Pathology at a Glance E-Book

Barry Newell

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: At a Glance
• Sprache: Englisch

Seitenzahl: 642

Veröffentlichungsjahr: 2021

Beschreibung

Following the familiar, easy-to-use at a Glance format and in full-colour, Pathology at a Glance is an accessible introduction and revision text for medical students. Reflecting changes to the curriculum content and assessment methods employed by medical schools, this new edition provides a user-friendly overview of pathology to encapsulate all that the student needs to know.

Pathology at a Glance, Second Edition:

• Addresses the key principles of pathology that are central to medicine
• Contains full-colour artwork throughout, making the subject easy to understand
• Presents schematic diagrams on the left page and concise explanations on the right
• Is divided into three sections, covering general and systematic pathology and clinical case examples
• Contains self-assessment material, including 10 structured case study questions
• Covers general pathology mechanisms and the clinical pathology of body systems
• Provides key information on the epidemiology, pathogenesis and clinical features of the major diseases
• Revision of many chapters, particularly gynaecological pathology, acute cardiac syndromes, paediatric tumours and haematopathology

This book is an invaluable resource for all medical students, of equal benefit for those starting their study of pathology or approaching finals; for junior doctors approaching their membership exams and anybody who needs a handy reference.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Dedication

Preface

Acknowledgements

Abbreviations

General pathology

Introduction

1 The normal human cell

Nucleus

Cytosol

Cytoskeleton

Organelles

2 Fluid dynamics

Electrolytes

Blood and blood filtration

Lymphatic system

Transudates

Exudate

Tissue damage

3 Tissue types and the effect of tissue damage

Normal tissue types

Proliferative and regenerative capacity

Tissue necrosis

Types of infarction

4 Cell death

Apoptosis

Necrosis

Autophagy

Free radicals

5 Harmful agents in the environment

Environmental pollution

Physical agents

Chemical agents

Water

Infectious agents

6 The effects of tobacco, alcohol and other drugs

Tobacco

Alcohol

General observations regarding common therapeutic and addictive drugs

7 Nutritional disorders

Nutritional deficiency

Obesity

Inflammation and immunity

8 The body's natural defences

Epithelial barriers

Types of immunity

Cells involved in the innate immune response

Protein mediators

Key events in the innate immune response

Adaptive immunity

9 B cells and immunoglobulins

Immunoglobulin structure and subtypes

Immunoglobulin variability

Limitation of the B‐cell response

10 T cells and the TCR

T cell receptor

T helper cells (Th cells)

Cytotoxic T cells (CTL)

Memory T cells (Tm)

Limiting the T‐cell response

11 The major histocompatibility complex

MHC class I molecules

MHC class II molecules

Tissue transplantation

Bone marrow transplantation

12 Primary and secondary lymphoid organs and the monocyte–macrophage (reticuloendothelial) system

Monocyte–macrophage system (also called the reticuloendothelial system)

Bone marrow

Lymphoid organs

13 Acute inflammation

Systemic effects

14 Chronic inflammation

Special types of chronic inflammation

15 Wound healing and repair

Wound healing

Wound healing at other sites

Complications of healing

16 Infection and immunodeficiency

Infective agents

Immunodeficiency

17 Shock

Definition

Causes

Clinical consequences

Acute tubular necrosis (ATN)

Adult respiratory distress syndrome (ARDS, ‘shock lung’)

18 Tolerance and autoimmune disease

B‐cell tolerance

T‐cell tolerance

Autoimmune diseases

19 Hypersensitivity reactions

Type I hypersensitivity (allergic and anaphylactic responses)

Type II hypersensitivity

Type III hypersensitivity

Type IV hypersensitivity (delayed hypersensitivity)

20 Overview of inflammation and immunity

Immune system

Summary

Genetics

21 Cell division

Mitosis

Meiosis

Terminology

22 Genetic disease

Chromosomal disorders

Autosomal disorders

X‐linked disorders

Mitochondrial disorders

Neoplasia

23 Disordered cell growth

Developmental disorders

Non‐tumorous growth disorders

24 Basic concepts in neoplasia

Nomenclature

Benign tumours

Malignant tumours

25 Tumorigenesis and oncogenesis

DNA protection

Control of cell division

Theories of oncogenesis

Target cells

Causes of mutation

26 Oncogenes and tumour suppressor genes

Oncogenes

Tumour suppressor genes

Telomerase

Role of genetic testing in tumour investigation and treatment

27 Common carcinoma histological subtypes

Specific carcinomas

Example generic descriptions

28 Tumour prognosis and treatment

Prognosis

Treatment

Cure and tumour‐free survival

Prevention

Methods in histocytopathology

29 Basic techniques in histopathology

Dissection

Tissue processing

The request form

30 Cytopathology

Gynaecological cytology (the cervical smear)

Diagnostic cytopathology

Utility of FNA

31 Molecular pathology

K‐Ras

EGFR

B‐Raf

c‐Kit

PD‐L1

Systems pathology

Multisystems disease

32 Sarcoidosis and syphilis

Sarcoidosis

Syphilis

33 Wilson's disease and haemochromatosis

Wilson's disease

Haemochromatosis

34 Systemic vasculitis

Common pathology

Wegener's granulomatosis

Microscopic polyarteritis

Polyarteritis nodosa

Churg–Strauss syndrome

Giant cell arteritis

Takayasu's arteritis

Cardiovascular disease

35 Normal blood vessels and types of aneurysm

Endothelium

Vascular smooth muscle cells

Aneurysms

36 Congenital heart disease

Acyanotic congenital heart disease

Cyanotic congenital heart disease

37 Systemic hypertension

Control of blood pressure

Causes

Complications of hypertension

Accelerated hypertension

38 Atherosclerosis

Definition

Aetiology

Precursor lesion

Pathogenesis

Complications

Treatment

39 Coronary heart disease

Definition

Angina pectoris

Myocardial infarction

40 Thrombosis

Normal haemostasis

Pathologically significant locations of thrombus

Venous thrombosis

Thrombolysis

Sequelae following thrombosis

41 Embolism and disseminated intravascular coagulation

Embolism

Disseminated intravascular coagulation

42 Cardiac valvular disease

Aortic and pulmonary valves

Mitral and tricuspid valves

Causes of cardiac valvular disease

43 Myocardial and pericardial disease

Hypertrophic cardiomyopathy

Dilated cardiomyopathy

Restrictive cardiomyopathy

Arrhythmogenic right ventricular dysplasia

Myocarditis

Pericarditis

Constrictive pericarditis

Tamponade

Respiratory disease

44 Pulmonary vascular disorders

Pulmonary embolism

Pulmonary infarction

Pulmonary hypertension

Clinical correlations

45 Pneumonia

Definition

Epidemiology

Microbiology

Pathology

Clinical correlations

46 Bronchiectasis

Definition

Causes

Epidemiology

Pathology

Clinical correlations

47 Tuberculosis

Sequelae following TB infection

Clinical diagnosis

Treatment

Prevention

HIV and TB are synergistic

48 Chronic obstructive pulmonary disease

Definition

Causes

Epidemiology

Pathology

Clinical correlations and complications

α1‐Antitrypsin deficiency

49 Fibrosing alveolitis

Fibrosing alveolitis

Extrinsic allergic alveolitis

50 Primary lung carcinoma

Definition

Epidemiology

Causes

Histological types

Macroscopic features

Spread

Staging

Clinical correlations

Prognosis

51 Other tumours of the lung and pleura

Malignant mesothelioma

Secondary tumours of the lung and pleura

Benign lung tumours

Other malignant lung tumours

Gastrointestinal tract disease

52 Malabsorption

Malabsorption

Diarrhoea

Coeliac disease

53 Peptic ulceration and

Helicobacter pylori

Helicobacter pylori

NSAIDs

Duodenal peptic ulcer

Gastric peptic ulcer

Pathological features of peptic ulcers

54 Oesophageal disease

Gastro‐oesophageal reflux disease

Oesophageal cancer

55 Tumours of the stomach and small intestine

Gastric cancer

Other tumours

56 Mechanical disease of the gastrointestinal tract

Diverticular disease

Volvulus

Intussusception

Other causes of bowel infarction

57 Inflammatory bowel disease: ulcerative colitis and Crohn's disease

Epidemiology

Aetiology and pathogenesis

Clinical presentation

Clinical investigations

Gross features (see diagram)

Microscopic features (see diagram)

Clinical course

Sequelae

58 Colorectal polyps, colorectal cancer and anal carcinoma

Colorectal polyps

Colorectal carcinoma

Anal cancer

Hepatic and pancreaticobiliary disease

59 Normal liver and the effects of liver damage

Normal liver

Acinar zone 3 is an ‘at risk’ region

Cirrhotic patients have altered blood flow

Liver regeneration

Hepatic failure

60 Jaundice, gallstones and carcinoma of the gallbladder

Causes of jaundice

Gallstones

Cholecystitis

Adenocarcinoma of the gallbladder

61 Fatty liver disease: alcoholic and non‐alcoholic

Alcoholic liver disease

Non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis

62 Autoimmune liver disease: AIH, PBC, PSC

Autoimmune hepatitis (AIH)

Idiosyncratic (i.e. unpredictable) drug reactions can mimic AIH

Primary biliary cholangitis

Primary sclerosing cholangitis

Secondary biliary sclerosis

63 Viral hepatitis

Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E

Hepatitis G

Pathology

64 Cirrhosis

Definition

Causes

Pathology

Clinical correlations

65 Acute and chronic pancreatitis

Acute haemorrhagic pancreatitis

Chronic pancreatitis

66 Tumours of the liver, biliary tree and pancreas

Secondary liver tumours

Benign primary liver tumours

Malignant primary liver tumours

Biliary tree tumours

Ampullary adenocarcinoma

Primary pancreatic tumours

Genitourinary tract disease

67 Congenital and inherited abnormalities of the kidney and urinary tract

Inherited abnormalities

Congenital and developmental abnormalities

68 The nephron and renal aspects of hypertension

Vascular diseases of the kidney

69 Glomerulonephritis

Nephritic syndrome

Nephrotic syndrome

Secondary glomerulonephritis

70 Important types of glomerulonephritis

Proliferative disease

Non‐proliferative disease

71 Tubulointerstitial diseases

Acute tubular necrosis

Tubulointerstitial nephritis

Acute and chronic pyelonephritis

Renal calculi

72 Renal neoplasms

Renal cell carcinoma

Urothelial carcinoma

Other tumours

73 Bladder tumours

Definition

Epidemiology

Risk factors

Pathology

Pattern of spread

Staging

Prognosis

74 Testicular cancer

Definition

Epidemiology

Risk factors

Pathology

Pattern of spread

Prognosis

75 Prostatic disease

Prostate cancer

Benign prostatic hyperplasia

Gynaecological and obstetric disease

76 Vulval and vaginal pathology

Vulval carcinoma

Other vulval neoplasms

Non‐neoplastic vulvovaginal conditions

77 Cervical cancer

Epidemiology

Aetiology and risk factors

Precursor lesions

Cervical screening

HPV vaccination

Pathology

Spread

Staging

Treatment

78 Benign uterine conditions

Endometrial polyps

Adenomyosis/adenomyoma

Endometriosis

Infections

Benign neoplasms

79 Uterine malignancies

Epithelial malignancies

Mesenchymal malignancies

Future developments

80 Ovarian neoplasia: part one

Benign neoplasms

Borderline ovarian neoplasms (atypically proliferating neoplasms)

Ovarian carcinoma

81 Ovarian neoplasia: part two

Germ cell tumours

Sex cord stromal tumours

Small cell carcinoma hypercalcaemic type

Paraneoplastic syndromes

Metastatic disease

82 Obstetric pathology

Gestational trophoblastic neoplasia

Ectopic pregnancy

Placenta creta

83 Paediatric tumours

Wilms' tumour (nephroblastoma)

Neuroblastoma

Retinoblastoma

Nervous system disease

84 Cerebrovascular accidents

Definition

Epidemiology

Types

Risk factors

Pathophysiology

Gross features

Microscopic features

Clinical correlations

85 Cerebrovascular accident syndromes

86 Raised intracranial pressure

Definition

Causes

Pathophysiology

87 Traumatic injury and intracranial haemorrhage

Extradural haemorrhage

Chronic subdural haemorrhage

Acute subdural haemorrhage

Subarachnoid haemorrhage

Cerebral contusions

Diffuse axonal injury

88 Central nervous system tumours

Primary tumours

Secondary tumours

89 Infections of the nervous system

Bacterial meningitis

Other forms of meningitis

Encephalitis

Brain abscess

Other infections

90 Movement disorders

General principles

Motor neurone disease

Parkinson's disease

Huntington's chorea

91 Acquired disorders of myelination

Multiple sclerosis

Other forms of CNS demyelination

Guillain–Barré syndrome

Chronic inflammatory demyelinating polyradiculoneuropathy

92 Dementia

Alzheimer's disease

Pick's disease

Creutzfeldt–Jakob disease

Vascular dementia

General considerations

Endocrine disease

93 Pituitary pathology

Syndrome of inappropriate ADH secretion

Diabetes insipidus

Hypopituitarism

Pituitary tumours

Craniopharyngioma

94 Non‐neoplastic pathology of the thyroid

Hyperthyroidism, e.g. Graves' disease

Hypothyroidism, e.g. Hashimoto's thyroiditis

De Quervain's thyroiditis

Riedel's thyroiditis

Goitre

95 Thyroid neoplasms

Follicular adenoma

Follicular carcinoma

Papillary carcinoma

Medullary carcinoma

Anaplastic carcinoma

General staging

96 Parathyroid gland pathology

Hyperparathryoidism

Hypoparathyroidism

Pseudohypoparathyroidism

Pseudopseudohypoparathyroidism

Multiple endocrine neoplasia

97 Adrenal pathology

Phaeochromocytoma

Addison's disease

Secondary hypoadrenalism

Cushing's syndrome

Mineralocorticoid excess

98 Diabetes mellitus

Epidemiology

Aetiology and pathogenesis

Clinical features

Clinical diagnosis

Gross features

Microscopic features

Complications

Head and neck pathology

99 Head and neck pathology

Cholesteatoma

Salivary glands

Nasal polyps

Tumours

Lymphoreticular disease

100 Assorted haematological conditions

Bone marrow failure

101 Leukaemia

Acute leukaemia

Chronic leukaemia

102 Lymphoma

Hodgkin lymphoma

Non‐Hodgkin lymphoma

Staging

Prognosis

103 Myeloma

Definition

Epidemiology

Pathology

Clinical diagnosis

Complications

Prognosis

104 Myeloproliferative disorders

Molecular aspects

Diagnosis

Polycythaemia vera

Essential thrombocythaemia

Primary myelofibrosis

Secondary myelofibrosis

Musculoskeletal disease

105 Muscle disorders

Myasthenia gravis

Eaton–Lambert syndrome

Polymyositis

Myotonic dystrophy

Duchenne muscular dystrophy

106 Arthritis

Rheumatoid arthritis

Osteoarthritis

Gout

Other forms of arthritis

107 Miscellaneous non‐neoplastic osteoarticular pathology

Osteoporosis

Osteomalacia

Paget's disease

Osteomyelitis

Septic arthritis

108 Bone tumours

Secondary tumours

Osteosarcoma

Ewing's sarcoma

Chondrosarcoma

Giant cell tumour

Osteoid osteoma

Skin disease

109 Inflammatory dermatoses

Terminology

Basic categories

Clinical correlations

110 Benign skin tumours

Fibroepithelial polyp

Seborrhoeic keratosis

Epidermoid cyst

Pilar cyst

Dermatofibroma

Melanocytic naevi

111 Malignant skin tumours

Basal cell carcinoma

Squamous cell carcinoma

Melanoma

Actinic keratosis and Bowen's disease

Breast disease

112 Benign breast disease

Fibroadenoma

Hamartoma

Fibrocystic/benign breast change

Papilloma

Epithelial hyperplasia

Others

113 Breast carcinoma

Definition

Epidemiology

Risk factors

Pathology

Pattern of spread

Staging

Prognosis

Case studies and questions

Case 1: Acute collapse with chest pain

Case 2: Recent weakness and malaise

Case 3: At the breast clinic

Case 4: Recent‐onset neurological signs

Case 5: Shortness of breath

Case 6: Facial rash and joint problems

Case 7: Long‐standing upper GI tract problems

Case 8: The wisdom of the ancients

Case 9: A small boy with big problems

Case 10: A pregnant woman with viral hepatitis

Answers

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Case 8

Case 9

Case 10

Glossary

Reference ranges

Biochemistry

Blood gases (room air)

Haematology

Hormones

Index

End User License Agreement

List of Tables

Chapter 18

Table 18.1 Common autoimmune diseases.

Chapter 24

Table 24.1 Tumour classification by histological subtype. Increasingly, mol...

Chapter 39

Table 39.1  Characteristic features of occlusion of major arteries.

Chapter 64

Table 64.1 Causes of cirrhosis.

Chapter 90

Table 90.1  Features of upper and lower motor neurone lesions.

Chapter 96

Table 96.1  Clinical features of hyperparathyroidism and hypoparathyroidism.

Chapter 109

Table 109.1  Types and properties of bullous disorders.

Guide

Cover

Table of Contents

Title Page

Copyright

Dedication

Preface

Abbreviations

Begin Reading

Case studies and questions

Answers

Glossary

Reference ranges

Index

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Pathology at a Glance

Second Edition

Barry Newell BSc, MBBS, MRCP, FRCPathCellular Pathology DepartmentSt George's Hospital Medical SchoolLondon, UK

Asma Z. Faruqi MBBS, FRCPathDepartment of Cellular PathologyBarts Health NHS TrustLondon, UK

Caroline Finlayson MBBS, FRCPathCellular Pathology Department (retired)St George's Hospital Medical SchoolLondon, UK

This edition first published 2022© 2022 John Wiley & Sons Ltd

Edition HistoryJohn Wiley & Sons Ltd (1e, 2009)

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Barry Newell, Asma Z. Faruqi and Caroline Finlayson to be identified as the authors of this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication Data applied for

PB ISBN: 9781119472452

Cover Design: WileyCover Image: © Asma Faruqi

We dedicate this book to our loving and supportive families.

Preface

We have greatly appreciated the feedback and comments received regarding the first edition of Pathology at a Glance. It is heartening to know that this guide to pathology, which aims to highlight the fundamental aspects of particular topics in the manner of a low‐scale roadmap, has been useful to healthcare professionals at all stages of their careers.

Pathology is fundamental to medicine, and a good core knowledge helps immensely to unite the apparently disparate collections of signs, symptoms and facts encountered in the study of other medical and surgical disciplines.

Students, faced with limitless layers of information in detailed textbooks and online learning platforms, found this book gave a balanced overview and a framework onto which information gleaned from other sources could be added. Doctors from house officer to consultant have thanked us for simplifying their starting point for the preparation of presentations. Pathology at a Glance is also a popular revision aid.

Acknowledgements

We are indebted to those whose expertise contributed to the first edition and several people who kindly pointed out errors or areas in which new information has supervened, in particular Dr Joe Houghton.

Dr Kate Wheeler, Consultant in Paediatric Oncology, gave us invaluable help with the chapter on paediatric tumours in the second edition. Mr Colin Jardine‐Brown's motivational skills and expert advice are also much appreciated (C.J.F.).

The help given in the first edition by Dr Jennifer Else (renal overview), Professor Neil Shepherd (Helicobacter pylori), Dr David Bevan (haemostasis), Professor Philip Butcher (tuberculosis), Professor Peter McCrorie (hypertension) and Dr Jonathan Williams (breast disease) continues to be greatly appreciated in the second edition of Pathology at a Glance.

Our thanks go also to the editorial staff for their patience and encouragement.

Barry NewellAsma Z. FaruqiCaroline Finlayson

Abbreviations

AC

alternating current

ACE

angiotensin‐converting enzyme

ACS

acute coronary syndromes

ACTH

adrenocorticotrophic hormone

ADH

antidiuretic hormone

ADPKD

autosomal dominant polycystic kidney disease

AFP

alpha‐fetoprotein

AIDS

acquired immune deficiency syndrome

AIH

autoimmune hepatitis

AIN

anal intraepithelial neoplasia; acute interstitial nephritis

ALD

alcoholic liver disease

ALL

acute lymphoblastic leukaemia

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AMI

acute myocardial infarction

AML

acute myeloblastic leukaemia

ANCA

antineutrophil cytoplasmic antibody

APC

adenomatous polyposis coli

APTT

activated partial thromboplastin time

ARDS

adult respiratory distress syndrome

ASH

alcoholic steatohepatitis

AST

aspartate aminotransferase

ATN

acute tubular necrosis

ATP

adenosine triphosphate

AV

atrioventricular

BAL

bronchoalveolar lavage

BCC

basal cell carcinoma

BCG

bacille Calmette–Guérin

BCR

B cell receptor

BE

Barrett's oesophagus

BMI

body mass index

CA

coronary artery

cAMP

cyclic adenosine monophosphate

CARS

compensatory anti‐inflammatory response syndrome

CBD

common bile duct

CCA

cholangiocarcinoma

CCK

cholecystokinin

CD

cluster of differentiation; coeliac disease

CF

cystic fibrosis

CFA

cryptogenic fibrosing alveolitis

CFTR

cystic fibrosis transmembrane conductance regulator

CFU

colony forming unit

CGIN

cervical glandular intraepithelial neoplasia

CHD

coronary heart disease

CIN

cervical intraepithelial neoplasia

CJD

Creutzfeldt–Jakob disease

CLL

chronic lymphocytic leukaemia

CML

chronic myeloid leukaemia

CMV

cytomegalovirus

CNS

central nervous system

CO

carbon monoxide

COPD

chronic obstructive pulmonary disease

CRC

colorectal carcinoma

CrD

Crohn's disease

CRP

C‐reactive protein

CSF

cerebrospinal fluid

CT

computed tomography

CVA

cerebrovascular accident

DAD

diffuse alveolar damage

DAI

diffuse axonal injury

DAMP

damage‐associated molecular pattern

DC

direct current

DCC

deleted in colon cancer

DCIS

ductal carcinoma in situ

DIC

disseminated intravascular coagulation

DIP

desquamative interstitial pneumonia

DM

diabetes mellitus

DNA

deoxyribonucleic acid

DPAS

diastase PAS

DU

duodenal peptic ulcer

dVIN

differentiated vulval intraepithelial neoplasia

DVT

deep venous thrombosis

EATCL

enteropathy‐associated T‐cell lymphoma

EBUS

endobronchial ultrasound

EBV

Epstein–Barr virus

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

ENaC

epithelial sodium channel

ENT

ear, nose and throat

ER

endoplasmic reticulum

ERCP

endoscopic retrograde cholangiopancreatography

ESR

erythrocyte sedimentation rate

ESS

endometrial stromal sarcoma

ET

endothelin

FAP

familial adenomatous polyposis

FDC

follicle dendritic cell

FEV

1

forced expiratory volume in 1 second

FFA

free fatty acid

FFPE

formalin‐fixed, paraffin‐embedded

FGF

fibroblast growth factor

FNA

fine needle aspiration

FOB

faecal occult blood (test)

FSH

follicle‐stimulating hormone

FVC

forced vital capacity

G6PD

glucose‐6‐phosphate dehydrogenase

GABA

gamma‐aminobutyric acid

GALT

gut‐associated lymphoid tissue

GBM

glomerular basement membrane

GC

gastric cancer

GDP

guanosine diphosphate

GFD

gluten‐free diet

GFR

glomerular filtration rate

GGT

gamma‐glutamyltransferase

GH

growth hormone

GI

gastrointestinal

GN

glomerulonephritis

GORD

gastro‐oesophageal reflux disease

GP

general practitioner

GTN

glyceryl trinitrate

GTP

guanosine triphosphate

HAART

highly active antiretroviral therapy

HAV

hepatitis A virus

Hb

haemoglobin

HBcAg

hepatitis B core antigen

HBeAg

hepatitis B e antigen

HBOC

hereditary breast and ovarian cancer (syndrome)

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCG

human chorionic gonadotrophin

HCV

hepatitis C virus

HDL

high density lipoprotein

HDV

hepatitis D virus

H&E

haematoxylin and eosin

HEV

hepatitis E virus; high endothelial venules

HGOC

high‐grade ovarian serous carcinoma

HIAA

hydroxyindoleacetic acid

HIV

human immunodeficiency virus

HLA

human leucocyte antigen

HNPCC

hereditary non‐polyposis colorectal carcinoma

H

2

O

2

hydrogen peroxide

HP

Helicobacter pylori

; hydrostatic pressure

HPV

human papillomavirus

HRSC

Hodgkin–Reed–Sternberg cell

HSIL

high‐grade squamous intraepithelial lesion

hsp

heat shock protein

5HT

serotonin/5‐hydroxytryptamine

IBD

inflammatory bowel disease

ICAM

intercellular adhesion molecule

IDC

invasive ductal carcinoma

IFN

interferon

Ig

immunoglobulin

IHC

immunohistochemistry

IL

interleukin

INR

international normalised ratio

ISLN

in‐situ lobular neoplasia

IUD

intrauterine device

IVC

inferior vena cava

JGA

juxtaglomerular apparatus

LAK

lymphokine‐activated killer

LDH

lactate dehydrogenase

LDL

low density lipoprotein

LH

luteinising hormone

LSIL

low‐grade squamous intraepithelial lesion

MALT

mucosa‐associated lymphoid tissue

MCHC

mean corpuscular haemoglobin concentration

MCV

mean corpuscular volume

MEN

multiple endocrine neoplasia

MGUS

monoclonal gammopathy of uncertain significance

MHC

major histocompatibility complex; mean haemoglobin concentration

MI

myocardial infarction

MMR

mismatch repair (enzymes)

MPD

myeloproliferative disease

MPTP

1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine

MRCP

magnetic resonance cholangiopancreatography

mRNA

messenger RNA

MSI

microsatellite instability

NADP

nicotinamide‐adenine‐dinucleotide phosphate

NADPH

reduced NADP

NAFLD

non‐alcoholic fatty liver disease

NASH

non‐alcoholic steatohepatitis

NET

neutrophil extracellular trap

NHL

non‐Hodgkin lymphoma

NK

natural killer (cell)

NLPHL

nodular lymphocyte predominant Hodgkin lymphoma

NMDA

N

‐methyl‐D‐aspartate

NO

nitric oxide

NOS

not otherwise specified

NSAID

non‐steroidal anti‐inflammatory drug

NSGCT

non‐seminomatous germ cell tumour

NSTEMI

non‐ST‐elevated myocardial infarction

PAF

platelet activating factor

PAH

polycyclic aromatic hydrocarbon

PAMP

pathogen‐associated molecular pattern

PAN

polyarteritis nodosa

PAS

periodic acid–Schiff

PBC

primary biliary cholangitis

PE

pulmonary embolism

PEG‐IFN

pegylated interferon

PGE

prostaglandin E

PHT

portal hypertension

PKD

polycystic kidney disease

PMN

polymorphonuclear neutrophil

PNET

primitive neuroectodermal tumour

POP

plasma oncotic pressure

PRR

pattern recognition sensor

PSA

prostate‐specific antigen

PSC

primary sclerosing cholangitis

PTH

parathyroid hormone

PVC

polyvinyl chloride

RA

rheumatoid arthritis

RF

rheumatoid factor

RNA

ribonucleic acid

ROS

reactive oxygen species

SA

sinoatrial

SAME

syndrome of apparent mineralocorticoid excess

SBP

spontaneous bacterial peritonitis

SCC

squamous cell carcinoma

SCFA

short‐chain fatty acids

SCID

severe combined immunodeficiency

SIADH

syndrome of inappropriate antidiuretic hormone secretion

SIRS

systemic inflammatory response syndrome

SLE

systemic lupus erythematosus

SMA

superior mesenteric artery

SMC

smooth muscle cell

SRBCT

small round blue cell tumour

SSL

sessile serrated lesion

STEMI

ST‐elevated myocardial infarction

T4

thyroxine

TB

tuberculosis

Tc

T cytotoxic (cell)

TCR

T cell receptor

T2DM

type 2 diabetes mellitus

TF

tissue factor

TDLU

terminal duct lobular unit

TGF

transforming growth factor

Th

T helper (cell)

TLR

Toll‐like receptor

TNF

tumour necrosis factor

TSA

traditional serrated adenoma

TSG

tumour suppressor gene

TSH

thyroid‐stimulating hormone

TT

thrombin time

UC

ulcerative colitis

UDCA

ursodeoxycholic acid

UIP

usual interstitial pneumonia

UTI

urinary tract infection

uVIN

usual vulval intraepithelial neoplasia

VEGF

vascular endothelial growth factor

VLDL

very low density lipoprotein

VOC

volatile organic compound

VSD

ventricular septal defect

vWF

von Willebrand factor

WCC

white cell count

WHO

World Health Organisation

WHR

waist/hip ratio

5YSR

five‐year survival rate

General pathology

Introduction

1The normal human cell

The important functions of the cell are: manufacture of proteins for local or distant use, energy generation, functions appropriate to tissue type and replication.

The main elements are the nucleus, the cytoplasm (cytosol), the cytoskeleton and the subcellular organelles, all bound by membranes.

Nucleus

The nuclear membrane contains pores to permit metabolites, RNA and ribosomal subunits in or out. It contains:

DNA, the nuclear chromatin, which only forms about 20% of the nuclear mass.

Nucleoli – ribosomal RNA synthesis and ribosome subunit assembly.

Nucleoprotein, e.g. synthetic enzymes for DNA, RNA and regulatory proteins, all made in the cytoplasm and imported into the nucleus.

Messenger, transfer and ribosomal RNA en route for the cytoplasm.

Cytosol

The nutritious fluid medium that bathes and supports the organelles, through which the cytoskeleton ramifies. Many reactions take place here.

Cytoskeleton

Microtubules: organelles such as secretory vesicles or internalised receptors can be transported through the cell via the cytoskeleton.

Microfilaments (actin, myosin): these stabilise cell shape and act as contractile proteins in muscle.

Intermediate filaments, e.g. cytokeratin, desmin, neurofilament proteins and glial fibrillary acidic protein (the types differ between tissues and all are structural).

Organelles

Mitochondria

These are the main ATP/energy‐generating organelles and house the Krebs cycle and oxidative phosphorylation. They have their own ssDNA (maternally derived) which codes a minority of their proteins. A porous outer membrane and folded inner membrane are present.

Ribosomes

Nucleolus‐produced ribosomal subunits aggregate in the cytosol and attach to the endoplasmic reticulum or lie loose in the cytosol, depending on the destination of the protein to be made (free ribosomes make proteins for inside the cell itself). Ribosomes translate RNA strands into a correctly assembled amino acid sequence (peptide molecule).

Endoplasmic reticulum (ER)

The ER is an irregular maze of membrane‐bound tubules, saccules and cisterns which ramifies through the cell.

Rough ER

is studded with ribosomes. Proteins made by the rough ER pass into the rough ER cisternae and undergo secondary folding and early glycosylation before being incorporated into membranes for export from the cell, receptor molecules on the cell, or components such as lysosomes within the cell.

Smooth ER

: there is a further addition of carbohydrate moieties to protein, folding to achieve tertiary structure.

Golgi apparatus

– see diagram.

Secretory vesicles

These membrane‐bound packets are moved via the cytoskeleton to fuse with the cell membrane to expel their contents outside.

Lysosomes

These are intracellular membrane‐bound vesicles, containing destructive chemicals and enzymes, which fuse with phagosomes to release their contents into the phagolysosome and destroy pathogens. Lysosomes also degrade worn‐out cell organelles (autophagy).

Peroxisomes

These small membrane‐bound granules contain oxidative enzymes which make hydrogen peroxide plus its regulator catalase.

Proteasomes

These identify defective proteins and degrade them into their component peptides and amino acids for reuse by the cell. Portions of broken‐down protein are bound by MHC class I molecules and displayed on the cell surface to Tc cells.

Centrosome

This contains the two linked centrioles, from which microtubules radiate into the cell. The centrioles duplicate and migrate to opposite ends of the cell during cell division, separating the duplicated chromosomes.

Membranes

Membranes are phospholipid barriers surrounding the cell itself and certain organelles. They isolate portions of the cell and permit several, often incompatible, metabolic processes to take place simultaneously.

The cell membrane

This phospholipid bilayer interacts with the extracellular world by assorted surface molecules. The centre is lipophilic and the surfaces hydrophilic, with cholesterol as a stabilising ‘spacer’ between them. The ‘raft theory’ suggests that intramembrane structures can float and be cross‐linked around the perimeter of the cell.

Membrane proteins: proteins that project through the membrane outside the cell usually have attached carbohydrates. Glycolipids are carbohydrates attached to the lipid membrane and are important in cell recognition, cell–cell bonds and adsorbing molecules. Some tissues have a protective glycocalyx.

Transport through the cell membrane: the main mechanisms are as follows.

Passive diffusion (needs only a concentration gradient), e.g. lipids and lipid‐soluble agents like ethanol.

Facilitated diffusion: the binding of a molecule triggers a conformational change which moves the molecule across the membrane.

Active transport: against a concentration gradient to maintain ion concentrations within the cell, e.g. the Na

+

/K

+

‐ATPase complex.

Bulk transport:

endocytosis

,

transcytosis

and

exocytosis

. Endocytosis includes

receptor‐mediated endocytosis

(ligands or viral particles) and

phagocytosis

(engulfing of particles).

Pinocytosis

, the sampling of small quantities of extracellular fluid, is not receptor mediated.

Transmission of messages across the cell membrane

Lipid‐soluble agents (e.g. steroids) diffuse directly across cell membranes.

Receptor binding and activation of secondary messengers: applies to protein messenger molecules, which bind to a specific cell surface receptor (

ligand

), resulting in active transport of the molecule through the membrane or the triggering of intracellular cascade reactions.

Neurotransmitters: these are chemical messengers for neurones or myocytes that cause an electrical response in the target by receptor‐mediated opening of an ion channel.

2Fluid dynamics

Approximately 70% of the body is composed of water. Water provides the essence of the fluid medium for the transport of cells, nutrients and waste products between organs, provides substance for cellular cytosol and is the solvent in which numerous chemical reactions occur. Disruptions of the quantity of water in the body and its distribution can have serious consequences.

Discussions of fluid balance tend to revolve around a compartmental model of fluid distribution. Three main compartments are described: the intracellular (66%), interstitial/intercellular (25%) and intravascular (7%). A fourth compartment of specialised fluids (2%) can also be considered and includes secretions of the gastrointestinal (GI) tract, peritoneal and pleural fluids, cerebrospinal fluid, synovial fluid, intraocular fluid and the vestibulocochlear fluids. The fourth compartment is often amalgamated into the interstitial.

Fluid movement is dynamic between all of the compartments and tends to follow passive osmotic and hydrostatic gradients, provided that the membrane separating the compartments is water permeable. If water movement between body compartments is required, manipulation of these gradients is typically the method by which this is accomplished. For example, the secretion of sweat involves the pumping of sodium and chloride ions into the lumen of the sweat duct. Water then follows passively through membrane pores and intercellular junctions.

Electrolytes

Electrolytes are one of the main classes of solute within body water. The chief intracellular cation is potassium and the principal extracellular cation is sodium. This differential distribution of sodium and potassium is maintained by the Na+/K+‐ATPase that is present on effectively all cells. It is the basis for the electrical activity of neurones, skeletal muscle and cardiac muscle. Alterations in the extracellular concentration of either potassium or sodium can destabilise the electrically excitable membranes of these cells, generating aberrant electrical activity such as seizures, arrhythmias or muscle weakness.

Electrolyte concentrations are also vital in maintaining turgor within cells. If the osmolarity of extracellular fluid is disturbed, water will move in or out of cells accordingly, resulting in cell swelling (and ultimately rupture) or shrinkage. Such are the potentially catastrophic effects of this inappropriate movement of water that body osmolarity is extremely tightly regulated by the antidiuretic hormone (ADH) system. In extreme situations, homeostatic mechanisms will strive to preserve blood osmolarity (which is in equilibrium with that of the other compartments) even at the expense of electrolyte levels and other parameters.

Blood and blood filtration

The vascular compartment contains 70 mL of blood per kilogram body weight (hence 4900 mL for a 70‐kg man). Cellular constituents (erythrocytes, leucocytes and platelets) comprise 40% of this volume, while the remaining 60% is plasma. Plasma is water in which electrolytes, numerous types of proteins and lipoproteins are dissolved. Blood serves as a transport medium to deliver nutrients to the tissues and to remove waste products from them. This movement of nutrients and metabolites occurs at the capillary level.

When blood reaches the capillaries, fluid and electrolytes can pass easily through the gaps between endothelial cells, but cells and larger molecules (proteins) cannot. This movement is bidirectional and the direction that dominates is regulated by the balance between the hydrostatic pressure (HP) exerted by the blood pressure generated by the heart and transmitted through the vascular tree and the plasma oncotic pressure (POP) generated by plasma proteins. The HP drives water from the blood into the tissues whereas the POP provides a gradient that draws fluid back into the blood from the extracellular space.

In the proximal capillary bed, HP exceeds POP and there is a net movement of fluid from the blood into the extracellular space. The interstitial fluid is in equilibrium with the intercellular fluid and there is ready movement of nutrients and metabolites between these two compartments. However, the HP falls across the capillary bed and on the distal side is overpowered by the oncotic pressure, causing a net movement of fluid and its accompanying solutes back into the blood. Nevertheless, the action of the POP is not complete and a small quantity of fluid remains in the extracellular space. This is lymph and is handled by the lymphatic drainage system.

Lymphatic system

Lymphatic vessels commence in the tissues as blind‐ended tubes lined by fenestrated endothelium. The lymph is massaged through progressively larger and more valve‐bearing, muscularised (non‐leaky) vessels to the thoracic duct, which empties into the venous system via the superior vena cava, returning the fluid to the circulation. En route, lymph is sieved through lymph nodes and thus lymph has a vital role in presenting extracellular material to the immune system.

Transudates

A transudate is an abnormal accumulation of fluid that has a low concentration of protein (typically defined as less than blood albumin). Transudates may occur in numerous locations, including the pleural and peritoneal cavities, and arise for one of two reasons.

Increased hydrostatic pressure

, typically back pressure within the venous system due to inadequate cardiac function. Fluid accumulates in the extracellular compartment and yields ‘pitting’ oedema of the skin. Pleural effusions may also be seen.

The

plasma oncotic pressure drops

due to either decreased hepatic protein synthesis (as in cirrhosis) or excessive protein loss via the kidneys (nephrotic syndrome). As well as pitting oedema, ascites and pleural effusions are common.

Exudate

An exudate is an abnormal collection of fluid that has a high protein concentration, typically greater than plasma albumin. Exudates are caused by inflammatory processes that markedly increase the leakiness of the capillary bed such that proteins that would not normally be able to leave the circulation are now able to. Constriction of post‐capillary venules raises the hydrostatic pressure and also contributes to exudate formation.

Tissue damage

3Tissue types and the effect of tissue damage

Normal tissue types

Epithelium

Epithelium, derived from embryonal ectoderm*, lines the body's surfaces. It constantly regenerates and heals quickly. The three main epithelial subtypes are:

Squamous

: functions as a barrier and protects against friction.

Stratified squamous

: covers skin, pharynx, tongue, oesophagus, anus, vagina, external auditory canal; keratinisation is only normally seen in the skin.

Simple squamous

: forms mesothelium lining the pleural and peritoneal cavities. Pathologists regard endothelium as a separate entity from simple squamous epithelium (See Note below).

Glandular

: lines all secretory organs. Its functions include:

Secretion

:

Non‐specialised, e.g. mucin, to trap bacteria in the nose or assist food transit in gut.

Specialised, e.g. hormone or acid secretion (gastric parietal) or absorption (gut, renal tubules).

Ion transfer

: renal tubules.

Clearance

: ciliated bronchial cells remove inhaled particles stuck in mucin (mucociliary escalator).

Urothelial (formerly ‘transitional’)

: this ‘pseudostratified’ epithelium lines the urinary tract. It contains

umbrella

cells that maintain the integrity of the surface on stretching to accommodate urine.

Note: Mesothelial cells, the single-layed simple epithelium lining the pleural and peritoneal cavities, are derived from mesoderm, but contain keratins. Endothelium (see later) is often described by non-pathologists as a simple squamous epithelium, but endothelial cells do not contain keratin fibres, a defining feature of epithelium (they are supported by vimentin fibres). Note that synovial cavities are not lined by epithelial cells, but by two cell types, derived from fibroblasts and macrophages.

Neuroectodermal‐derived tissue

This forms the central and peripheral nervous system. Scattered neuroendocrine cells populate various epithelia and secrete site‐specific substances, e.g. skin melanocytes, gut hormone‐secreting cells and in the bronchus (where they are thought to give rise to pulmonary small cell carcinoma).

Connective tissue

This forms structural tissues.

Fat

(adipo‐) stores lipid, can regenerate and may secrete or respond to cytokines. Adipokines can drive inflammation.

Bone

(osteo‐) consists mainly of matrix‐containing sparse osteocytes and is constantly remodelled by osteoblasts, which lay down matrix, and osteoclasts, which resorb it, in response to physical stresses and hormones (e.g. parathyroid hormone or calcitonin). It heals excellently.

Fibrous tissue

(fibro‐), such as tendon, which consists mainly of acellular and avascular collagenous tissue and heals poorly.

Cartilage

(chondro‐) consists mainly of avascular matrix, in which a few chondrocytes are embedded; it heals poorly.

Nerve sheath

(neurofibro‐) there are several nerve sheath components, which may undergo benign proliferation, e.g. after amputation, or form malignant tumours. Myelin is made by Schwann cells, which can form schwannomas.

Smooth muscle

(leio‐) forms the walls of medium‐sized and large blood vessels and lymphatics, the uterine myometrium, the vaginal wall and the muscular layers of the GI, respiratory and urological tracts. It can regenerate but often heals by scarring.

Striated muscle

((rhabdo)myo‐) forms voluntary muscle. Regeneration is limited.

Cardiac muscle

: myocardium only; does not regenerate.

Endothelium

arises from ‘blood islands’ of the embryonal mesoderm. Different types line the blood vessels, lymphatics and the hepatic and splenic sinusoids. Endothelium readily regenerates.

Haemopoietic and lymphoreticular tissue

These tissues generate blood cells and form the immune system. They are discussed in Chapters 8–12.

Germ cells

These are the ovarian and testicular reproductive cells. They are constantly produced by the testis; the ovary contains a finite number from birth.

Proliferative and regenerative capacity

Labile tissues

readily regenerate and constantly proliferate in life, e.g. the epithelia of the skin, gastrointestinal tract, bronchus.

Stable tissues

include the liver and kidney, and can, if necessary, regenerate but usually show only very limited cell turnover. The liver has huge regenerative capacity: over half can be removed yet the remainder can undergo compensatory regeneration. Renal tubules are quick to regenerate following damage such as transient ischaemia.

Permanent tissues

show little to no regeneration so cell death can be catastrophic (e.g. cardiac myocytes, neurones).

Stem cells are progenitor cells that can potentially form any tissue but respond to local hormones and cytokines to yield cells appropriate to the place in which they are generated. Stem cells divide to form a copy of themselves (and are thus immortal) plus a population of ‘committed’ progenitor cells. These divide into ‘transit amplifying cells’ and after several cell divisions yield terminally differentiated cells which die once their lifespan is over, to be replaced by further stem cell progeny.

Cell replacement in tissues with a high turnover is by stem cells. In tissues such as liver, with a low cell turnover, replacement of individually damaged cells is by division of adjacent cells, but larger amounts of hepatocyte loss requires stem cells for replacement. Each tissue has a compartment containing its own stem cell.

Tissue necrosis

Necrosis is a form of unregulated cell death which has a variety of causes, chiefly physical trauma, infarction, infection or chemicals. The appearance of necrosis varies according to the stimulus and the tissue. The major types are as follows.

Coagulative necrosis

due to ischaemia is commonest and usually appears as a firm, pale, wedge‐shaped region of tissue reflecting the territory supplied by an occluded arteriole. The cells retain their shape but lose their nuclei and are known as ‘ghost cells’.

Liquefactive necrosis

typically affects the central nervous system (CNS), often after a stroke. Once the damaged tissue has been cleared there is no healing and no scar, and only a cystic space remains; the mechanism is not well understood. Abscesses also show liquefactive necrosis, due to enzymic digestion of tissues by the infecting organism.

Caseation

is a white, crumbly, cottage cheese‐like appearance found in tuberculosis and some fungal infections. It is a mixture of coagulative and liquefactive necrosis.

Fat necrosis

: hard, bright yellow nodules of fat necrosis occur, possibly secondary to trauma and may become calcified and resemble tumour clinically. Digestion of fat by pancreatic enzymes with fat necrosis and calcification is commonly seen in acute and chronic pancreatitis.

Types of infarction

Infarction is necrosis of a tissue or organ due to disruption of its blood supply. In arterial infarction there is inadequate flow into the organ. In venous infarction the outflow is obstructed, preventing flow through the organ and causing congestion and stagnation. Arterial infarction is typically due to occlusion of the vessel by a thrombus or embolus; external compression is rare. Venous infarction often reflects compression of the veins, as occurs in strangulation of a hernia. Watershed zone infarctions are illustrated opposite.

4Cell death

In the living person, cell death occurs all the time and is often a necessary process. The two mechanisms that produce cell death are apoptosis and necrosis. It is becoming clear that these entities are not always distinct, but generalisations are made below.

Apoptosis

Apoptosis, often called ‘programmed cell death’, occurs during embryological development, as new tissues are formed and remodelled, or in physiological cycles such as the menstrual cycle. Apoptosis is characterised by the orderly breakdown of cellular constituents, which are packaged into membrane‐bound vesicles and tagged for collection by phagocytes. This requires energy.

The initiation of apoptosis is as follows.

Binding of a ‘death ligand’ (e.g. TNFR1 or Fas) on the cell surface, e.g. direct binding by T cells or NK cells, or tumour necrosis factor (TNF) secretion by immune cells.

Membrane disruption by perforin, then intracellular injection of granzyme B by a cytotoxic T cell (Chapter 10).

Release of pro‐apoptotic proteins, e.g. cytochrome

c

, from leaky mitochondrial membranes, a process largely regulated by pro‐ and anti‐apoptotic proteins of the Bcl‐2 family.

TP53

, a ‘gatekeeper’ gene in the cell cycle. p53 protein instigates apoptosis if there is a failure to repair DNA damage (Chapter 26).

Once started, apoptosis is generally irreversible, involving a final common pathway of an intracellular cascade of caspases. Proteolytic cleavage of cell contents and water loss causes cell shrinkage. Fragments bud off, enveloped by cell membrane, which expresses new ligands. Apoptosis does not stimulate an acute inflammatory response; instead, macrophages and adjacent cells bind the new ligands and phagocytose the fragments.

Necrosis

The death of a group of cells due to a noxious stimulus is referred to as necrosis. Necrosis is caused by many physical and chemical agents, amongst the most common of which are ischaemia, infection and drugs (e.g. chemotherapy). Necrotic cellular debris stimulates an acute inflammatory response which may increase the area of tissue damaged due to the leakage of lysosomal enzymes from polymorphs and macrophages.

It has been suggested that necrosis is what happens after cell death (i.e. irreversible damage) and that changes up to this point, which can be reversed, should be classed as cell damage. The point of no return is best recognised when there is a loss of membrane integrity and influx of calcium into the cytosol from the interstitial fluid or from the endoplasmic reticulum.

Factors that influence whether the damage is reversible include:

The duration of the stimulus

, e.g. ischaemia due to coronary artery thrombosis will cause myocardial infarction, but if the occlusion is rapidly cleared the area of cardiac muscle that dies will be reduced (Chapter 36). Reperfusion may cause problems due to the release of free radicals in the reperfused territory.

The dose of a chemical agent

: what can cause cell death in some people, does not in others due to genetic polymorphism (variation in inherited genes encoding the liver enzymes that metabolise the drugs).

The tissue type and its metabolic activity

: the neurones of the brain and cardiac muscle cells are highly metabolically active. Energy production from glycolysis via anaerobic pathways is available for liver or muscle (which store starch) but produces toxic lactic acid within the cell. Damage begins within minutes in the brain, but limb striated muscles can be deprived of oxygen for several hours. Cooling of tissues reduces their metabolism and increases survival time.

The state of health of the existing tissue

, e.g. iron overload in haemochromatosis renders the liver more susceptible to damage by other toxins, like alcohol.

Autophagy

The body attempts to preserve cells through times of adversity by undergoing autophagy, a particular type of cellular adaptation commonly seen in starvation and also in infection. It is also initiated by growth factor deprivation.

Portions of cytoplasm are bound by membranes to form a vesicle (autophagosome), which fuses with a lysosome and its contents, once degraded by hydrolase enzymes, are then recycled. The process is like hibernation and can be reversed once the lean times pass, but if taken to extremes because the stimulus persists, the cell dies either by apoptosis or necrosis.

Pathological examples of diseases in which autophagy plays an important role include neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. Much interest has recently developed in the role played by autophagy in cancer.

Free radicals

Free radicals are highly reactive anions with an unpaired outer orbital electron. They react with inorganic or organic chemicals to form further free radicals. Important examples are:

Reactive oxygen species (ROS): hydrogen peroxide (H

2

O

2

), superoxide anion radical (O

2−

·) and hydroxyl radical (·OH).

Nitric oxide (NO) made by endothelium, macrophages, neurones and other cells.

Formation

During normal cellular energy generation by oxygen reduction and electron transfer.

Killing of pathogens by phagocytes: ROS are preformed in a membrane complex.

Unwanted by‐product of intracellular oxidase reactions.

Radiation (generates hydroxyl and hydrogen free radicals by ionising water).

Toxic by‐product of drug/chemical metabolism by cellular enzymes, e.g. in the liver.

Harmful effects

Lipid membrane damage by peroxidation (affects the cell membrane and the membranes of organelles).

Protein damage by amino acid oxidation, cross‐linkages or protein breakdown, e.g. microtubule aggregation.

DNA damage can cause mutations and cancer.

Protection

Natural decay to oxygen and H

2

O

2

.

Antioxidants, e.g. glutathione and vitamins A, C and E.

Binding of copper and iron to transport proteins.

Scavenging enzymes that break down H

2

O

2

and superoxide anion, e.g. catalase, superoxide dismutases or glutathione peroxidase.

5Harmful agents in the environment

Environmental pollution

Air, soil and water are all liable to contamination (see diagram). Air pollution is a major cause of mortality and morbidity due to asthma, chronic obstructive pulmonary disease (COPD), lung cancer, myocardial infarction (MI), stroke, and neurodegenerative and skin disorders. Globally, more than 6 million annual deaths are attributed to air pollution.

Physical agents

Electrocution

Electrocution by lightning or contact with DC or AC currents from the domestic electricity supply often causes charring of the skin at the entry (e.g. hand or head) and exit (e.g. foot) points. The damage is related to the type of shock and the resistance of the tissue. Muscle tetany may render the subject unable to let go of a faulty electrical wire or socket. Electrical currents are conducted through the body best by fluids with high ion content, i.e. blood, nerves and tissue fluids. In electrically resistant tissue, such as fat, bone or tendon, the heat generated can cause severe burns and joints are often damaged. CNS injury is likely if the head is struck by lightning for example, or current passing across the body may cause cardiac arrhythmias and sudden death. Electrocution can cause respiratory arrest, seizures and rhabdomyolysis. Therapeutically, a DC shock applied to the praecordium to treat ventricular fibrillation during cardiac arrest may shock the heart back into sinus rhythm.

Extremes of temperature

Cellular homeostasis depends on temperature‐sensitive enzyme reactions and the maintenance of ion concentrations within a fairly narrow range of normal values. The normal core temperature is maintained by the hypothalamus and is regulated by interleukin (IL)‐1 release from macrophages and local prostaglandin production. Heat is generated by muscle and metabolic activity within the body and is lost through the skin, sweat and breath.

Excess heat: Heat exhaustion (core temperature 37–40°C with dizziness, headache, thirst, malaise and nausea) requires rehydration and cooling. Left untreated it may progress to a medical emergency, heatstroke (core temperature 40–42°C with severe confusion, problems with cardiac function and respiration); 42.5°C is virtually always fatal. The cause may be increased heat generation (e.g. exercise), an inability to lose heat (e.g. clothing or medication) or a disturbance of hypothalamic thermal regulatory mechanisms. The body responds by profound vasodilatation.

Burns: Cause damage by coagulating the skin and variable amounts of subcutaneous tissue. Lipid membranes melt, enzymes denature and proteins precipitate. Burns are classified as first, second or third degree according to the depth of tissue damaged and the surface area of the body affected. Plasma and tissue fluid leak from the surfaces of the burned areas and may cause hypovolaemic shock if >70% of the body surface is involved with third‐degree burns. The loss of vital protein molecules in the exudate impairs the acute inflammatory response and healing. Inhalation of fire and smoke damages the respiratory tract mucosa and the alveolar walls, causing acute respiratory distress syndrome. The damaging effect of heat is utilised in radiofrequency ablation.

Cold: Hypothermia occurs when the core temperature drops to 35°C. If shivering and increased muscle activity fail to halt the fall in temperature, respiration rate, pulse, blood oxygenation and tissue perfusion decreases. Blood sludges as plasma is lost by cold‐induced diuresis and leaky endothelium. The patient becomes confused, then deeply unconscious. Death is usual by 28°C.

Sudden exposure to extreme cold, as seen in frostbite, causes hypothermic damage to exposed or less well‐perfused parts, such as fingers, nose or toes. The fluid in the capillaries, cells and tissues freezes and thereby increases the volume of the cells. The plasma membranes rupture, as do those of the organelles. There is gangrenous ischaemic necrosis of the extremities. Treatment is by gradual warming. Often the extent of the damage is less than initially feared, so delay hasty amputation.

Perfusion with cooled blood reduces metabolic demands and complications during cardiac transplant surgery. The transplanted heart will have been transported to the donor's hospital in a supercooled state to reduce tissue deterioration.

Radiation

Radiation causes ionisation of molecules in tissue fluid, forming free oxygen radicals (reactive oxygen species) which damage tissues. Risks are related to the type, extent and cumulative dose of radiation and the tissues exposed to it (see diagram).

Chemical agents

Exposure to strong acid or alkali ruptures cell membranes, producing cell and tissue necrosis and capillary damage with leakage of blood into tissues. The effects can mimic burns. Healing of extensive wounds is often by scarring.

Many industries generate harmful substances as by‐products. Some chemicals react with cellular constituents or are altered by normal metabolic pathways to create toxic metabolites, for example:

Conjugation with glucuronide may render a molecule safe until it is excreted by the kidney, when the glucuronide is conserved and the urinary epithelium is exposed to the toxic metabolite.

Volatile organic compounds (VOCs), e.g. polycyclic aromatic hydrocarbons (PAHs), are generated by the petrochemical industry or by combustion of tars (e.g. soot) and also found in cigarette smoke. When converted to epoxides by cytochrome P450 they can bind and mutate DNA. Soot was linked to scrotal cancer in chimney sweeps by Percival Pott in 1775. Smoking‐related PAHs are strongly linked to the development of lung cancer.

Vinyl chloride monomers, produced during PVC manufacture, may generate chloracetaldehyde when metabolised by hepatic cytochrome P450; this can bind and mutate DNA.

Cancer treatment employs drugs that interfere with DNA replication to attack dividing cells, working on the premise that more tumour than normal cells are usually proliferating at any one time, e.g. cyclophosphamide alkylates DNA and causes nonsense mutations.

Water

Death by drowning is due to asphyxia. Diatoms from the water enter the blood and tissues. Death is four to five times faster in fresh water than salt water because the hypotonic fresh‐water solution that enters the blood via the pulmonary capillary bed causes haemodilution, with low chloride and potassium levels, and later hyperkalaemia due to red cell lysis. Sea water may be almost isotonic, although usually it is hypertonic and the blood chloride level is increased, but haemolysis does not occur, and thus resuscitation efforts have more chance of success in people rescued from the sea. People who survive near‐drowning may develop pneumonitis from organisms in dirty water.

Infectious agents

In order to cause damage, organisms must evade the body's primary defences and enter the tissues (see Chapter 16).

6The effects of tobacco, alcohol and other drugs

Tobacco

Tobacco is damaging when smoked either directly or indirectly (‘passive smoking’), but also has deleterious effects when chewed, or inhaled as snuff. It is addictive because of pleasurable effects such as increased feeling of well‐being and alertness and decreased appetite. It has effects on children, the unborn fetus and on pregnancy itself. Long‐term use causes cancer (smoking is considered a significant causative factor in 86% of lung cancers and 19% of all UK cancers), cardiovascular disease and respiratory disease.

Tobacco smoke is absorbed into the blood via the alveolar capillaries or via the gastrointestinal tract in swallowed sputum. It has a direct effect on the mucous membranes lining the oropharynx, respiratory tract and oesophagus. The toxic effects of tobacco smoke are due to both gaseous and particulate agents.

Gaseous elements

Carbon monoxide (CO) shows 200 times oxygen's affinity for haemoglobin and reduces oxygen availability to the tissues.

CO or hydrogen cyanide may paralyse the cilia, impairing the removal of inhaled particles from the respiratory tract.

Particulate elements

Nicotine

Nicotine stimulates nicotine receptors in the brain to cause addiction.

It increases blood pressure by direct catecholaminergic effects.

It mobilises free fatty acids from the tissues, important in atherogenesis.