Nelson’s Organic Pathology Contents 1. The cell and cell injury 3 2. Cellular adaption and ageing 18 3. Acute inflammation 24 4. Healing 36 5. Chronic inflammation 44 6. Immunopathology 53 7. Resistance to infection 64 8. Immune deficiency 69 9. Granulomatous diseases 74 10. The effects of infection and injury on the body 86 11. Fluids and ions 97 12. Oedema and congestion 102 13. Hypertension 107 14. Atherosclerosis and aneurysms 113 15. Thrombosis, embolism, and infarction 121 16. Congenital and inherited disorders 130 17. Neoplasia 138 18. Iatrogenic disease 166 19. Alimentary system 168 20. Liver, gall-bladder and pancreas 185 21. Cardiovascular system 199 22. Respiratory system 208 23. Urinary system 222 24. Reproductive system 231 25. Breast 239 26. Endocrine system 241 27. Haemopoietic and lymphoid tissues 251 28. Connective tissue diseases 260 29. Musculo-skeletal system 264 30. Nervous system 271 1. The cell and cell injury STRUCTURE AND FUNCTION OF CELL COMPONENTS Nucleus The nucleus is composed principally of deoxyribonucleic acid (DNA) in combination with a protein (histone) within a ground substance. The nucleic acid material (chromatin) stains well with basic dyes such as haematoxylin and methylene blue, and DNA can be stained specifically by the Feulgen technique. Chromatin patterns vary from cell to cell. The plasma cell, for example, has a distinctive 'cartwheel' pattern. The nucleus is separated from the cytoplasm by a double membrane - the nuclear envelope - containing circular holes 50 to 70 nm in diameter - nuclear pores. The pores, which are usually crossed by a diffuse membrane, probably represent the sites of interchange between nucleus and cytoplasm. Functions of the nucleus 1. Replication of DNA 2. Production of messenger RNA 3. Synthesis of some nuclear proteins Nucleolus The nucleus normally contains one or more small basophilic structures - nucleoli, composed of a dense network (nucleolonema) enclosing paler areas (the pars amorpha). The granules of the nucleolonema are thought to represent newly-synthesised ribosome subunits which pass out of the nucleus along with messenger RNA and direct the synthesis of specific proteins in the cytoplasm. Cytoplasm Cytosol differs from extracellular fluid in having a high concentration of potassium, magnesium and phosphate. Sodium is actively excluded by the ATP-dependent 'sodium-pump' across the cell membrane. Many functions reside in the cytosol or cytoplasmic matrix, namely: 1. Glycolysis 2. Some reactions in gluconeogenesis 3. Activation and synthesis of some amino acids 4. Fatty acid synthesis 5. Mononucleotide synthesis 6. Phosphogluconate pathway 7. Second messenger signalling pathways Mitochondria These round, ovoid, or sinuous cytoplasmic organelles possess a complete outer trilaminar membrane and an inner membrane which shows numerous infoldings termed cristae. Although all mitochondria have this basic structure there is considerable variability both in the number and length of the cristae and in the number and general outline of the mitochondria. Cells with a high metabolic activity have large mitochondria with numerous cristae, for example cardiac muscle and gastric parietal cells. In the liver, whilst the mitochondria are large, the cristae are sparse and irregular. Mitochondria contain most of the enzymes of the citric acid cycle and the energy derived from the oxidation of acetyl Co-A in the cycle is used to convert adenosine diphosphate to triphosphate - oxidative phosphorylation. 2 Endoplasmic reticulum All cells contain a system of complex paired membranes enclosing small vesicles or channels - the cisternae. These membranes form the endoplasmic reticulum (ER) and are either studded with ribosomes forming so-called rough ER or are devoid of granules and are termed smooth ER. The main function of the rough ER, together with free ribosomes in the cytoplasm, is protein synthesis. Protein produced by the rough ER is usually for export via the Golgi apparatus. Ribosomes are basophilic so that the cytoplasm of cells capable of rapid protein synthesis stains well with haematoxylin or pyronin. Examples of cells showing such cytoplasmic basophilia are plasma cells, exocrine cells of the pancreas, and hepatocytes. The smooth ER is concerned with synthesis of triglycerides from free fatty acids, drug metabolism and detoxification, glycogen synthesis, and the synthesis of steroid hormones. Cells rich in smooth ER (as well as mitochondria) show a greater affinity for acidic dyes such as eosin and acid fuchsin. The Golgi apparatus The Golgi apparatus is a series of membrane lamellae, membranebound vacuoles and small vesicles, best seen in secretary cells such as those of the exocrine pancreas, goblet cells, and the absorptive cells of the gut. The Golgi is thought to package secretions which reach it through the cisternae of the ER. The secretion granules then bud off and migrate to the apex of the cell. Microfilaments Microfilaments are thin filaments with an average diameter of 6 nm composed of polymerised actin. They are usually found in bundles within a network and are important in retaining the shape of cells and in cell motility. Microtubuies Microtubuies are non-contractile structures, about 25 nm in diameter, and of variable length. They are composed of subunits (dimers) of tubulin which can be rapidly re- assembled thus providing a dynamic cytoskeleton, and are found in cilia and flagella as well as forming mitotic spindles and centrioles in all types of cells. Microtubuies are involved in: 1. Maintaining the cytoskeleton 2. Mitotic division 3. Transport pathways for secretions and other organelles 4. Ciliary activity 5. Phagocytosis 6. Sensory transduction, e.g. in polymorphs 7. Cell motility Intermediate filaments 3 Intermediate filaments are tubular structures 7-11 nm in diameter composed of polymers of one or more (up to 10) polypeptides. The various polymers show a degree of tissue specificity and their detection has proved useful in the characterisation of tumour cells. Tissue specificity is as follows: 1. Vimentin - mesenchymal cells 2. Desmin - muscle cells 3. Cytokeratins - epithelial cells 4. Neurofilaments - neurones 5. Glial fibrillary acidic protein - glial cells Lysosomes These are rounded, membrane-bound bodies showing wide variation in their size, shape, and internal structure. They are the main components of an intracellular digestive system and contain numerous hydrolases active at acid pH, such as phosphatase, betaglucuronidase, esterases, ribonuclease and deoxyribonuclease. The digestive activity is generally contained within the lysosomes themselves. In heterophagy exogenous material enters the cell by endocytosis and the vacuole thus formed fuses with primary lysosomes, probably produced by the Golgi apparatus. In autophagy, damaged cytoplasmic components are enveloped to form an autophagic vacuole which fuses with primary lysosomes. Digestion proceeds in the secondary lysosomes so-formed and products diffuse out to be re-utilised by the cell. Undigested material can in some instances be expelled by exocytosis, otherwise it remains in the cell as a residual dense body. Examples of proteins taken into cells and digested within lysosomes are: 1. Haemoglobin 2. Native immunoglobulin and immune complexes 3. Denatured proteins 4. Protein reabsorption in renal tubules Lysosomes are important in: 1. Polymorphs and macrophages in killing and digesting infective agents 2. Removal of unwanted cells during embryonic development 3. Disposal of excess secretary products in glandular cells 4. Osteociastic remodelling of bone by secreted enzymes 5. Supply of nutrients, e.g. in liver Microbodies Microbodies or peroxisomes consist of a homogeneous matrix sometimes containing a central crystalline nucleus enclosed in a single membrane. They contain a number of enzymes, including amino-acid oxidases, urate oxidase and catalase, and are most numerous in liver and kidney cells. Their role in the cell economy is obscure but one of their functions may be the regulation of blood lipid levels. Cell membrane 4 Cells are enclosed by a unit membrane composed of lipids, proteins, and oligo- and polysaccharides. The membrane is essentially a phospholipid bilayer with the hydrophobic lipid moieties internalised and the proteins (and glycoproteins) present as: 1. Integral membrane proteins - globular proteins intercalated to varying depths within the bilayer and in some instances completely spanning the membrane. Integrated glycoproteins are always arranged so that their carbohydrate moieties are exposed at the cell surface where they act as specific receptor molecules. Whilst some integral proteins are capable of lateral movement within the lipid bilayer (thus altering the molecular pattern presented at the surface) others appear to be attached to microtubules and microfilaments and mediate 'transmembrane cytoskeletal control' 2. Peripheral membrane proteins - are not essential to structural integrity and are bound to integral proteins or glycolipids by ionic bonds. The cell membrane has a number of important functions: 1. Intake of exogenous material by phagocytosis, pinocytosis or micropinocytosis 2. Selective permeability 3. The ATP-associated sodium-pump which actively shifts sodium ions across the membrane out of the cytoplasm 4. Cell-to-cell contact and adhesion by means of junctional complexes - tight junction, intermediate junction, and desmosome 5. Contact inhibition - the mechanism whereby further proliferation and movement of cells is inhibited