metabolic problems in the manufacture, maintenance or disposal systems in the body that can be inherited or acquired throughout a person’s life. Haemophilia and Wilson’s disease are just two such problems, but more than 1,500 inborn errors of metabolism are known to exist.

Haemophilia is a genetic disorder in which the blood clots extremely slowly because of a deficiency of one or other of these clotting or coagulation factors. Prothrombin is essential not only for blood clotting but also for regulating the synthesis of several other clotting factors. These vital factors are normally present in the blood plasma.

When an injury leads to bleeding, these coagulation factors undergo a series, or cascade, of chemical reactions, which result in the liquid blood being converted to a solid. Lack of any one of these factors results in the inability of the blood to clot. Two such factors are Factor VIII, the antihaemophilic factor and Factor IX, also known as the Christmas factor.

Haemophilia is a sex-linked hereditary disease in which women carry the disease down the generations, but sufferers are almost exclusively male – that is, they are the sons of the carriers. Treatment may be by the simple transfusion of blood plasma, which contains the missing factor, or alternatively by the use of concentrated preparations of Factor VIII or Factor IX, obtained by freezing fresh plasma.

Exact copies of these same factors have been made using recombinant DNA technology, and although they are many times more expensive than the natural products, they are much safer to use, as they do not carry the possible risks of infection with hepatitis, HIV or CJD that may be present in the natural product.

Wilson’s disease, an inborn metabolic disorder, is caused by the body’s inability to utilise copper properly. Free copper is deposited in the liver, causing jaundice and cirrhosis. It also accumulates in the brain, resulting in mental retardation and other symptoms similar to those of Parkinson’s disease. The corneas in the eyes become stained with a characteristic brown ring.

In 1993 there was a report of a patient who had developed acute liver failure with cirrhosis. This failure was attributed to the patient taking excessive copper supplements for a long period of time, which resulted in chronic copper intoxication.

In Menke’s disease, an X-linked genetic disorder, the body is unable to make the copper-transporting protein required. This results in a chronic lack of copper, which leads to retarded growth, cerebral degeneration and death in infancy. A therapy for Menke’s disease, introduced in the 1970s, is available but is not very effective, with most sufferers dying by the age of six.

In many of these inherited conditions, there is a disturbance in the structure, synthesis, function or transport of proteins. Phenylketonuria, the porphyrias and hypogammaglobulinaemia are inborn errors of amino-acid metabolism, and there are many others, which, although not as common, are nonetheless serious and can be fatal. Usually there is no treatment available, other than the use of a specially modified diet in addition to vitamin supplements.

PKU (phenylketonuria) is one of the best-known metabolic conditions. It is an inherited defect of protein metabolism, usually due to a defect in the enzyme phenylalanine hydroxylase. This results in raised blood concentrations of phenylalanine in the newborn baby, which if untreated will produce a characteristic pattern of signs and symptoms, including skin rash, hypertonia and seizures which can lead to severe mental retardation.

All newborn babies are tested for PKU with the Guthrie test. Named after its originator, American paediatrician Dr Robert Guthrie (1916-1995), the Guthrie test is a heel-prick blood spotting test in which a drop of the newborn’s blood is placed on a special card, which is then tested for the presence of phenylalanine. This test enables the condition to be detected as soon as possible after birth so that affected infants can be given a diet in which the offending amino acid, phenylalanine, is present at the lowest possible level. The gene responsible for PKU is recessive, which means that a baby will only be affected where both parents carry the offending gene.

Maple syrup urine disease is another inborn defect of amino-acid metabolism. This condition results in excess of the amino acids valine, leucine, isoleucine and alloisoleucine in the urine of sufferers, which gives it the odour of maple syrup. The only treatment is dietary, and if the condition is left untreated it can lead to mental retardation and death.

Fish odour syndrome, as the name suggests, is characterised by a foul body odour due to a problem in the liver from a genetic impairment of the oxidation of trimethylamine derived from the diet. Trimethylamine is formed in the gut by bacterial degradation of foods rich in choline and carnitine, and is readily absorbed from the gut into the blood supply, which carries it to the liver.

If it cannot be oxidised in the liver, the trimethylamine is excreted on the breath or in the urine, sweat and vaginal secretions. It smells of rotting fish and has a high olfactory potency – which is a polite way of saying that it is very noticeable. Treatment of someone with this problem involves modifying the diet to avoid choline-rich foods, such as eggs, liver, peas, soya beans and sea fish. Sometimes drugs such as metronidazole, neomycin and lactulose are used to reduce the intestinal flora and decrease production of trimethylamine.

Porphyrias are one of a group of inherited or acquired disorders, and are due to deficiencies in the enzymes involved in the biosynthesis of haem, the iron-bearing red pigment in blood. Deficiencies of specific enzymes result in the accumulation of various porphyrins and their precursors. The deficient enzyme may be missing from the liver (hepatic porphyria) or from the bone marrow (erythropoietic porphyria) or both.

The main features of porphyrias are highly coloured urine or urine that changes colour on standing, and skin that is very sensitive to sunlight, due to a build-up of metabolites in the flesh, which may cause chronic inflammation or blistering. There may also be neuritis, due to inflammation of the nerves, and mental disturbances, as well as abdominal pain. King George III (1738-1820) suffered from bouts of insanity believed to be due to porphyria.

Haem is responsible not only for the red colour of our blood, but also for its oxygen-carrying capacity. Haem is used in the treatment of porphyrias, as sufferers cannot synthesise it properly themselves. Tin, like iron, is also able to combine with porphyrin to produce substances that can inhibit the enzyme involved in the breakdown of haem, haem oxygenase, to bile pigments. These substances have been tried in the treatment of porphyria as a means of delaying the normal breakdown of haem.

Hypogammaglobulinaemia is due to a deficiency of the protein gammaglobulin in the blood. It can occur in a variety of inherited disorders, or as an acquired defect, as can happen in certain lymphomas. Gammaglobulin consists mainly of antibodies, also called immunoglobulins, so it is hardly surprising that the condition hypogammaglobulinaemia results in an increased susceptibility to infections in those who inherit or acquire it. Treatment is by replacement therapy of special formulations of immunoglobulins which are prepared from donations of human plasma.

Coeliac disease is an inflammatory disorder of the small intestine that results from a sensitivity to gluten and causes an immunological reaction. Gluten is a mixture of two proteins, gliadin and glutenin, present in wheat flour and to a lesser extent in barley, oats and rye. The first, gliadin, belongs to one of the main groups of plant proteins known as the prolamines while the second, glutenin, belongs to another group, the glutelins. Those who suffer from coeliac disease are sensitive to the gliadin fraction of gluten.

Treatment is simple: the affected person must avoid wheat products, and hence gluten, in the diet. Coeliacs need to ensure that the flour, bread, pasta and biscuits they eat are gluten free. There are a number of manufacturers who specialise in making this type of foodstuff, which are available to buy freely or on prescription. This type of diet has also been found to be of use in patients with dermatitis herpetiformis, who also suffer from gluten hypersensitivity.

Treatments aren’t always this simple and can sometimes be downright traumatic, as the next chapter will reveal.