Family studies

Strong evidence for the genetic cause of a disease, with little or no environmental contribution, comes from observations of its higher than expected incidence in families, particularly if they are affected by a disease that is otherwise very rare in the general population. Such diseases are said to ‘run in families’.

Having identified the abnormality in a family, it is then important to provide genetic counselling so that parents can make informed decisions about future pregnancies. The precise mode of inheritance (p. 36) will determine the proportion of family members (i.e. children) likely to be affected. Because inherited genetic disorders are either sex-linked or autosomally dominant or recessive, not all individuals in one family may be affected even if the disease has no environmental component.

Studies on migrants

The unusually high incidence of a particular disease in a country or region could be due either to the higher prevalence of a genetic predisposition in the racial or ethnic group(s) in that country or to some environmental factor such as diet or climatic conditions. Compelling evidence of the relative contributions of genetic and environmental factors in the aetiology and pathogenesis of a disease can be yielded by observations on disease incidence in migrant populations (Fig. 3.2). For example, if a racial group with a low incidence of a particular disease migrates to another country in which the disease is significantly more common, there are two possible outcomes leading to different conclusions:

Fig. 3.2 Clues to genetic and environmental causes from disease incidence in migrants. When people with a low incidence of a disease migrate to a country in which the indigenous population has a high incidence, any change in the incidence of the disease in the migrants provides important clues to the role of genetic and environmental factors in causing the disease. A rapid rise in incidence would attribute the disease to unavoidable environmental factors such as climate or widely prevalent micro-organisms. A more gradual rise would be due to factors such as diet, over which there may be some initial cultural resistance to change. No change in disease incidence attributes the high incidence to genetic factors in the indigenous population. The distinctions are rarely as clear-cut as in this graphic example.

Most observations on disease incidence in migrant populations have been made on neoplastic disorders (cancer). This is because cancer is a major illness, likely to be reliably diagnosed by biopsy, and, in many countries, documented in cancer registries.

Association with gene polymorphisms

Within the population there are many normal genetic variations or polymorphisms. The effect of some of these polymorphisms is obvious: examples are skin, hair and eye colour, body habitus, etc. When possessed by large groups of people of common ancestry, a cluster of polymorphic variants constitutes racial characteristics. In other instances the polymorphism has no visible effects: examples are blood groups and HLA types (see below); these are evident only by laboratory testing.

The polymorphisms of greatest relevance to disease susceptibility are:

Gender and disease

Gender, like any other genetic feature of an individual, may be directly or indirectly associated with disease. An example of a direct association, other than the absurdly simple (e.g. carcinoma of the uterus and being female), is haemophilia. Haemophilia is an inherited X-linked recessive disorder of blood coagulation. It is transmitted by females to their male children. Haemophilia is rare in females because they have two X chromosomes, only one of which is likely to be defective. Males always inherit their single X chromosome from their mother; if the mother is a haemophilia carrier, half of her male children are likely to have inherited the disease.

Some diseases show a predilection for one of the sexes. For example, autoimmune diseases (e.g. rheumatoid disease, systemic lupus erythematosus) are generally more common in females than in males; the reason for this is unclear. Atheroma and its consequences (e.g. ischaemic heart disease) tend to affect males earlier than females, but after the menopause the female incidence approaches that in males. Females are more prone to osteoporosis, a common cause of bone weakening, particularly after the menopause.

In some instances the sex differences in disease incidence are due to social or behavioural factors. The higher incidence of carcinoma of the lung in males is due to the fact that they smoke more cigarettes than do women.

Racial differences

Racial differences in disease incidence may be genetically determined or attributable to behavioural or environmental factors. Racial differences may also reflect adaptational responses to the threat of disease. A good example is provided by malignant melanoma (Ch. 24). Very strong evidence implicates ultraviolet light in the causation of malignant melanoma of the skin; the highest incidence is in Caucasians living in parts of the world with high ambient levels of sunlight, such as Australia. The tumour is, however, relatively uncommon in Africa, despite its high sunlight levels, because the indigenous population has evolved with an abundance of melanin in the skin; they are classified racially as blacks and benefit from the protective effect of the melanin in the skin.

Some abnormal genes are more prevalent in certain races. For example, the cystic fibrosis gene is carried by 1 in 20 Caucasians, whereas this gene is rare in blacks and Asians. Conversely, the gene causing sickle cell anaemia is more common in blacks than in any other race. These associations may be explained by a heterozygote advantage conferring protection against an environmental pathogen (Table 3.3).

Table 3.3 Associations between disease and race

Other diseases in different races may be due to socio-economic factors. Perinatal mortality rates are often used as an indicator of the socio-economic welfare of a population. Regrettably, the perinatal mortality rate is much higher in certain racial groups, but this outcome is due almost entirely to their social circumstances and is, therefore, theoretically capable of improvement.

Parasitic infestations are more common in tropical climates, not because the races predominantly dwelling there are more susceptible, but often because the parasites cannot complete their life-cycles without other hosts that live only in the prevailing environmental conditions.

Nuclear DNA

Each of the 23 paired human chromosomes contains, on average, approximately 107 base (nucleotide) pairs arranged on the double helix of DNA; genes are encoded in a relatively small proportion of this DNA. To accommodate this length of DNA within the relatively small nucleus, the DNA is tightly folded. The first level of compaction involves wrapping the double helix around a series of histone proteins; the bead-like structures thus formed are nucleosomes. At the second level of compaction, the DNA strands are coiled to form a chromatin fibre and then tightly looped. During metaphase, when the duplicated chromosomes separate before forming the nuclei of two daughter cells, the DNA is even more tightly compacted.

During DNA synthesis (S phase) the bases are copied by complementary nucleotide pairing. Any copying errors are at risk of being inherited by the daughter cells and may result in disease. Copying during DNA synthesis starts in a co-ordinated way at approximately 1000 places along an average chromosome.

Nuclear genes

Genes are encoded by combinations of four nucleotides (adenine, cytosine, guanine, thymine) within DNA. Nuclear DNA is double-stranded with complementary specific bonding between nucleotides on the sense and anti-sense strands—adenine to thymine, guanine to cytosine—the anti-sense strand thereby serving as a template for synthesis of the sense strand. Most of the DNA in eukaryotic (nucleated, e.g. mammalian) cells is within nuclei; a relatively smaller amount resides in mitochondria.

The nuclear DNA in human cells is distributed between 23 pairs of chromosomes: 22 are called autosomes; 1 pair are sex chromosomes (XX in females, XY in males). Only approximately 10% of nuclear DNA encodes functional genes; the remainder comprises a large quantity of anonymous variable and repetitive sequences distributed between genes and between segments of genes. These non-coding sequences include satellite DNA which is highly repetitive, located at specific sites along the chromosomes and probably important for maintaining chromosome structure. A crucial site of repetitive non-coding DNA is the telomere at the ends of each chromosome. Its integrity is essential for chromosomal replication. In cells lacking telomerase (i.e. most somatic cells) the telomeres shorten with each mitotic division, until eventually the cells are incapable of further replication.

The segments of genes encoding for the final product are known as exons; the segments of anonymous DNA between exons are called introns (Fig. 3.3). The exons comprise sequences of codons, triplets of nucleotides each encoding for an amino acid via messenger RNA (mRNA). In addition, there are start and stop codons defining the limits of each gene. Some genes are regulated by upstream promoters. During mRNA synthesis from the DNA template, the introns are spliced out and the exons may be rearranged.

Fig. 3.3 Simplified structure of a gene and its mRNA product. Upstream of the gene is a promoter DNA sequence through which, by specific binding with regulating proteins, the translation of the gene is controlled. Start and termination codons mark the limits of the gene, bounded by untranslated sequences. The encoding portion of the gene is divided into exons, four in this example, interspersed with introns which do not appear in the mRNA product.

Gene transcription and translation

The normal flow of biochemically encoded information is that a messenger RNA transcript is made corresponding to the nucleotide sequence of the gene encoded in the DNA (in RNA, uracil replaces thymine). The RNA transcript comprises nucleotide sequences encoding only the exons of the gene. The RNA is then translated into a sequence of amino acids specified by the code and the protein is assembled.

Under some circumstances, however, the flow of genetic information is reversed. In the presence of reverse transcriptase, an enzyme present in some RNA viruses, a DNA copy can be made from the RNA (Fig. 3.4).

Fig. 3.4 Reverse transcription of DNA from RNA. Normally, the genetic information encoded in DNA is transcribed to RNA and translated into amino acids from which the protein is synthesised. However, some RNA viruses contain reverse transcriptase, an enzyme that produces a DNA transcript of the RNA; this may then be incorporated into the genome of the cell, possibly altering permanently its behaviour and potentially leading to tumour formation (Ch. 11).

Recently, RNA-mediated interference (RNAi) has been discovered as a potentially important mechanism of target gene inhibition. This may have novel therapeutic uses.

Mitochondrial genes

Most inherited disorders are carried on abnormal genes within nuclear DNA. There are, however, a small but significant number of genetic abnormalities inherited through mitochondrial DNA. Mitochondrial DNA differs from nuclear DNA in several important respects; it is characterised by:

The structure of mitochondrial DNA resembles that of bacterial DNA. Consequently, it is postulated that eukaryotic cells acquired mitochondria as a result of an evolutionary advantageous symbiotic relationship with bacteria.

Because the head of the fertilising spermatozoon consists almost entirely of its nucleus, the mitochondria of an individual are derived from the cytoplasm of the mother’s ovum. Thus, mitochondrial disorders are transmitted by females, but may be expressed in males and females.

The genes in mitochondrial DNA encode mainly for enzymes involved in oxidative phosphorylation. Therefore, defects of these enzymes resulting from abnormal mitochondrial genes tend to be associated with clinicopathological effects in tissues with high energy requirements, notably neurones and muscle cells. Examples of disorders due to inheritance of defective mitochondrial genes include familial mitochondrial encephalopathy and Kearns–Sayre syndrome.

Gene therapy

Currently, significant advances are anticipated in the specific treatment of genetic disorders (such as inherited metabolic disorders and cancer). This is the relatively new clinical science of gene therapy.

There are two approaches. First, it may be possible to replace a defective gene with a normal version in the affected tissues. This would be an ideal solution to the problem of inherited disorders such as cystic fibrosis and Duchenne muscular dystrophy. Indeed, attempts are being made to correct the respiratory tract problems in cystic fibrosis by local gene therapy applied by inhalation to the airways. Second, the function of an abnormal gene may be abrogated by administering anti-sense RNA or by RNA-mediated interference, as is being explored for Huntington’s disease.

Modes of inheritance in families

May be inherited as autosomal or sex-linked genes

Genes coding for abnormalities may be dominant or recessive

Abnormal genes may be detected either directly from the presence of the gene itself or the defective product, or indirectly by virtue of its linkage with a detectable polymorphism

Although some inborn errors are attributable to genetic mutations, most are inherited through parental genes. Genes located on autosomes (chromosomes other than the sex chromosomes) are autosomal; genes on the sex chromosomes are sex-linked. By studying the pattern of inheritance in an affected family (Fig. 3.5), the mode of transmission can be classified as either:

Single gene defects inherited as an autosomal dominant are almost twice as common as autosomal recessive disorders. A minority of single gene defects are sex-linked. Most inborn errors of metabolism are autosomal recessive disorders, whereas inherited disorders resulting in structural defects are autosomal dominant disorders; there are, however, exceptions to these general tendencies. A few inherited disorders are sex-linked; haemophilia (Ch. 23) is a notable example.

Chromosomal analysis

The chromosomal constitution of a cell or individual is known as the karyotype. The 46 chromosomes in human nuclei can be seen more clearly during mitosis, especially in metaphase, when they separate. To obtain a sufficient number of cells in metaphase, colchicine can be added to the culture medium in which they are growing; this inhibits polymerisation of tubulin, preventing formation of the mitotic spindle along which the chromosomes migrate and thus blocking cell division in metaphase. The chromosomes can be:

Counting reveals disorders associated with abnormal numbers of chromosomes (e.g. trisomy in, for example, Down’s syndrome). Banding is a technique revealing, at a fairly gross level, the structure of a chromosome (Fig. 3.6). The most widely used technique is G-banding; the chromosomes are first partially digested with trypsin and then treated with Giemsa stain. This reveals alternating light and dark bands characteristic to each chromosome; the light bands comprise euchromatin (gene-rich DNA); the dark bands comprise heterochromatin (rich in repetitive sequences).

Fig. 3.6 Structure of a chromatid after banding. The centromere is a constriction at which the chromatids are joined. The short arm is designated ‘p’ (petit) and the long arm is ‘q’. The arms terminate in telomeres rich in repetitive sequences. The dark bands are numbered in order from the centromere to the tip of each arm; sub-bands are preceded by a decimal point (for example, the cystic fibrosis gene locus is on chromosome 7 and designated 7q31.3).

The size, characteristic banding, and position of the centromere enable each pair of chromosomes to be identified according to a scheme in which they are numbered from 1 to 22 (the sex chromosomes, X or Y, are not identified by number).

Probing for specific DNA sequences (either genes or repetitive sequences) can be done by incubating either chromosome spreads or interphase nuclei with complementary DNA sequences labelled with a reporter molecule such as a fluorescent dye (revealed by ultraviolet microscopy). This powerful technique enables individual genes to be mapped to chromosomes.

Molecular analysis of genetic disorders

With the techniques of molecular biology the genetic abnormality in many disorders can be identified precisely. Formerly, this identification could be done only at the level of the gene product (e.g. the defective protein); now it is possible to locate which part of which chromosome is defective and to determine the gene sequence.

The motivation to study these conditions at the genetic level of detail is twofold:

This approach is yielding important advances, but many inherited disorders are not yet completely characterised at the genetic level.

Prenatal detection can be achieved by the molecular analysis of chorionic villus biopsies in cases known to be at risk.

Functional and positional genetics

There are two possible strategies for the elucidation of the genetic abnormality in genetic diseases—functional and positional (Fig. 3.7). Which strategy is used depends on the nature of the genetic disorder and, in particular, whether the key biochemical abnormality is known.

Fig. 3.7 Functional and positional genetics. Functional genetics is the strategy employed to investigate a genetic disorder in which the biochemical defect is known. This enables determination of the amino acid sequence of the abnormal protein and deduction of the DNA sequence. A complementary DNA probe can then be synthesised and used, for example in diagnostic testing for the abnormality. Positional genetics is employed when the biochemical defect associated with the genetic disorder is unknown. However, the abnormal gene can be located by studying its linkage with neighbouring genes in affected individuals. The gene can then be analysed and the protein encoded by it deduced from the DNA sequence. Complementary DNA can be used as a diagnostic probe and the function of the defective protein can be determined.

If the biochemical abnormality resulting from the genetic defect is known, then the chromosomes or DNA from them can be probed with a complementary DNA sequence corresponding to the gene being investigated. The sequence can be deduced from the amino acid sequence of the known gene product. This is the strategy of functional genetics.

If the biochemical abnormality is not known, it can be determined by an alternative strategy of positional genetics (also called reverse genetics). ‘Positional’ in this context refers to the position of the abnormal gene in relation to well-characterised neighbouring genes with which it is linked on the same chromosome. The neighbouring genes will probably be inherited along with the defective gene, so that by studying the affected and unaffected individuals it may be possible to determine the DNA sequence of the defective gene and deduce the amino acid sequence of the gene product.

Genetic linkages

Immediately prior to meiosis leading to the production of haploid germ cells (ova and spermatozoa) from their diploid precursors, there is a random interchange of DNA segments between the homologous paternally or maternally derived chromosomes to form new, recombinant chromosomes. The process of interchange occurs over such short lengths of DNA that only those genes lying adjacent on chromosomes are likely to remain together and be inherited through successive generations. This phenomenon is useful in positional genetics only if the genes and their products are polymorphic; polymorphic genes show natural (and normal) variations in their base sequences and protein products—HLA types are good examples. This polymorphism enables the gene and its immediate neighbours to be mapped through a family and to the chromosomal level (Fig. 3.8).

Fig. 3.8 Identification of the chromosome locus for an inherited disease by genetic linkage. Prior to meiosis there is interchange of segments of DNA between homologous chromosomes, but adjacent genes are unlikely to be separated by this process. Polymorphic (variant) DNA sequences for normal genes (e.g. for blood groups) or restriction fragment length polymorphisms in ‘anonymous’ DNA may be used as markers for the inheritance of a congenital disease, if the abnormal gene for the disease is on the same part of the same chromosome as the polymorphic marker. In this simplified example showing homologous chromosomes from three different individuals, two of whom are affected by the disease, the evidence favours the abnormal gene being very close to the polymorphic gene A2.

DNA polymorphisms

Although polymorphic genes are useful for the mapping of abnormalities, it must be remembered that most of the DNA in chromosomes is redundant or anonymous; it does not encode any genes and has no phenotypic manifestations. However, because it lacks any function, this anonymous DNA tolerates a higher frequency of polymorphic variation than the DNA in which genes are encoded. In human nuclear DNA, these random polymorphic variations occur in approximately 1 in 200 base pairs. These variations are inherited and can be used to map the inheritance of neighbouring linked genes, even though the neighbouring genes may not have been fully characterised.

These polymorphisms comprise:

• RFLP (restriction fragment length polymorphisms)

• VNTR (variable number tandem repeats)

• satellites—mini- and micro-.

Polymorphic variations arise as a result of:

• substitution of a single base on the DNA strand

• presence of variable numbers of tandem repeats of base sequences.

Variations in anonymous DNA are detected, not by using its polymorphic products (it has none), but by determining the variations in size of the smaller DNA fragments produced by incubation with restriction enzymes. These enzymes, derived from bacteria, break DNA strands at specific points by virtue of the ability of the enzymes to recognise specific sequences of bases. By electrophoretic separation of the broken DNA strands according to their size, it is possible to detect polymorphic differences between individuals (Fig. 3.9).

Fig. 3.9 Restriction fragment length polymorphism. Homologous regions of anonymous DNA from two individuals are shown. The polymorphic variations can be detected as follows: Step 1. The DNA is isolated. Step 2. The DNA is incubated with a restriction enzyme (EcoR1 in this example) that specifically recognises and splits DNA at sites only where there is a GAATTC base sequence. One such site exists in polymorphism A; an additional site is present in polymorphism B. Step 3. The enzymatically digested DNA fragments are loaded on to a gel and separated in an electric field according to their molecular size. After absorption on to a sheet of nitrocellulose filter paper (Southern blot), the location of the fragments of the polymorphous region can be visualised by probing with a radioactive complementary DNA strand. (MW, molecular weight.)

Some gene variants of clinical significance are single nucleotide polymorphisms (SNPs or ‘snips’) resulting from substitution of a single nucleotide. Arbitrarily, such variations must occur in at least 1% of the population to qualify as an SNP. SNPs can predispose to disease; for example, the E4 allelic variant of apolipoprotein E is associated with an increased risk of Alzheimer’s disease (Ch. 26).

Polymerase chain reaction

The polymerase chain reaction (PCR) technique is being used increasingly for the prenatal identification of genetic polymorphisms associated with congenital diseases when the precise base sequence of the polymorphic gene is known (e.g. in cystic fibrosis). The technique is especially applicable to prenatal diagnosis because it enables the abnormal gene to be amplified biochemically from only minute starting samples, even a single cell.

The PCR technique has wide applications in molecular medicine. It is a method of specifically amplifying predetermined segments of DNA from a small sample. The specificity is determined by primers, short DNA sequences complementary to the known flanking regions of the DNA segment being sought. The amplification is achieved by using a type of DNA polymerase enzyme that can withstand the cyclical heating of the reaction mixture necessary to separate the DNA strands and then cooling to permit DNA synthesis. The reaction mixture must also contain free nucleotides for incorporation into the newly synthesised DNA segments. Within a few hours the specific DNA segment, if present in the starting sample, will have been amplified about 1 million-fold. It can then be analysed in a variety of ways including determination of the full DNA sequence.

The PCR technique can be used also to study RNA, first employing reverse transcriptase to produce an amplifiable DNA transcript.

Abnormal chromosome numbers

Abnormal chromosome numbers are usually obvious in karyotypic analyses and are frequently associated with grossly evident morphological abnormalities (Table 3.5). If three copies, rather than the normal pair, of a particular chromosome are present, the abnormality is referred to as trisomy. If only one of the normally paired chromosomes is present, this is monosomy. A complete triploid karyotype resulting from fertilisation of the ovum by two haploid sets of paternal chromosomes is often associated with formation of a partial hydatidiform mole (Ch. 19).

Autosomes

The commonest numerical autosomal abnormality is Down’s syndrome; the features are listed in Table 3.5. The risk of a child being affected by Down’s syndrome increases dramatically with maternal age (Fig. 3.10). In most cases, the abnormality is trisomy 21. Some of the consequences may be attributable to an increased level of gene products encoded on chromosome 21; for example, patients with Down’s syndrome develop changes in their brains similar to those seen in Alzheimer’s disease, characterised by deposition of an amyloid glycoprotein, the gene for which resides on chromosome 21 (Ch. 26).

Fig. 3.10 Down’s syndrome and maternal age. The risk of a child being born with Down’s syndrome increases dramatically with maternal age.

Fragile sites and chromosomal translocations

Some individuals have an inherited predisposition to chromosomal translocations (Table 3.5); that is, there is a tendency for chromosomal material to be exchanged between one chromosome and another. These translocations depend on the presence of ‘fragile sites’ at specific locations on the affected chromosomes. Translocations are often involved in the molecular pathogenesis of cancer (Ch. 11); it is, therefore, not surprising that individuals with these rare conditions associated with an increased risk of translocations have a significantly increased risk of developing tumours.

Although they are rare, study of these conditions enables a better understanding of the functional role of the genes involved in translocations and in the tumours and other abnormalities resulting from them.

Single gene defects

Single gene defects usually cause discrete biochemical or structural abnormalities. For example, most of the inherited metabolic disorders (inborn errors of metabolism) are due to single gene defects (Ch. 7).

As a rule (there are exceptions) single gene abnormali-ties resulting in structural manifestations (e.g. tumours) in adult life are inherited in a dominant manner; those resulting in biochemical abnormalities (e.g. enzyme deficiencies) in childhood are inherited in a recessive manner (Table 3.5)

Single gene defects may result from (Fig. 3.11):

Fig. 3.11 Genetic abnormalities causing disease. The molecular consequence of a genetic abnormality depends on whether the resulting nucleotide sequence corresponds either to a codon for an alternative amino acid (mis-sense mutations) or to a premature stop or non-coding codon (non-sense mutations).

The effect of the genetic alteration may be:

Mechanisms of chemical injury

The cellular mechanisms of chemical injury are described in Chapter 6.

Important chemical agents

There is insufficient space comprehensively to list all chemicals known to be harmful, but major examples are summarised here.

Mechanical injury

Mechanical injury to tissues is called trauma (although by common usage this word has acquired a wider meaning, e.g. ‘psychological trauma’). Cells and tissues are disrupted by trauma, causing cell and tissue loss. Depending on the tissue, regeneration may be possible. The reaction of different tissues to trauma is described in Chapter 6.

Thermal injury

The body is more tolerant of reductions in body temperature than of increases. Indeed, cooling of tissues and organs is commonly used for their short-term preservation prior to transplantation. For major cardiac surgery the body is often cooled to reduce the metabolic requirements of vital organs, such as the brain, when the circulation is temporarily arrested. Accidental hypothermia is a common medical emergency in the elderly during winter in countries such as the UK; however, recovery is usually possible unless the body temperature has fallen below 28°C.

Increased body temperature is known as pyrexia. In infections, it is usually mediated by the action of interleukins on the hypothalamus. Body temperatures above 40oC are associated with increasing mortality. Enzyme systems are severely disturbed, with severe metabolic consequences.

Local heating of the skin causes increasing local damage. Heat coagulates proteins and thereby disrupts the structure and function of cells. As the temperature rises, burns occur in the following ascending order of severity:

Thermal injury is commonly used in surgery to coagulate tissues and arrest bleeding; this is the technique of diathermy.

Radiation injury

Potentially harmful radiant energy is a source of considerable alarm because it is invisible and there is no immediate sensation of its presence.

The effects depend upon the type of radiation, the dose and the type of tissue. Cell and tissue injury from radiation is described in detail in Chapter 6.

Exotoxins

These are enzymes secreted by bacteria and have local or remote effects. Their effects tend to be more specific than those of endotoxins. Examples of exotoxin-mediated effects of bacteria include:

The genes directing the synthesis of exotoxins are usually an intrinsic part of the bacterial genome. In a few instances, however, bacteria acquire the gene in the form of a plasmid, a loop of DNA that can convey genetic information from one bacterium to another; this is also a mechanism by which bacteria can acquire resistance to an antibiotic. Genes encoding for exotoxins can also be transmitted by phages: these are viruses that affect bacteria. The toxin produced by Corynebacterium diphtheriae is encoded on a gene conveyed to the bacterium by a phage; strains of this and other organisms synthesising exotoxins are known as toxigenic.

Occasionally, disease results from the ingestion of preformed exotoxin; this is the mechanism in some cases of food poisoning. A typical, but fortunately rare, example is botulism due to contamination of food with a neurotoxin from Clostridium botulinum. Toxins acting upon the gut are often referred to as enterotoxins.

Endotoxins

These are lipopolysaccharides from the cell walls of Gram-negative bacteria (e.g. Escherichia coli). They are released on death of the bacterium. The most potent is lipid A, a powerful activator of:

When these effects are severe, as in an overwhelming infection, the patient is said to suffer from endotoxic shock. The patient is feverish and hypotensive; cardiac and renal failure may ensue. Disseminated intravascular coagulation may be evinced by bruising and prolonged bleeding from venepuncture sites, as well as more serious internal manifestations. Bilateral adrenal haemorrhage, particularly associated with overwhelming meningococcal infection (Waterhouse–Friderichsen syndrome, Ch. 17), is a dramatic consequence of endotoxic shock.