Chapter 1 Introduction to pathology
Of all the clinical disciplines, pathology is the one that most directly reflects the demystification of the human body that has made medicine so effective and so humane. It expresses the truth underpinning scientific medicine, the inhuman truth of the human body, and disperses the mist of evasion that characterizes folk medicine and everyday thinking about sickness and health.
Pathology is the scientific study of disease. Pathology constitutes a large body of scientific knowledge and investigative methods essential for understanding disease and for effective medical practice.
Pathology embraces the functional and structural changes in disease, from the molecular level to the effects on the individual.
Pathology is continually subject to change, revision and expansion as new scientific research illuminates our knowledge of disease.
The ultimate goal of pathology is the identification of the causes of disease, a fundamental objective leading to successful therapy and to disease prevention.
The evolution of concepts about the causes and nature of human disease reflects the prevailing ideas about the explanation for all worldly events and the techniques available for their investigation (Table 1.1). Thus, the early dominance of animism, in the philosophies of Plato (424–348 bc) and Pythagoras (c. 580–c. 500 bc), resulted in the belief that disease was due to the adverse effects of immaterial or supernatural forces, often as punishment for wrongdoing. Treatment was often brutal and ineffective.
Table 1.1 Historical relationship between the hypothetical causes of disease and the dependence on techniques for their elucidation
| Hypothetical cause of disease | Techniques supporting causal hypothesis | Period |
|---|---|---|
| Animism | None | Primitive, though the ideas persist in some cultures |
| Magic | None | Primitive, though the ideas persist in some cultures |
| Humours (excess or deficiency) | Early autopsies and clinical observations | c. 500 bc to c. ad 1500 |
| Spontaneous generation (abiogenesis) | Analogies with decomposing matter | Prior to ad 1800 |
| Environmental | 1850 to present | |
| Genetic | Molecular pathology (e.g. DNA analysis) and clinical observations on inherited defects | 20th century to present |
Even when the clinical significance of many abnormal physical signs and postmortem findings was established early in the long history of medicine, the underlying disease was thought to be due to an imbalance (‘isonomia’) of the various humours—phlegm, black bile, and so on—as proposed by Empedocles (490–430 bc) and Hippocrates (c. 460–370 bc). These concepts are now firmly and irrevocably consigned to medical antiquity.
Galen (129–c. 200) built on Hippocrates’ naturalistic ideas about disease by giving it an anatomical and physiological basis. However, it was probably Ibn Sina (980–1037)—commonly known as Avicenna — who, by his Canon of Medicine, had the greatest influence on advancing medicine through scientific discovery.
Some of the greatest advances in the scientific study of disease came from the thorough internal examination of the body after death. Autopsies (necropsies or postmortem examinations) have been performed scientifically from about 300bc and have revealed much information that has helped to clarify the nature of many diseases. As these examinations were confined initially to the gross (rather than microscopic) examination of the organs, this period is regarded as the era of morbid anatomy. During the 18th and 19th centuries in Europe, medical science was advanced by Baillie, Rokitansky and Aschoff, who meticulously performed and documented many thousands of autopsies and correlated their findings with the clinical signs and symptoms of the patients and with the natural history of a wide variety of diseases.
Pathology, and indeed medicine as a whole, was revolutionised by the application of microscopy to the study of diseased tissues from about 1800. Before this, it was postulated that tissue alterations in disease resulted from a process of spontaneous generation; that is, by metamorphosis independent of any external cause or other influence. This notion seems ridiculous to us today, but 200 years ago nothing was known of bacteria, viruses, ionising radiation, carcinogenic chemicals, and so on. So Louis Pasteur’s (1822–1895) demonstration that micro-organisms in the environment could contaminate and impair the quality of wine was a major advance in our perception of the environment and our understanding that pathogens within it cause disease.
Rudolf Virchow (1821–1902), a German pathologist and ardent advocate of the microscope, recognised that the cell was the smallest viable constituent unit of the body and he contrived a new and lasting set of ideas about disease—cellular pathology. The light microscope enabled him to see changes in diseased tissues at a cellular level and his observations, extended further by electron microscopy, have had a profound influence. That does not mean to say that Virchow’s cell pathology theory is immutable. Indeed, advances in biochemistry have revolutionised our understanding of many diseases at a molecular level.
The impact of molecular pathology is exemplified by advances in our knowledge of the biochemical basis of congenital disorders and cancer. Techniques with relatively simple principles (less easy in practice) reveal the change of a single nucleotide in genomic DNA resulting in the synthesis of the defective gene product that is the fundamental lesion in a particular disease (Ch. 3).
As a result of the application of modern scientific methods, we now have a clearer understanding of the ways in which diseases can be attributed to disturbances of normal cellular and molecular mechanisms (Table 1.2).
Table 1.2 Examples of the involvement of cellular and extracellular components in disease
| Component | Normal function | Examples of alterations in disease |
|---|---|---|
| Cellular | ||
| Nucleus | Genes encoded in DNA | |
| Mitochondria | Oxidative metabolism | |
| Lysosomes | Enzymic degradation | Functional defects cause metabolic storage disorders and defects in microbial killing |
| Cell membrane | Functional envelope of cell | Defects in ion transfer (e.g. cystic fibrosis, hereditary spherocytosis) |
| Adhesion molecules | Cellular adhesion | |
| HLA molecules | Immune recognition | |
| Receptors | Specific recognition | |
| Secreted products | ||
| Collagen | Mechanical strength of tissues | |
| Immunoglobulins | Antibody activity in immune reactions | |
| Nitric oxide | Endothelium-derived relaxing factor causing vasodilatation, inhibition of platelet aggregation and of proliferation | Increased levels in endotoxic shock and in asthma |
| Hormones | Control of specific target cells | Excess or deficiency due to disease of endocrine organs |
| Cytokines | Regulation of inflammatory and immune responses and of cell proliferation | Increased levels in inflammatory, immunological and reparative tissue reactions |
| Free radicals | Microbial killing | Inappropriate or excessive production causes tissue damage |
Pathology is the foundation of medical practice. Without pathology, the practice of medicine would still rely on myths and folklore.
Scientific knowledge about human diseases is derived from observations on patients or, by analogy, from experimental studies on animals and cell cultures. The greatest contribution comes from the detailed study of tissue and body fluids from patients. Pathology has a key role in translational research by facilitating the transfer of knowledge derived from laboratory investigations into clinical practice.
Clinical medicine is based on a longitudinal approach to a patient’s illness—the patient’s history, the examination and investigation, the diagnosis, and the treatment. Clinical pathology is more concerned with a cross-sectional analysis at the level of the disease itself, studied in depth—the cause and mechanisms of the disease, and the effects of the disease upon the various organs and systems of the body. These two perspectives are complementary and inseparable: clinical medicine cannot be practised without an understanding of pathology; pathology is meaningless if it is bereft of clinical implications.
In the UK, it is estimated that c.70% of clinical diagnoses rely on pathology investigations. In the USA, c.90% of the objective data in electronic patient records are derived from pathology laboratories.
Pathology is a vast subject with many ramifications. In practice, however, it has major subdivisions:
These subdivisions are more important professionally (because each requires its own team of expert specialists) than educationally at the undergraduate level. The subject must be taught and learnt in an integrated manner, for the body and its diseases make no distinction between these professional subdivisions.
This book, therefore, adopts a multidisciplinary approach to pathology. In the systematic section (Part 3), the normal structure and function of each organ is summarised, the pathological basis for clinical signs and symptoms is described, and the clinical implications of each disease are emphasised.
Experimental pathology is the observation of the effects of manipulations on experimental systems such as animal models of disease or cell cultures. Although advances in cell culture technology have reduced the usage of laboratory animals in medical research and experimental pathology, it is extremely difficult to mimic in cell cultures the physiological milieu that prevails in the intact human body.
Our knowledge of the nature and causation of disease has been disclosed by the continuing application of technology to its study.
Before microscopy was applied to medical problems (c.1800), observations were confined to those made with the unaided eye, and thus was accumulated much of our knowledge of the morbid anatomy of disease. Gross or macroscopic pathology is the modern nomenclature for this approach to the study of disease and, especially in the autopsy, it is still an important investigative method.
The gross pathology of many diseases is so characteristic that, when interpreted by an experienced pathologist, a fairly confident diagnosis can often be given before further investigation by, for example, light microscopy.
Advances in optics have yielded a wealth of new information about the structure of tissues and cells in health and disease.
If solid tissues are to be examined by light microscopy, the sample must first be thinly sectioned to permit the transmission of light and to minimise the superimposition of tissue components. These sections are routinely cut from tissue hardened by permeation with and embedding in wax or, less often, transparent plastic. For some purposes (e.g. histochemistry, very urgent diagnosis) sections have to be cut from tissue that has been hardened rapidly by freezing. The sections are stained to help distinguish between different components of the tissue (e.g. nuclei, cytoplasm, collagen).
The microscope can also be used to examine cells from cysts, body cavities, sucked from solid lesions or scraped from body surfaces. This is cytology and is used widely in cancer diagnosis and screening.
Histochemistry is the study of the chemistry of tissues, usually by microscopy of tissue sections after they have been treated with specific reagents so that the features of individual cells can be visualised.
Immunohistochemistry and immunofluorescence employ antibodies (immunoglobulins with antigen specificity) to visualise substances in tissue sections or cell preparations; these techniques use antibodies linked chemically to enzymes or fluorescent dyes, respectively. Immunofluorescence requires a microscope specially modified for ultraviolet illumination and the preparations are often not permanent (they fade). For these reasons, immunohistochemistry has become more popular; in this technique, the end product is a deposit of opaque or coloured material that can be seen with a conventional light microscope and does not deteriorate. The repertoire of substances detectable by these techniques has been greatly enlarged by the development of monoclonal antibodies.
Electron microscopy has extended the range of pathology to the study of disorders at an organelle level, and to the demonstration of viruses in tissue samples from some diseases. The most common diagnostic use is for the interpretation of renal biopsies.
Biochemical techniques applied to the body’s tissues and fluids in health and disease are now one of the dominant influences on our growing knowledge of pathological processes. The clinical role of biochemistry is exemplified by the importance of monitoring fluid and electrolyte homeostasis in many disorders. Serum enzyme assays are used to assess the integrity and vitality of various tissues; for example, raised blood levels of cardiac enzymes and troponin indicate damage to cardiac myocytes.
Haematological techniques are used in the diagnosis and study of blood disorders. These techniques range from relatively simple cell counting, which can be performed electronically, to assays of blood coagulation factors.
Cell cultures are widely used in research and diagnosis. They are an attractive medium for research because of the ease with which the cellular environment can be modified and the responses to it monitored. Diagnostically, cell cultures are used to prepare chromosome spreads for cytogenetic analysis.
Medical microbiology is the study of diseases caused by organisms such as bacteria, fungi, viruses and parasites. Techniques used include direct microscopy of appropriately stained material (e.g. pus), cultures to isolate and grow the organism, and methods to identify correctly the cause of the infection. In the case of bacterial infections, the most appropriate antibiotic can be selected by determining the sensitivity of the organism to a variety of agents.
Molecular pathology reveals defects in the chemical structure of molecules arising from errors in the genome, the sequence of bases that directs amino acid synthesis. Using in situ hybridisation it is possible to visualise specific genes or their messenger RNA in tissue sections or cell preparations. Minute quantities of nucleic acids can be amplified by the use of the polymerase chain reaction using oligonucleotide primers specific for the genes being studied.
DNA microarrays can be used to determine patterns of gene expression (mRNA). This powerful technique can reveal novel diagnostic and prognostic categories, indistinguishable by other methods.
Molecular pathology is manifested in various conditions, for example: abnormal haemoglobin molecules, such as in sickle cell disease (Ch. 23); abnormal collagen molecules in osteogenesis imperfecta (Chs 7, 25); and alterations in the genome governing the control of cell and tissue growth, playing a pivotal role in the development of tumours (Ch. 11).
Pathology is best learnt in two stages:
General pathology is our current understanding of the causation, mechanisms and characteristics of the major categories of disease.
These processes are covered in Part 2 of this textbook and many specific diseases are mentioned by way of illustration. The principles of general pathology must be understood before an attempt is made to study systematic pathology. General pathology is the foundation of knowledge that has to be acquired before studying the systematic pathology of specific diseases.
Systematic pathology is our current knowledge of specific diseases as they affect individual organs or systems. (‘Systematic’ should not be confused with ‘systemic’. Systemic pathology would be characteristic of a disease that pervaded all body systems!) Each specific disease can usually be attributed to the operation of one or more categories of causation and mechanism featuring in general pathology. Thus, acute appendicitis is acute inflammation affecting the appendix; carcinoma of the lung is the result of carcinogenesis acting upon cells in the lung, and the behaviour of the cancerous cells thus formed follows the pattern established for malignant tumours; and so on.
There are two apparent difficulties facing the new student of pathology: language and process. Pathology, like most branches of science and medicine, has its own vocabulary of special terms. These need to be learnt and understood not just because they are the language of pathology: they are also a major part of the language of clinical medicine. The student must not confuse the learning of the language with the learning of the mechanisms of disease and their effects on individual organs and patients. In this book, each important term will be clearly defined in the main text or the glossary, or both.
A logical and orderly way of thinking about diseases and their characteristics must be cultivated. For each disease entity the student should be able to list the chief characteristics:
Our knowledge about many diseases is still incomplete, but at least such a list will prompt the memory and enable students to organise their knowledge.
Pathology is learnt through a variety of media. Even the bedside, operating theatre and outpatient clinic provide ample opportunities for further experience of pathology; hearing a diastolic cardiac murmur through a stethoscope should prompt the listening student to consider the pathological features of the narrowed mitral valve orifice (mitral stenosis) responsible for the murmur, and the effects of this stenosis on the lungs and the rest of the cardiovascular system.
Although medicine, surgery, pathology and other disciplines are still taught as separate subjects in some curricula, students must develop an integrated understanding of disease.
To encourage this integration, in this textbook the pathological basis of common clinical signs is frequently emphasised so that students can relate their everyday clinical experiences to their knowledge of pathology.
In general, the development of a clinicopathological understanding of disease can be gained by two equally legitimate and complementary approaches:
In learning pathology, the disease-oriented approach is more relevant because medical practitioners require knowledge of diseases (e.g. pneumonia, cancer, ischaemic heart disease) so that correct diagnoses can be made and the most appropriate treatment given.
The problem-oriented approach is the first step in the clinical diagnosis of a disease. In many illnesses, symptoms alone suffice for diagnosis. In other illnesses, the diagnosis has to be supported by clinical signs (e.g. abnormal heart sounds). In some instances, the diagnosis can be made conclusively only by special investigations (e.g. laboratory analysis of blood or tissue samples, imaging techniques).
The links between diseases and the problems they produce are emphasised in the systematic chapters (Part 3) and are exemplified here (Table 1.3).
Table 1.3 The problem-oriented approach: examples of combinations of clinical problems and their pathological basis
| Problems | Pathological basis (diagnosis) | Comment |
|---|---|---|
| Weight loss and haemoptysis | Lung cancer or tuberculosis | Can be distinguished by finding either cancer cells or mycobacteria in sputum |
| Dyspnoea and ankle swelling | Heart failure | Due to, for example, valvular disease |
| Chest pain and hypotension | Myocardial infarction | Should be confirmed by ECG and serum assay of cardiac enzymes |
| Vomiting and diarrhoea | Gastroenteritis | Specific microbial cause can be determined |
| Headache, impaired vision and microscopic haematuria | Hypertension | May be due to various causes or, more commonly, without evident cause |
| Headache, vomiting and photophobia | Subarachnoid haemorrhage or meningitis | Can be distinguished by other clinical features and examination of cerebrospinal fluid |
The disease-oriented approach is the most appropriate way of presenting pathological knowledge. It would be possible to produce a textbook of pathology in which the chapters were entitled, for example, ‘Cough’, ‘Weight loss’, ‘Headaches’ and ‘Pain’ (these being problems), but the reader would be unlikely to come away with a clear understanding of the diseases. This is because one disease may cause a variety of problems—for example, cough, weight loss, headaches and pain—and may therefore crop up in several chapters. Consequently, this textbook, like most textbooks of pathology (and, indeed, of medicine), adopts a disease-oriented approach.
Diagnosis is the act of naming a disease in an individual patient. The diagnosis is important because it enables the patient to benefit from treatment that is known, or is at least likely, to be effective from having observed its effects on other patients with the same disease.
The process of making diagnoses involves:
Although experienced clinicians can diagnose many patients’ diseases quite rapidly (and usually reliably), the student will find that it is helpful to adopt a formal strategy based on a series of logical steps leading to the gradual exclusion of various possibilities and the emergence of a single diagnosis. For example:
This strategy can be refined and presented in the form of decision trees or diagnostic algorithms, but these details are outside the scope of this book.
In living patients we often investigate and diagnose their illness by applying pathological methods to the examination of tissue biopsies and body fluids. If there are clinical indications to do so, it may be possible to obtain a series of samples from which the course of the disease can be monitored.
The applications of pathology in clinical diagnosis and patient management are described in Chapter 4.
Autopsy (necropsy and postmortem examination are synonymous) means to ‘see for oneself’. In other words, rather than relying on clinical signs and symptoms and the results of diagnostic investigations during life, here is an opportunity for direct inspection and analysis of the organs.
The clinical use of information from autopsies is described in Chapter 4.
For the medical undergraduate and postgraduate, the autopsy is an important medium for the learning of pathology. It is an unrivalled opportunity to correlate clinical signs with their underlying pathological explanation.
Although pathology, as practised professionally, is a laboratory-based clinical discipline focused on the care of individual patients and the advancement of medical knowledge, our ideas about the causes of disease, disability and death have wide implications for society.
There is socially (and politically) relevant controversy about what actually constitutes the cause of a disease. Critics argue that the science of pathology leads to the identification of merely the agents of some diseases rather than their underlying causes. For example, the bacterium Mycobacterium tuberculosis is the infective agent resulting in tuberculosis but, because many people exposed to the bacterium alone do not develop the disease, social deprivation and malnutrition (both of which are epidemiologically associated with the risk of tuberculosis) might be regarded by some as the actual causes. Without doubt, the marked fall in the incidence of many serious infectious diseases during the 20th century was achieved at least as much through improvements in housing, hygiene, nutrition and sewage treatment as by specific immunisation and antibiotic treatment directed at the causative organisms. This distinction between agents and causes is developed further in Chapter 3.
Because the methods used in pathology enable reliable diagnoses to be made, either during life by, for example, biopsy or after death by autopsy, the discipline has an important role in documenting the incidence of disease in a population. Cancer registration data are most reliable when based on histologically proven diagnoses; this happens in most cases. Epidemiological data derived from death certificates are notoriously unreliable unless verified by autopsy. The information thus obtained can be used to determine the true incidence of a disease in a population and the resources for its prevention and treatment can be deployed where they will achieve the greatest benefit.
Laboratory methods are used increasingly for the detection of early disease by population screening. The prospects of cure are invariably better the earlier a disease is detected.
For example, the incidence of death from cancer of the cervix is lowered by screening programmes; in many countries, women have their cervix scraped at regular intervals and the exfoliated cells are examined microscopically to detect the earliest changes associated with development of cancer. Screening for breast cancer is primarily by mammography (X-ray imaging of the breast); any abnormalities are further investigated either by examining cells aspirated from the suspicious area or by histological examination of the tissue itself.