Several mechanisms have been suggested for the pathogenesis:

• Matrix loss is caused by the action of matrix metalloproteinases such as collagenase (MMP-1), gelatinase (MMP-2) and stromelysin (MMP-3). These are secreted by chrondrocytes in an inactive form. Extracellular activation then leads to the degradation of collagen and proteoglycans.
• Tissue inhibitors of metalloproteinases (TIMPs) regulate the MMPs. Disturbance of this regulation may lead to increased cartilage degradation and contribute to the development of OA.
• There is synovial inflammation in OA, producing interleukin-1 (IL-1) and tumour necrosis factor (TNF-α). These cytokines stimulate metalloproteinase production and IL-1 inhibits type II collagen production.
• Growth factors, including insulin-like growth factor (IGF-1) and transforming growth factor (TGF-β), are involved in collagen synthesis, and their deficiency may play a role in impairing matrix repair.
• Vascular endothelial growth factor from macrophages is a potent stimulator of angiogenesis and may contribute to inflammation and neovascularization in OA.
• Mutations in the gene for type II collagen (COL2A1) have been associated with early polyarticular OA.
• Twin studies suggest a strong hereditary element underlying OA, and further studies may reveal genetic markers for the disease. The influence of genetic factors is estimated at 35-65%.
• In the Caucasian population there is an inverse relationship between the risk of developing OA and osteoporosis.
• A large population study has suggested that a high intake of vitamin C and other antioxidants may reduce the risk of OA. The lack of antioxidants is thought to contribute to many ageing processes.
• In women, weight-bearing sports produce a two- to threefold increase in risk of OA of the hip and knee.
• In men, there is an association between hip OA and certain occupations – farming and labouring.
• Obesity is a risk factor for developing OA in later life.

The term primary OA is sometimes used when there is no obvious known predisposing factor.

Box 10.5 shows some of the predisposing factors for the development of OA, whilst Table 10.11 shows other conditions that sometimes cause secondary arthritis.

Patients present with tumour site-specific symptoms, e.g. pain, and physical signs, e.g. a mass, which readily identify the primary site of the cancer. On the other hand, many seek medical attention when more systemic and non-specific symptoms occur such as weight loss, fatigue, and anorexia. These usually indicate a more advanced stage of the disease except in some paraneoplastic and ectopic endocrine syndromes (see below). Other patients are only diagnosed upon the discovery of established metastases such as the back pain of metastatic prostatic cancer or the liver enlargement of metastatic gastrointestinal cancer.

Other indirect effects of the cancer manifest as paraneoplastic syndromes (Box 9.1) that are often associated with specific types of cancer and are reversible with treatment of the cancer. The effects and mechanisms can be very variable. For example in the Lambert-Eaton syndrome there is cross-reactivity between tumour antigens and the normal tissues, e.g. the acetylcholine release at neuromuscular junctions.

The coagulopathy of cancer may present with thrombophlebitis, deep venous thrombosis and pulmonary emboli, particularly in association with cancers of pancreas, stomach and breast.

Other symptoms are related to peptide or hormone release, e.g. carcinoid or Cushing’s syndrome.

Cachexia of advanced cancer is due to release of chemokines such as tumour necrosis factor (TNF), as well as the fact that patients have a loss of appetite.

Cancer-associated immunosuppression can lead to reactivation of latent infections such as herpes zoster.

Fever

Body temperature is controlled by the thermoregulatory centre in the anterior hypothalamus in the floor of the third ventricle. Gram-negative bacteria contain lipopolysaccharide (LPS) and peptidoglycan, which is also a component of Gram-positive bacterial cell walls. Toll-like receptors (TLR) on monocytes and dendritic cells recognize these lipopolysaccharides and generate signals leading to formation of inflammatory cytokines, e.g. IL-1, -6, -12, TNF-α and many others. These cytokines act on the thermoregulatory centre by increasing prostaglandin (PGE2) synthesis. The antipyretic effect of salicylates is brought about, at least in part, through its inhibitory effects on prostaglandin synthase.

Fever production has a positive effect on the course of infection. However, for every 1°C rise in temperature, there is a 13% increase in resting metabolic rate and oxygen consumption. Fever therefore leads to increased energy requirements at a time when anorexia leads to decreased food intake. The normal compensatory mechanisms in starvation (e.g. mobilization of fat stores) are inhibited in acute infections. This leads to an increase in skeletal muscle breakdown, releasing amino acids, which, via gluconeogenesis, are used to provide energy.

Tumour necrosis factor (TNF)

TNF-α is released from a variety of phagocytic cells (macrophages/monocytes) and TNF-β from non-phagocytic cells (lymphocytes, natural killer cells) in response to infections (bacterial endotoxin) and inflammatory stimuli. TNF itself then stimulates the release of a cascade of other mediators involved in inflammation and tissue remodelling, such as interleukins (IL-1 and IL-6), prostaglandins, leukotrienes and corticotropin. TNF is therefore responsible for many of the effects of an infection.

The biological behaviour of the pathogen and the consequent host response are responsible for the clinical expression of disease that often allows clinical recognition. The incubation period following exposure can be helpful (e.g. chickenpox 14-21 days). The site and distribution of a rash may be diagnostic (e.g. shingles) while symptoms of cough, sputum and pleuritic pain point to lobar pneumonia. Fever and meningismus characterize classical meningitis. Infection may remain localized or become disseminated and give rise to the sepsis syndrome and disturbances of protein metabolism and acid-base balance. Many infections are self-limiting, and immune and non-immune host defence mechanisms will eventually clear the pathogens. This is generally followed by tissue repair, which may result in complete resolution or leave residual damage.

Tumour cell death may also be dysregulated. Normal cells usually die by an active and tightly regulated process known as apoptosis, or ‘programmed cell death’. Apoptosis can occur in response to a number of physiological or pathological stimuli (tumour necrosis factor, Fas ligand, and DNA-damaging cytotoxic drugs) and is mediated within the cell by a family of proteins known as caspases. Caspase activity is, in turn, regulated by intracellular inhibitors such as the Bcl-2 family of proteins and the inhibitor of apoptosis proteins (IAPs). Disturbances in the normal balance of these various proteins have been identified which favour survival of tumour cells over their normal counterparts. An example is the upregulation of the bcl-2 protein in follicular non-Hodgkin’s lymphoma.

Haemopoietic growth factors are glycoproteins which regulate the differentiation and proliferation of haemopoietic progenitor cells and the function of mature blood cells. They act on receptors expressed on haemopoietic cells at various stages of development to maintain the haemopoietic progenitor cells and to stimulate increased production of one or more cell lines in response to stresses such as blood loss and infection.

The pluripotential stem cells are under the influence of a number of haemopoietic growth factors including interleukin-3 (IL-3), IL-6, -7, -11, β-catenin and stem cell factor (SCF, Steel factor or C-kit ligand). Colony-stimulating factors (CSFs, the prefix indicating the cell type, as well as interleukins and erythropoietin (EPO) regulate the lineage committed progenitor cells. Thrombopoietin (TPO, which, like erythropoietin, is produced in the kidneys and the liver) along with IL-6 and IL-11 control platelet production. In addition to these factors stimulating haemopoiesis, other factors inhibit the process and include tumour necrosis factor (TNF) and transforming growth factor-β (TGF-β). Many of the growth factors are produced by activated T cells, monocytes and bone marrow stromal cells such as fibroblasts, endothelial cells and macrophages; these cells are also involved in inflammatory responses.

Many growth factors have been produced by recombinant DNA techniques and are being used clinically. Examples include G-CSF, which is used to accelerate haemopoietic recovery after chemotherapy and haemopoietic cell transplantation, and erythropoietin, which is used to treat anaemia in patients with chronic renal failure. Thrombopoietin is undergoing clinical trials in patients with idiopathic thrombocytopenic purpura.