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TEXT-BOOK OF MEDICINE.
NUNQUAM ALIUD XATURA, ALIUD SAPIENTIA DIGIT.
TEXT-BOOK
OF
MEDICINE
EDITED BY
GEORGE ALEXANDER GIBSON
M.D., D.Sc., F.KC.P.Ei).
PHYSICIAN TO THE ROYAL INFIRMARY, EDINBURGH
VOLUME FIRST
EDINBURGH & LONDON YOUNG J. PENTLAND
1901
EDINBURGH : PRINTED FOR YOUNG J. PENTLAND, 11 TEVIOT PLACE, AND 3>> WEST .SM1THFIELD, LON'OON, B.C., BY MORRISON AND GIBB LIMITED
(All rights reserved.)
PREFACE.
A CONSIDERABLE lapse of time has occurred since the publication in this country of a text-book similar to that now submitted to the public. The advances in every branch of medicine have during the interval been so great as to create a want for a work reflecting modern English teaching, and it has been felt that this can be most satisfactorily met by the united efforts of several writers who represent different important schools in the United Kingdom.
In arranging the scheme and determining the scope of the work, certain points have demanded consideration, and it has by no means been easy to arrive at a decision regarding them. The wisdom of including a prelimin- ary discussion of general etiological and pathological problems, by way of introduction to the more practical portion of the work, has been care- fully weighed, and the conclusion reached that such a section would be of real utility. The position of cutaneous diseases has also been a subject of anxious deliberation. Although fully recognising that in every medical school Dermatology ought to have the thorough teaching which can only be given by a specialist, it has seemed inexpedient to exclude diseases of the skin from a text-book on the Practice of Medicine. Another matter requires a word of remark. Certain symptoms, occasionally dignified by the title of separate diseases, will be sought in vain under individual headings, but will be found as parts of the subjects to which they properly belong.
It only remains for the Editor to return his grateful thanks to all his coadjutors for the unfailing consideration and loyal support which they have rendered in the production of these volumes, and to express the profound regret occasioned by the death, during the progress of the work, of Professor Kanthack, which has inflicted a grievous loss on scientific medicine
G. A GIBSON.
EDINBURGH, April 1901.
LIST OF CONTRIBUTORS.
AFFLECK, J. O., M.D., F.R. C.P.ED., Consulting Physician to the Royal Infirmary, Edinburgh.
ASHBY, HENRY, M.D., F.R.C.R, Physician to the General Hospital for Children, Manchester.
AULD, A. G., M.D., M.R.C.P., Late Assistant Physician to the Royal Infirmary, Glasgow.
BRADFORD, JOHN ROSE, M.D., D.Sc., F.R.C.P., F.R.S., Physician to University College Hospital, London.
BRUCE, ALEXANDER, M.A., M.D., F.R.C.P.ED., Assistant Physician to the Royal Infirmary, Edinburgh.
BRUCE, J. MITCHELL, M.A., M.D., LL.D., F.R.C.P., Physician to Charing Cross Hospital, London.
BRUNTON, SIR LAUDER, M.D., D.Sc., LL.D., F.R.C.R, F.R.S., Physician to St. Bartholomew's Hospital, London.
COLMAN, W. S., M.D., F.R.C.P., Assistant Physician to St. Thomas's Hospital, London..
GIBSON, G. A., M.D., D.Sc., F.R.C.P.ED., Physician to the Royal Infirmary, Edinburgh.
GILLESPIE, A. LOCKHART, M.D., F.R.C.P.ED., Medical Registrar to the Royal Infirmary, Edinburgh.
COWERS, SIR WILLIAM R., M.D., F.R.C.R, F.R.S., Consulting Physician to University College Hospital, London.
HARRIS, V. D., M.D., F.R.C.P., Physician to the City of London Hospital for Diseases of the Chest.
HAWKINS, HERBERT P., M.A., M.D., F.R.C.R, Physician to St. Thomas's Hospital, London.
JAMIESON, W. ALLAN, M.D., F.R.C.P.ED., Physician for Diseases of the Skin to the Royal Infirmary, Edinburgh.
KANTHACK, A. A., M.D., F.R.C.P., Late Professor of Pathology in the University of Cambridge.
KER, CLAUDE B., M.D., F.R.C.P.ED., Medical Superintendent of the City Hospital, Edinburgh.
LAWRENCE, T. W. R, M.B., F.R.C.S., Curator of the Museum of Anatomy, University College, London.
LUFF, A. P., M.D., B.Sc., F.R.C.P., Physician to St. Mary's Hospital, London.
viii LIST OF CONTRIBUTORS.
MACKENZIE, HECTOR, M.A., M.D., F.R.C.P., Physician to St. Thomas's Hospital, London.
HANSON, PATRICK, C.M.G., M.D., LL.D., F.R.C.P., F.R.S., Lecturer on Tropical Diseases, London School of Tropical Medicine.
MARTIN, SIDNEY, M.D., B.Sc., F.R.C.P., F.R.S., Physician to University College Hospital, London.
MOORE, SIR JOHN WILLIAM, B.A., M.D., F.R.C.P.I., Physician to Meath Hospital, Dublin.
MOTT, F. W., M.D., F.R.C.P., F.R.S., Physician to Charing Cross Hospital, London.
OLIVER, THOMAS, M.A., M.D., F.R.C.P., Physician to the Royal Infirmary, Newcastle-on-Tyne.
PASTEUR, W., M.D., F.R.C.P., Physician to Middlesex Hospital, London.
PHILIP, R. W., M.A., M.D., F.R.C.P.ED., Assistant Physician to the Royal Infirmary, Edinburgh.
RUSSELL, S. RISIEN, M.D,, F.R.C.P., Assistant Physician to University College Hospital, London.
RUSSELL, WILLIAM, M.D., F.R.C.P.ED., Assistant Physician to the Royal Infirmary, Edinburgh.
STOCKMAN, RALPH, M.D., F.R.C.P.ED., Professor of Materia Medica and Therapeutics in the University of Glasgow.
TAYLOR, FREDERICK, M.D., F.R.C.P., Senior Physician to Guy's Hospital, London.
TAYLOR, JAMES, M.A., M.D., F.R.C.P., Physician to the National Hospital for the Paralysed and Epileptic, London.
TURNER, W. ALDREN, M.D., F.R.C.P., Assistant Physician to King's College Hospital, London.
WHITE, W. HALE, M.D., F.R.C.P., Physician to Guy's Hospital, London.
WILLIAMSON, R. T., M.D., F.R.C.P., Physician to Ancoats Hospital, Manchester.
WOOD, G. E. CARTWRIGHT, M.D., B.Sc., Superintendent of the Bacterio- logical Department of the Laboratories of the Royal Colleges of Physicians (London) and Surgeons (England).
WOODHEAD, G. SIMS, M.D., F.R.C.P.ED., Professor of Pathology in the University of Cambridge.
CONTENTS OF VOLUME FIRST.
INTRODUCTION. THE GENERAL PATHOLOGY OF DISEASE.
PAGE
The Reactions of the Body and its Tissues 1
Cloudy Swelling ........... 2
Fatty Changes ........... 2
Amyloid Changes ........... 6
Hyaline and Waxy Degeneration ........ 9
Colloid Changes . . . . . . . . . . .10
Mucous Changes . . . . . . . . . . .10
Wasting and Atrophy . . . . . . . . . .11
Necrosis and Necrobiosis . . . . . . . . .12
Calcification and Concretions . . . . . . . . .14
Pigmentation .... ...... 15
Acute Inflammation . . . . . . . . . .18
Chronic Inflammation .......... 35
Regeneration and Repair ......... 40
Metaplasia . . . . . . . . . . . .41
Hypertrophy ........... 42
Pathology of Bacterial Infection ......... 43
Characters of Bacteria . . . . . . . . . .44
Requirements of Bacterial Life ........ 46
Vital Manifestations of Bacteria . . . . . . . .48
Infection ....... .... 53
Predisposition ........... 59
Contagion ............ 62
Immunity ............ 64
Immunisation ........... 66
Theory of Immunity .......... 75
Seruru Therapeutics ....... .81
Toxemia .... 87
Treatment by means of Organic Extracts .... .93
Preventive Inoculation ..... .98
SECTION I. GENERAL DISEASES.
Typhus Fever .100
Relapsing Fever . . .113
Typhoid Fever .....
x CONTENTS.
PAGE
Variola and Vaccinia . . .146
Varicella — Chickenpox . .160
Morbilli — Measles — Eubeola . .163
Scarlatina — Scarlet Fever . .169
Rubella — Roseola Epidemica — Rubeola Notha . .179
Pertussis — Wh coping-Cough . .181
Mumps — Epidemic Parotitis • 186
Influenza — Epidemic Catarrhal Fever ... .189
Diphtheria 197
Erysipelas .... .217
Septic Diseases .221
Saprsemia ........
Septicaemia . . 222
Pyaemia .223
Acute Pneumonia .... .226
Tetanus .245
Epidemic Cerebro-Spinal Meningitis .... . . 249
Bubonic Plague .... .251
Cholera .255
Dysentery . .261
Liver Abscess of Warm Climates ........ 265
Mediterranean Fever . . . . . . . . . . .270
Sprue 274
Dengue 277
Yellow Fever .279
Beriberi . . . . ... .283
Yaws 287
Verruga 289
Malaria and Malarial Disease ......... 290
General Gonorrhoeal Infection . . . . . . . . . 317
Syphilis .... . . . .318
Tuberculosis ... . 348
Acute Miliary Tuberculosis . . . . . . . . .371
Tuberculosis of the Alimentary System . . . . . . .377
Mouth and Tongue . . . . . . . . .377
Pharynx and Tonsils .379
(Esophagus, Stomach, and Duodenum . . . . . .380
Intestine 380
Liver and Pancreas . . . . . . . . .384
Tuberculosis of the Lymphatic System . 384
Lymphatic Glands .......... 384
Spleen 387
Lymphatics ........... 387
Tuberculosis of the Vascular System . . . . . . . 388
Tuberculosis of the Serous Membranes . . . . . .388
Pleura 388
Pericardium . . . . . . - . . . . . 392
Peritoneum ........... 394
Multiple Serous Tubercle . 398
Tuberculosis of the Eespiratory System . ... . 398
Nose . . 398
CONTENTS. xi
FAOK
Tuberculosis — continued.
Larynx 398
Trachea and Bronchi . ' -. . . , . . . 403
Lungs 403
Acute Pneumonic Phthisis ........ 404
Chronic Pulmonary Tuberculosis . . „ . . . . 406
Tuberculosis of the Genito-Urinary System .... . 433
Urinary Organs . . . . . ... . . 433
Testicle 436
Female Generative Organs . . . . . . . .437
The Breast . 438
Tuberculosis of the Integumentary System . . . . . . 439
Lupus Yulgaris . . . . . . . ...439
Other Forms of Cutaneous Tubercle . . . . . . 441
Tuberculosis of the Nervous System . . ' . . . . . 442
Chronic Meningitis ......... 443
Tuberculous Tumours of the Brain and Cord ..... 443
Leprosy ............. 444
Actinomycosis . . . . . . . . . . . 448
Hydrophobia — Rabies .......... 450
Anthrax . 453
Glanders - ." 456
Snake-Bite . . . .459
Gout . 460
Acute Rheumatism or Rheumatic Fever '.472
Chronic Rheumatism . . . . .. . . . .479
Muscular Rheumatism ....... . 480
Rheumatoid Arthritis .... ... .481
Rickets .489
Foetal Rickets, Osteo-Genesis Imperfects, Achondro-plasia . . . 498
Late Rickets • .498
Fragilitas Ossium .... .503
Osteo-Malacia — Mollities Ossium ..... . 504
Diabetes Mellitus .... • 505
Diabetes Insipidus ... .519
Sunstroke ....... • 522
African Lethargy ... . . .525
SECTION II.
DISEASES CAUSED BY ANIMAL PARASITES.
Protozoa .527
Rhizopoda ... .527
Gregarinidae ..... .528
Infusoria ..... • 530
Amuiloida ..... . . • 532
Cestoda • 532
Trematoda ....
Nematoda ....... .544
PAGE
xii CONTENTS.
SECTION III. DISEASES CAUSED BY CHEMICAL SUBSTANCES.
Lead Poisoning
Lead Poisoning in Children .
r TQ
Arsenical Poisoning .
Phosphorus Poisoning
Mercurial Poisoning .
Alcoholic Poisoning .
Meat or Ptomaine Poisoning
Poisoning by Vegetable Alkaloids and other active Principles
Poisoning by Grain, Ergotism, and Pellagra
Lathyrism .
SECTION IV. ALIMENTARY SYSTEM.
Diseases of the Mouth Stomatitis .
Catarrhal Stomatitis Aplitlious Stomatitis Gum-boil .
Diseases of the Tongue Ulceration .
Traumatic Ulceration ....
Dyspeptic Ulceration
Syphilitic Ulceration .
Tuberculosis
Cancerous Ulceration Tumours . Inflammation Atrophy . Hypertrophy
The Tongue as an Index of Disease
Diseases of the Salivary Glands Functional Disorders . Organic Diseases
Diseases of the Fauces and Tonsils Acute Tonsillitis . Follicular Tonsillitis . Chronic Tonsillitis
Diseases of the Pharynx Pharyngitis .
Diseases of the (Esophagus Inflammation Diverticula . . . Dilatation . Stricture
Spasmodic Stricture
Malignant Stricture . .647
CONTENTS. xiii
PAGE
Diseases of the Stomach . . . . . . . . . .649
Introductory ........... 649
Gastric Indigestion .......... 654
Gastric Irritation . . . ..'-.'. . . .. . 655
Gastric Insufficiency . •> •. '"• •'.'• . .-- . . . 660 Nervous Dyspepsia . . . . - .' '. . . • . . 661
Gastritis . . . . . .•;'.. . . 670
Acute Catarrha! Gastritis . . • '•; - •«."*' . . .670
Chronic Catarrhal Gastritis ..... v'" . . 673
Acute Toxic Gastritis . ... . . . . . .677
Infective Gastritis . . . . . . . . .678
Atrophy and Degenerations . . . . ..-.'. . . 678
Cirrhosis . . . . ... . . •„*•*• . . 679
Hsemorrhage . . . -. . . . . . . 679
Gastric Ulcer . . . . . . . . . ,^.%, . 682
Cancer . . . 693
Dilatation . . . . • '» 697
Diseases of the Intestines 703
Enteritis 703
Catarrha] Enteritis 703
Catarrhal Enteritis in Children ....... 705
Cholera Nostras . . . : . . . . .710
Cholera Infantum . . . . . . . . .711
Croupous or Diphtheritic Enteritis . . . . . .713
Phlegmonous Enteritis . . . . . . . . .714
Mucous Colitis . . . . . . . . . .714
Ulcerative Colitis . . . . ... . . . .716
Intestinal Obstruction . . . . . . . . . .717
Constipation . . . . . . . . . . .731
Appendicitis ... . . . . . . . . • 735
Diseases of the Liver . . . 746
Jaundice . . * . ' . . . . . . . . . 748
Catarrh of the Common Duct . . . . •. . . .752
Acute Yellow Atrophy . . . . . . . .753
Icterus Neonatorum . . . . . . • . . . 755
Nervous Jaundice .......... 756
Gallstones 756
Active Hyperaemia of the Liver . . . . . . 768
Diseases of the Portal Vein . . . . '. . . . 769
Diseases of the Hepatic Artery ........ 769
Abscess of the Liver . . . . . . . . . .770
Multiple Small Abscesses . . . . . . . .770
Single Large Abscesses . . . . . . . . .771
Cirrhosis of the Liver .......... 774
Alcoholic Cirrhosis ... . . . . . . . 774
Hypertrophic Cirrhosis . . . - . . . . . .779
Malarial Cirrhosis . . . . . . . . .779
Saturnine Cirrhosis . . . . . . . . .780
Other Forms of Cirrhosis ........ 780
New Formations in the Liver . . . . . . . .780
Malignant Disease . . . . . . . . .780
Secondary Cancer . . .781
Primary Carcinoma ....... .783
Primary Carcinoma of the Gall Bladder . 784
Primary Carcinoma of the Bile Ducts ... .784
xiv CONTENTS.
PAGE
Diseases of the Liver — continued.
Sarcoma of the Liver ...... . . 785
Pigment Tumours of the Liver . . . . . . .785
Angioma .... . 785
Secondary Affections of the Liver . . . . . . . .785
Passive Hyperswnia . . . . . . . . - 785
Fatty Degeneration ......... 786
Waxy Degeneration ......... 786
Syphilis ... .... . 786
Actinomycosis . . . . . . . . . .787
Tuberculosis . . . . . . . . . .788
Hydatid of the Liver 788
Other Cysts 792
Peril) epatitis . . 792
Diseases of the Pancreas ... .... . 794
Cirrhosis ............ 794
Atrophy ...........'. 795
Fatty Changes ........... 795
Calculi 795
Malignant Disease . . . . . . . . . .796
Primary 796
Secondary Growths . . . . . . . . .707
Malignant Adhesions . . . . . . . . .798
Pancreatic Cysts . . . . . . . . . . .798
Tubercle 799
Acute Pancreatitis . . . . . . . . . .799
Hsemorrhagic Pancreatitis ........ 799
Suppurative Pancreatitis ..... . . 800
Gangrenous Pancreatitis ........ 800
Haemorrhage . . . . . . ... . . . 801
Fat Necrosis ... .... . 801
Diseases of the Peritoneum. . 802
Introductory ........... 802
Peritonitis . . . . . 802
Acute Peritonitis .......... 802
Chronic Peritonitis ......... 809
Tuberculous Peritonitis . . . . . . . . .811
Tabes Mesenterica . . . . . . . . .814
Malignant Peritonitis . . . . . . . . .815
Syphilitic Peritonitis . . . . . . . .817
Simple Tumours . . . . .. . . . . .818
Peritoneal Fluids and Ascites . 818
LIST OF ILLUSTRATIONS.
FIO. PAGE
1. Fatal case of typhus in a male adult ; examples of the temperature curve
during the period of invasion . . . . . . . .102
2. A case of typhus in a young adult ; examples of termination by crisis . 103
3. Complete course of typhus in a child, set. 4 . . . . .104
4. Complete course of typhus in a woman, set. 67 ; rare instance of termina-
tion by lysis . . . . . . . ... 105
5. A case of relapsing fever (after Muirhead) . . . . . .115
6. A moderately severe case of typhoid fever in a female, set. 22 . . . 125
7. A severe case of typhoid fever, showing a tendency to hyperpyrexia on the
twenty-sixth day . . . . . . . . .-.127
8. Case of a female, set. 17, terminating fatally by hemorrhage . . .130
9. Fatal termination by perforation in a female, set. 22 . . .131
10. A mild or abortive case of typhoid fever. . . . . . .133
11. Smallpox mortality curve . . . . . . . . .147
12—13. Discrete smallpox . . . . . . . . 153
14. Coherent smallpox — secondary fever . . . . ....154
15. Confluent smallpox — severe secondary fever . . . . . .154
16. Malignant smallpox . . . . . . . . . .155
17. Measles mortality curve . . . . . . . . . .164
18. Ordinary measles . . . . . . . . . . ..166
19. Defervescence in measles . . . . . . . . .166
20-21. Measles after scarlatina ....... .168
22. Scarlatina mortality curve ... ... .170
23. Enteric fever mortality curve . . . . . . . . .170
24—25. Simple scarlatina . . . . . . . . 174
26. Anginose scarlatina . . ... . . . . .174
27. Ataxic scarlatina . . . . . . . . . .175
28. Malignant scarlatina ........ .175
29. Influenza — cardio-pulmonary . . . . . . .193
30. „ gastric . .. 193
31. „ febrile .... .194 32-34. Influenza in child .... . . .194
35. Temperature in erysipelas . . . . . . . . .219
36. Temperature chart from a case of acute septicsemia ending in recovery . 223
37. „ „ a fatal case of pyaemia .. . . .225
38. Parasite of tertian malaria . . . . . . . .291
39. Evolution of the benign tertian parasite (compiled from Mannaberg) . . 292
40. Evolution of the flagellated body in the tertian and quartan parasites
(compiled from Thayer and Hewetson) .... . 293
41. Malaria parasite ; evolution of the flagellated body from the crescent . 293
42. Microgametocyte emitting four microgametes (flagella) . . 295
43. Transformation of the zygote in the stomach wall of the mosquito (after
Grassi) .295
44. Zygotes protruding on the outer surface of the mosquito (after Ross) . . 295
VOL. I. — b
xvi LIST OF ILLUSTRATIONS.
FIG. PAOE
45. Rupture of zygote cyst into the body cavity of the mosquito ; free sporo-
zoites (after Grassi) .... .296
46. Parasite of quartan malaria ..... .299
47. Parasite of malignant tertian (aestivo-autumnal) malaria . . . 299
48. Amoeba coli ; A. dysenterice fixed and stained (after Councilman); A.
dysenteric? in stools (after Lb'sch) . . . . . . . .527
49. Coccidium oviforme, from the liver of the rabbit. Stages of spore-formation
only observed in the free state (after Leuckart) . . . . .529
50. Rainey's tubes, x about 40 diameters ; extremity of one of Miescher's tubes
with its contents. At the side are the kidney-shaped bodies, much enlarged (after Leuckart) . . . . . . . . .530
51. Monas pyophila ........... 530
52. Trichomonas vaginalis (after Kolliker) . . . . . . .531
53. Lamblia intestinalis . . . . . . . . . .531
54. Balantidium coli, with widely opened peristomo, dorsal view (after
Leuckart) 531
55. Tapeworm form of Tcenia saginata s. mediocanellata (after Leuckart) . . 532
56. Apex and hooks and head of T. solium (after Leuckart) . . . .532
57. Embryos containing egg of T. solium and of T. nymphmt (after Leuckart) . 533
58. The common bladder worm of the pig with invaginated head ; the same
with evaginated head (after Leuckart) . ...... 533
59. Head of T. saginata in contracted and extended condition (after Leuckart) . 534
60. Cysticercus tcenice saginatce, embedded in the muscle (after Leuckart) . . 534
61. Measly pork (after Leuckart) . . . . . . . . .535
62. Bothriocephahis latus (after Leiickart) ....... 535
63. Club-shaped head of B. latus (after Leuckart) . . 536
64. Ovum of B. latus, with yoke cells and shell (after Leuckart) . . . 536
65. Larvae of B. latus from the pike (after Leuckart) . . . . .536
66. T. nana (after Leuckart) 537
67. Distomum liepaticum . . . . . . . . . .538
68. Redice (after Leuckart) 539
69. D. sinense ............ 540
70. D. buski 540
71. D. rinyeri (after Leuckart) . . . . . . . . .541
72. Ova of D. ringeri in sputum . . . . . . . . .541
73. D. hcematobium, male and female, the latter in the canalis gyncecophorus of
the former (after Leuckart) . . . . . . .542
74. Ovum and free embryo of Bilharzia . . . . . . .542
75. Ascaris lumbricoides, female (after Leuckart) .... . 545
76. Egg from A. lumbricoides, fresh from the fajces (after Leuckart) . . . 545
77. Oxyuris vermicularis, male and female (after Leuckart) .... 546
78. Eggs of 0. vermicularis (after Leuckart) .... . 546
79. Ankylostomum duodenale, male and female (after Blanchard) . . . 548
80. Male A. duodenale ........... 548
81. A. duodenale (after Sonsino) .. . . . . . . .548
82. Trichocephalus dispar, in situ (after Leuckart) ... . . . . 550
83. T. dispar (after Sonsino) ........ . 550
84. Trichina spiralis (after Leuckart) . . . . . . .551
85. Guinea-worm (after Leuckart) ....... . 553
86. Embryos of guinea-worm . . . . . . . . . 554
87. Filariu loa (after Argyll Robertson) ..... .556
88. Embryo Rhabdonema intestinale in faeces (after Golgi and Monti) . 557
89. Filaria sanguinis hominis nocturna ..... 558 90- „ „ „ perstans, X 160 .' . . .561
91-93. Temperature charts in simple perityphlitis . 740
94. Temperature chart in perityphlitic abscess . . 741
TEXT-BOOK OF MEDICINE.
TEXT-BOOK OF MEDICINE
INTRODUCTION.
THE GENERAL PATHOLOGY OF DISEASE.
WITHOUT a knowledge of the causation and the processes of disease, it is impossible to appreciate the nature and symptoms of a lesion. The physi- cian, in making his diagnosis, should always reflect upon the changes, structural and functional, which might lead to the production of a symptom, or any complex of symptoms. A knowledge of pathology will lead him not to confound the symptom with the disease, either in diagnosis or in treat- ment. Every disease has a cause. It may be, and often is, easy to detect this cause, and to trace the relation between cause and effect, but obscure symptoms may be due to changes in the body, of which those unacquainted with pathology must necessarily remain unaware. Pathology enables the physician to determine the limits and mode of treatment, and also the probable or possible prognosis of a case, for it teaches the reactions of the body and its tissues, the understanding of which is as necessary to him as is a familiarity with Euclid's axioms in the study of mathematics.
A student working in the wards soon learns that without a thorough knowledge of pathology and pathological methods a sound diagnosis is often impossible ; he finds that the post-mortem room is one of the best training schools for the physician, for there it is that he is brought face to face with the diagnosis he has made, that imagination is controlled by fact, and that what appeared to be mysterious and inexplicable finds its natural explana- tion. Before studying disease itself, it is necessary to consider generally but carefully the processes, causes, effects, and concomitants of disease.
THE BEACTIONS OF THE BODY AND ITS TISSUES.
Degenerations, inflammation, and repair, hypertrophy and atrophy, are the most essential and elementary amongst the processes of disease. Of these, degenerations and atrophy may be said to be retrogressive re- actions, through which the functional activity of an organ or a tissue is VOL. i. — i
2 GENERAL PA THOL OGY OF DISEA SE.
lowered; inflammation, repair, and hypertrophy, on the other hand, are to be classed as progressive reactions.
CLOUDY SWELLING.
The simplest form of degeneration is the so-called cloudy swelling, which is best observed in the renal and hepatic epithelium and in the heart muscle. The organs are slightly enlarged, are pale and cloudy on section, arid have a parboiled appearance. The cells or fibres swell and assume a granular and cloudy appearance, their nuclei being indistinct or refusing to stain. These changes are observed in most of the infections, e.g. scarlet fever, diphtheria, typhoid fever, septicaemia, smallpox, and erysipelas ; but also in many other lesions and intoxicative processes, such as acute yellow Atrophy, acute Bright's disease, and phosphorus poisoning, and are the expression of the deleterious action of certain toxic substances which alter the albuminous or protoplasmic constituents of the cells, producing a kind of intracellular coagulation. The change may go on to coagulative necrosis, the cell breaking down and being completely destroyed; it may survive, undergoing, however, fatty degeneration ; or may recover completely. Injury to the cells and insufficient food supply are also common causes of cloudy swelling; thus in cardiac disease and marasmus the renal epithelium becomes cloudy. Inflammation, whether due to chemical, physical, or bacterial agencies, by injuring the cell directly or indirectly, will produce cloudy swelling. Virchow believed that the cloudy swelling in the early acute Bright's disease was the evidence of increased cellular activity on the part of the renal cells, and this he regarded as the sign and essence of the parenchymatous inflammation, wherefore this disease has been called parenchyrnatous nephritis. It is, however, held by some that cloudy swelling is a sign of degeneration, due to the pressure exerted on the renal parenchyma by the inflamed interstitial tissue and the inadequate nutri- tion of the cells, resulting from the stagnation of blood in the inflamed areas.
FATTY CHANGES.
Fatty changes are observed in the tissues and organs in many diseases and under the most varied conditions. Although they are as a rule the effect of a general lesion, it is obvious that they themselves must produce disturbances and impairment of function, and may become the starting-point or cause of other lesions and morbid states. Before discussing the nature of fatty changes, it will be advisable shortly to state the varieties of fatty changes as they are usually met with in the body.
Accumulation. — An increase of fat may take place in situations where it normally exists, e.g. (a) in the panniculus adiposus ; (&) in the pmental tissues ; (c) in the epicardium ; (d) in the bone marrow ; and (e) in the liver, where, at certain periods after the ingestion of food, fat is always found.
Such accumulation may be — (1) temporary or transient, as for instance in the athlete who is " beefy " and out of training — it is then hardly pathological ; or it may be (2) permanent and lasting, when it is morbid. Thus in obesity or lipo- matosis, there is always a considerable storage of fat in the subcutaneous and omental tissues, and the liver of a beer-drinker is generally exceedingly fatty. The accumulation obviously must be due to one of two processes, or probably to both
FATTY CHANGES IN TISSUES. 3
of them. Either the supply of fat-forming material is in excess, too much fat being formed by the cell ; or the fat formed is not split up as quickly or completely as it should be, owing to the exhausted condition or altered nutrition of the cells. It is evident that when the accumulation is excessive or too persistent, the func- tions of the fat-laden organ or tissues may gradually become impaired, and there- fore, if the causes which in the first instance led to the fatty changes prevail, the process of combustion or splitting up of the deposited fat will also be interfered with ; a vicious circle is thus established. Impairment of the cell function leads to fat accumulation, the latter increases the interference with the cell func- tion, and so on. The statement that the accumulation of fat is due either to over- production of fat or to failure of combustion, or to both, is merely a suggestion of what is obvious ; it is no explanation of the process. Why should fat be stored up in some people and not in others living under the same conditions, why should obesity be commoner amongst women than amongst men 1 Some people " run into fat " on any diet, whatever they may do to keep their flesh down ; others it is impossible to fatten.
It is difficult to state in concise and definite terms the causes of fat accumulation, but attention must be drawn to some leading, or it may be predisposing factors. Amongst these are — (a) inherited or congenital tendencies ; (b) certain habits of life, such as indolence and sedentary occupations ; (c) errors of diet ; (d) chronic poisoning (e.g. alcohol) ; (e) sex, and diseases and morbid states of the reproductive organs in women ; (/) morbid states of the liver, pancreas (?), or thyroid gland (?).
A truly morbid accumulation of fat is progressive. Any exaggeration of ordinary physiological conditions, due to errors in living, eating and drinking, may be set right again by correcting these errors.
Encroachment. — An extension of fat into tissues which normally are free from it may occur — (d) in the intermuscular tissues of the heart, spreading thither from the epicardial fat ; (b) in the interstitial tissue of skeletal muscle (pseudo-hypertrophy) ; and (c) in the endocardial connect- ive tissues.
In the fatty heart (lipomatosis) of an obese person there is first an accumulation of epicardial fat, whence it spreads between the muscle fibres, especially of the right ventricle, often reaching the connective tissue under the endocardium.
These two conditions are generally included under the single term infiltration. They commonly occur together in the same organ, and in the same individual they may affect one organ alone, or all the organs and tissues capable of undergoing fatty changes. Fat accumulation may be so localised as to produce a distinct tumour — a lipoma. In all these con- ditions the fat is, as a rule, collected in the cell in the shape of large drops or droplets, the nucleus being pushed to one side ; the cell substance or protoplasm is sound, and after disappearance of the fat shows no defects.
Degeneration. — This differs from fatty accumulation, in which the fat is formed in the cell and stored up by it, in so far that the fat is formed at the expense of the cell albumin. Here the cell substance contains globules or numberless small granular droplets of fat, often so densely packed as to hide the nucleus or obscure the structure of the cell, the protoplasm of which is destroyed; on dissolving out the fat the cell appears vacuo- lated. Fatty degeneration is therefore a destructive process, a metabolic metamorphosis. It is best studied in the cardiac and voluntary muscles, in the liver cells and renal epithelium, in pus cells, and in nervous tissues.
4 GENERAL PA THOLOG Y OF DISEASE.
The causes of fatty degeneration are those which produce serious disturbance of the nutrition or vitality of the cells. Amongst these are — (a) changes in the blood and nutriment supplied to the cells, as, for instance, in diabetes and various forms of cachexia ; (b) vital depression and asphyxia of the tissues, e.g. venous engorge- ment, inflammation, pressure, fever, and starvation ; (c) local and general anaemia, e.g. haemorrhages, leukaemia, pernicious anaemia, and carbon monoxide poisoning ; (d) intoxications, which include — (1) Bacterial intoxications (infective fevers, such as diphtheria, pneumonia, etc.) ; (2) intoxications by inorganic or organic chemical poisons, such as phosphorus, arsenic, carbolic acid, corrosive sublimate, and alcohol ; (3) so-called auto-intoxications (e.g. acute yellow atrophy) ; (e) nervous lesions, which may lead to fatty degeneration in the muscles ; (/) disuse of the muscles from whatever cause ; (g) fatty accumulation and infiltration.
The extent of the fatty degeneration varies with the condition producing it. Thus a local anaemia, circumscribed pressure, or a focal inflammation can only pro- duce a limited area of degeneration. Given a general cause, certain organs are more predisposed to it than others, as for instance the liver, heart, and kidneys ; but one organ may be affected whilst others escape, although the cause be a general one. Thus, in leukaemia, the heart shows the fatty degeneration more strikingly than other organs; it may be the part solely affected. In a single organ, the degeneration, again, may be general or local, as in the kidney.
As to the process of degeneration in the cell, our knowledge is very limited ; Gautier's view is that, under physiological conditions, the cell passes through two phases — (a) one of hydrolysis, during which the protoplasm is changed into urea and its allies, and the carbohydrates are converted into fat. This is followed by (b) the second phase of oxidation, during which the sugars partly disappear, partly change into fat, the fats eventually being burnt up. Imperfect oxidation, there- fore, would produce a change of the cell protoplasm into fat. Pavy, who holds that protoplasm is a glucoside, believes that through some ferment action the carbohydrate molecule of the proteid is converted into a fat.
Long-continued or excessive fatty accumulation may lead to fatty degeneration. In the heart, the fat which has extended into and accumu- lated in the intermuscular substance, exerts pressure on the muscular fibres, impairs their nutrition, and gives rise to fatty degeneration. Similarly, a liver or pancreas heavy with accumulated fat eventually degenerates, and in the case of the pancreas the glandular substance may disappear altogether. This is probably due to two factors — (a) the fat accumulation reacts deleteriously on the vitality of the higher structures ; and (b) the agent which produces this accumulation is often a tissue poison (e.g. alcohol), which, first causing an accumulation of fat, still continues to act on the already impaired tissues, and so advances the degeneration. In the same way the continued consumption of carbohydrates must be harmful to liver cells already overloaded with fat.
The fatty changes in the more important tissues or organs are the following : —
In the heart there is (a) an increase of the epicardial fat, which may almost surround the whole heart ; (b) this fat may spread into the myocardium, along the intermuscular tissue, and so to the subendocardial tissue; (e) this accumulation of fat may, by pressure, cause fatty degeneration of muscular fibres themselves ; or (d) the degeneration of the myocardium may be primary, without any previous accumulation of fat between the fibres. It is then generally patchy, giving rise to the well-known "tabby-cat" striation, "thrush's breast" or "dead leaf" appearance often so well marked in the musculi papillares. Under the microscope the degenerated fibres appear granular, and innumerable minute droplets of fat take the place of the striation.
FATTY CHANGES IN TISSUES. 5
In voluntary muscles the changes observed are analogous to those met with in the cardiac muscle.
In the kidney the fatty changes are usually purely degenerative, and they generally accompany other lesions, such as so-called parenchymatous or inter- stitial nephritis. They may occur independently — for instance, as the result of phosphorus, arsenic, metallic, or carbolic acid poisoning, or as the result of anaemia, diabetes, infective fevers, or circulatory disturbances. They may be diffuse or focal, and in either case are generally restricted to the cortex. When focal — as e.g. in diphtheria — the looped tubules of Henle and secondary con- voluted tubules are affected ; when general, the degeneration spreads also to the large convoluted tubules, the Malpighian bodies, and even to the connective tissue. The fat droplets appear first in the part of the cell nearest the membrana propria ; they then gradually invade the whole cell, and eventually the cell may break down completely and be cast off. The large globules of fat found distend- ing the cells can scarcely be of this nature.
In atheroma of the aorta the branched cells of the intima are filled with innumerable droplets of fat, the nucleus being obscured, although itself often not degenerated.
Fatty changes in nerves are easily recognised in the so-called peripheral neuritis. The myelin sheath l breaks up into globules and irregular masses of fat, which stain intensely black with osmic acid, and analogous changes may be observed in the cord in cases of degeneration, whether ascending or descending.
Next to the heart, fatty changes have been most completely studied in the liver.'*
1 Normal myelin is not stained black with March i's fluid (osmic acid solution in dilute Muller's fluid), although ordinary body. fat (which is a neutral fat) docs. The myeliu has therefore been changed into fat.
2 Kanthack follows Cohnheim, and does not use the term infiltration. He says: "The intestinal epithelium absorbs fat from the intestinal contents, and leucocytes and phagocytes take up fat granules from a degenerated area— these are the nearest approaches to an infiltration ; it is, however, an ingestion, followed probably by assimilation and digestion. The fat appearing in the tissues under normal conditions, whether in the secreting mammary gland, in the liver, or in the panniculus adiposus, has been produced by chemical action, or by a fatty metamorphosis from the albuminous cell protoplasm ; this cannot be called an infiltration. In fact, the physiological secretion of milk depends on a true, though partial, fatty degeneration of the cells lining the alveoli."
" Pathologists are in the habit of distinguishing between fatty infiltration and fatty degener- ation in the liver ; their criteria are partly anatomical, partly morphological. In fatty infil- tration the globules are said to be larger, and arranged either at the periphery of the liver acini, or centrally around the intra-acinous vein, or in the interstitial tissue between the acini ; while in degeneration the droplets are said to be small, to occupy the whole cell, and the meta- morphosis is stated to be, as a rule, general. It is asserted that in the former case the fat has been stored up in the cell ; in the latter, it has been formed at the expense of the cell sub- stance. Most observers describe infiltration in obesity, nutmeg liver, phthisis, cirrhosis, and similar conditions on account of the anatomical distribution and morphological appearances of the fat. In obesity, at least in the early stages, there may possibly be an accumulation of fat without the cell sutfering, the cell being over-active, and forming fat from the material generally supplied in excess ; but it is difficult to understand how a true accumulation or infiltration could occur in diseases in which the fat disappears from the subcutaneous and omental tissues, i.e. in wasting diseases. In them the fat must have been formed in the cell, and at the expense of the cell, whether the appearances are those of infiltration or degeneration, as gener- ally described. In the obese person the liver cells, after forming an excess of fat, are capable of replacing the cell albumin which has been used up in the manufacture of fat, and only when they cease to do this will degeneration also appear. As Cohnheim puts it, the guiding rule of distinction between degeneration and infiltration, or, as 1 prefer to say, accumulation, is this : 'Does the fat occupy a cell with diminished or normal albuminous contents?' In the early stages of obesity there is merely an accumulation of fat in the ' legitimate local- ities ' ; in the later stages this becomes excessive, and the fat extends beyond these localities, and, as far as the liver is concerned, instead of being restricted to the |>eriphery of the lobule, occupies the whole of it, producing a large, fatty liver." The accumulation of fat in this case is probably due to the two factors mentioned previously, namely, incomplete oxidation and excessive supply of the precursors of fat ; it is not, to begin with, an atrophy, although eventu- ally this also may follow in some of the organs (e.g. heart and liver). He agrees with Cohn- heim that the fatty changes observed in the liver with anaemia, phthisis, cancer, etc., are all
6 GENERAL PATHOLOGY OF DISEASE.
The true accumulations — or infiltrations, to use the more familiar term
are— (a) the normal physiological storage of fat; (&) the transient
accumulation in persons of sedentary habits; and (c) all but the most advanced stages of obesity. Other conditions are atrophic, and are asso- ciated with fatty degeneration. There are undoubtedly two varieties of fatty degeneration. In one the destruction or disintegration of the cell albumin is rapid and excessive, and the cells break down quickly, as for instance in acute yellow atrophy, phosphorus and arsenic poisoning; in the other the cell destruction goes on more slowly, and the fat formed at the expense of the cell substance has a chance of accumulating for a long time (e.g. phthisis, anaemia, cachexia). Local fatty changes in the liver are also atrophic, and may be produced by pressure of tumours, or by the con- traction of newly formed fibrous tissue.
Termination. — An accumulation may either disappear by oxidation and resorption on change of habits, or it may pass on to degeneration. Degeneration, especially if local, may be repaired by restitution of the tissues (e.g. in muscles and nerves), the fat granules being removed by phagocytosis or oxidation ; or it may end in complete disintegration, death, and necrosis, the fat then being replaced by fibrous tissue, e.g. sclerosis of voluntary muscle or of the nervous tracts in the cord, in accordance with the law that "degenerate tissue, if not regenerated, is replaced by connective or fibrous tissue."
AMYLOID CHANGES.
In amyloid disease curious deposits make their appearance in certain tissue elements. When these are extensive, they are not unlike boiled starch, and the tissues are transformed into glassy or hyaline masses. Amyloid deposits can be readily demonstrated by the following chemical reactions: — (a) A solution of iodine stains amyloid a deep mahogany-brown ; if a weak solution of iodine be allowed to act for a long period, and sulphuric acid be added, a bluish or violet colour may sometimes be obtained. From this modified starch reaction the name " amyloid " was derived. (&) Methyl-violet stains the amyloid material red, leaving the other parts bluish. The reaction is best marked if, after staining with methyl- or gentian-violet, the tissues be washed in water, acidulated with hydrochloric, oxalic, or acetic acid. It must be remembered that other substances, such as " colloid " and " hyaline," occa- sionally stain somewhat like amyloid ; everything that gives a red reaction with methyl-violet must not be regarded as amyloid. According to Lubarsch, the methyl-violet test is convincing (a) wherever iodine or iodine-sulphuric acid gives a positive reaction ; (&) in the absence of the iodine or iodine- sulphuric acid reaction wherever the substances which stain red with methyl-violet optically, chemically, and topographically agree with genuine amyloid ; or (c) wherever it appears under conditions which are generally associated with amyloid degeneration.
true fatty atrophies, whatever they may appear to be on histological rules, more or less arbi- trarily laid down. "In phthisis," Kanthack continues, "the fat is often found in large drops at the periphery of the hepatic lobule, and many describe this as infiltration or accumulation without degeneration. They believe that the excessively fatty liver of emaciated con- sumptives is due to an infiltration with fat, which has been formed elsewhere during the process of wasting. How can this be? The fat must have been formed at the expense of the cell substance, and it remains in situ on account of diminished combustion. The fatty changes of starvation are also certainly atrophic."
AMYLOID CHANGES. 7
Amyloid, though a proteid, does not react like an ordinary albumin, and resists digestion. It is asserted, however, that in a finely divided condition it undergoes both peptic and tryptic digestion ; it is dissolved on heating in water or alkalies.
Causation. — (1) The commonest cause is chronic suppuration, and especially that accompanying chronic pulmonary phthisis, tuberculous disease of the bones and joints, syphilitic bone disease; ulcerating cancers and varicose ulcers of the legs are also given as causes ; (2) tuberculosis and syphilis (especially in the tertiary or congenital form) without con- comitant suppuration ; (3) actiuomycosis ; (4) Bright's disease ; and (5) various forms of grave ansemia and cachexia may also lead to amyloid disease.1
If the various lesions with which amyloid changes may occur be reviewed, it will be found that the common factors are — (1) continued loss of albumin, pro- ducing chronic anaemia, or marked hydraemia ; and (2) the incidence or inter- currence of infective processes, often secondary, such as suppuration of bone, or in connection with ulceration.
Localisation. — In general amyloid disease, certain organs, the liver, spleen (oftener than any other organ), kidney, suprarenal capsules, lymphatic glands, and intestinal mucosa, especially that of the large intestine, are more especially selected, and, as a rule, several of them are simultaneously affected.2
Most of the attempts to produce amyloid disease experimentally have been negative, but a few positive results have been recorded. Czerny kept up a chronic suppuration in dogs by means of turpentine and nitrate of silver injec- tions, and found that the spleen and liver invariably showed amyloid changes. Examining the pus corpuscles and leucocytes, he found that during the experi- ments they showed granules which stained dark brown with iodine, and turned blue on the addition of sulphuric acid ; he assumes that this substance is pre- amyloid matter, which is carried by the leucocytes to the tissues, deposited there, and then changed into amyloid. Similarly, he found that during suppur-
1 In 269 cases Birch-Hirschfeld found amyloid changes —
In spleen alone liver ,, kidneys ,,
spleen, liver, and k dneys spleen and kidney spleen and liver kidneys and liver
2 Birch-Hirsclifeld has analysed 262 cases, and in these there were present -
1. Chronic tuberculous disease of the lungs .
2. Pulmonary phthisis and bony tuberculosis
3. ,, ,, intestinal tuberculosis
4. ,, ,, syphilis
5. Bony tuberculosis alone
6. Chronic suppuration of bone (non- uberculous)
7. Syphilis (gummatous, especially in
8. Cancerous ulcers
9. Varicose ulcers of leg
10. Visceral suppuration
11. Actinomycosis . •
12. Noma ' .
13. Peritoneal tuberculosis
14. Chronic arthritis .
15. Suppurative cystitis and pyelitis
16. Doubtful causes
liver)
Times.
35
2
1
142
77
10
2
Times".
140
21
18
2 28
4 15
5
3
8
1
1
4
1
1 10
262
8 GENERAL PATHOLOGY OF DISEASE.
ative processes in man pre-amyloid substances appear in the leucocytes, and he concludes that the precursors of amyloid are formed in the pus — whether micro- organisms are present or not is immaterial; that they are diffused or distributed in the various organs and deposited there as true amyloid ; and that this deposi- tion shows itself first in the spleen.
Krakow made repeated inoculations into rabbits and other animals with pure cultures of the Staphylococcus pyogenes aureus until they showed marked wasting ; he thus produced amyloid changes in their organs, which also began in the spleen, and in every detail agreed with what is observed in man, microscopically and histologically. He believes that microbic infection is absolutely necessary. Other observers have failed to obtain results similar to those obtained by Czerny and Krakow.
Processes. — How is the amyloid substance deposited in the tissues? There exist two conflicting views — (1) that the amyloid is produced in situ by the cells from their albuminous constituents — degeneration ; (2) that it is formed in the blood and carried to the tissues — infiltration. It is generally accepted that amyloid matter appears in the interstitial tissue only, never in epithelial cells, although such excellent observers as Dickinson and v. Recklinghausen spoke, and the latter still speaks, of intercellular and intracellular infiltration. Most patho- logists hold that it is exclusively the connective tissue which contains the amyloid, whether it be deposited there by a process of degeneration or by infiltration. If Czerny's observations be accepted, the amyloid change is an infiltration. Against this is the fact that amyloid has never been observed in the blood. It is un- doubted that amyloid appears first in the intercellular substance. It has been stated by some observers that in the liver the amyloid is deposited first in the hepatic cells (Dickinson) ; but others, and especially more recent observers, em- phatically deny that these cells ever show amyloid changes, and that amyloid changes ever occiir in (a) epithelium, (b) striped or unstriped muscular tissue, or (c) leucocytes, but that the deposition is always an interstitial one, and that the tissue cells degenerate through pressure exerted by the amyloid tracts.
Amyloid changes during the earliest stages are most frequently observed in or along the capillaries and smallest arterioles. Their walls become swollen, and their lumen narrowed ; in the arterioles the amyloid matter is deposited in the middle coat, the muscular elements remaining intact, the material appearing in the connective tissue ; in the capillaries it is deposited in the interstitial substance of their walls. From these points the amyloid change extends into the surrounding tissues, impli- cating the connective tissue and the basement membranes. In the liver and kidney the epithelial cells outside the amyloid tracts alway show marked fatty degeneration, and those within these tracts disappear alto- gether ; and when vital organs are concerned, the final results must be anaemia, hydraemia, marasmus, and death. The amyloid matter not only presses on the cells, but also narrows the lumina of the vessels ; vascular obstruction is produced, which, if arterial, still further impairs nutrition and function; and, if venous, may lead to oedema and dropsy. Thus, in amyloid disease of the liver, ascites, due to portal obstruction, is common ; in amyloid disease of the kidney, albuminuria not unfrequently occurs.
Terminations. — Is amyloid substance, once formed, ever reabsorbed ? Litten attempted to answer this question experimentally by placing frag- ments of amyloid tissue in the peritoneal cavity of the rabbit ; what was left of the amyloid tissue no longer gave the methyl-violet reaction. It is known that wandering cells may ingest amyloid matter. There is some clinical evidence that occasionally an amyloid liver may diminish in size.
HYALINE AND WAXY DEGENERATION. 9
It must, however, be remembered that the clinical diagnosis is by no means always certain.
In the liver the amyloid is early deposited along the capillary walls in the intermediate or hepatic zone of a few lobules, compressing the liver cells, which themselves, however, remain otherwise unaffected, and the naked-eye appearances are almost unchanged ; later, the liver becomes enlarged and firm, smooth, and almost opalescent on section. The degeneration affects specially the intermediate portions of the acini. Such as are left of the liver cells must be looked for at the extreme periphery or the extreme centre of the lobule ; those at the periphery are almost always in a state of fatty degeneration. In the amyloid zone nothing is found of the cell outlines ; the cells have vanished, or only the merest remnants are found.
(a) In diffuse amyloid spleen, usually associated with heart disease, the sinuses and capillaries are surrounded by amyloid tracts, which also extend along the reticulum, gradually compressing the spleen cells, and pressing upon the follicles, which are unaffected except in many cases as to the central vessel.
(6) In sago amyloid spleen, the capillaries and reticulum of the follicles become amyloid ; the lymphocytes eventually may disappear altogether through pressure. The central vessel is seldom affected, and then at a late stage of the disease.
In the kidneys the amyloid 'changes are best observed in the cortex, but are present also in the medulla. In the cortex, the glomeruli, membranse pro- priae, arteries, and capillaries are affected, and in the medulla the vessel walls and membranse propriae, but, as stated by modern observers, the renal epithelium seldom or never suffers. The glomeruli become enlarged and transparent, and filled by amyloid capillary loops ; the nuclei of the glomerular epithelium disappear.
I?itestine.—The amyloid changes are observed in the walls of the vessels of the villi, mucosa, and submucosa, and in the reticulum of the villi.
Lymphatic glands. — The capillaries and reticulum become amyloid, and appearances resembling those described in the spleen are seen.
Occasionally amyloid changes may appear locally, as in the conjunctiva and in the connective tissue, or in tumours. These require no special description or discussion.
HYALINE AND WAXY DEGENERATION.
Under certain conditions hyaline masses, transparent, homogeneous, and bright in appearance, are met with in the organs and tissues. Hyaline is not a definite chemical substance, but includes bodies all of which are charac- terised by their great resistance to water, alcohol, acids, and ammonia, and their affinity for acid aniline dyes, such as acid-fuchsin and eosin ; von Kecklinghausen includes hyaline, mucous, and amyloid changes under colloid metamorphosis, but this is misleading. Klebs restricts the terms colloid to all hyaline substances derived from epithelium and hyaline to similar substances derived from connective tissue; this seems to be the safest classification, although it indicates but roughly the chemistry of these bodies.
Certain authors maintain that there are two varieties of hyaline — (a) that secreted by the connective tissue cells (i.e. of intracellular origin) ; and (6) that produced by coagulation of plasmatic fluids, serum, plasma, or lymph (i.e. of extracellular origin). It is best to agree with Birch- Hirschfeld that intracellular hyaline formation is merely a form of so- called coagulation necrosis, and that hyaline degeneration is due to a coagulation of fluid derived from the blood plasma, muscle plasma, lymph or cell plasma.
io GENERAL PATHOLOGY OF DISEASE.
Hyaline changes may be hsematogenous, as in thrombi in the capillaries, especially in infective diseases; or exudative, when a diph- theritic membrane becomes hyaline ; or when, in chronic Bright's disease, the albuminous casts become hyaline. The muscle substance in some cases, especially in infective fevers (e.g. typhoid and diphtheria) may break up into hyaline transparent masses, no doubt due to a coagulative change in the muscle plasma. This condition is frequently spoken of as vitreous degeneration, and may be caused also by injury, chemical, physical, or mechanical, to the muscle. The fibres break up inside the sarcolemma into irregular hyaline masses which swell, and as a rule are broader than the unchanged fibres. On microscopic examination the muscle has a cloudy or boiled appearance. Fibrin, which itself is a product of coagulation, may become hyaline, as frequently observed in croupous pneumonia, in thrombi, and in the walls of aneurysms.
Hyaline changes must be regarded as the result of coagulative processes, all the more that they are generally observed in inflammatory lesions, or where there has been an increased exudation. The vessel wall or surrounding connective tissue or muscle substance imbibes some kind of fluid Avhich coagulates. Some writers believe that hyaline is closely allied to amyloid, because hyaline degenera- tion may be an antecedent condition ; hyaline and amyloid changes are often found together, and there is a gradation in staining reactions from amyloid to hyaline ; hyaline changes are common in and around the capillary or arterial vessel wall, and amyloid changes always begin there ; lastly, infective processes are common causes of both foims of degeneration.
COLLOID CHANGES
These are allied to mucous and hyaline degeneration. Colloid differs from mucin in that it is not precipitated by alcohol and acetic acid. It is a gelatinous hyaline substance and is always of epithelial origin. Many changes are frequently described as colloid which are not of this nature. Physiologically colloid appears in the follicles of the thyroid gland, and if, as in goitre, the production of colloid becomes excessive, the condition becomes pathological. In tumours also (carcinoma) colloid may be formed, the cells becoming distended with globules and masses of colloid which they discharge, while they themselves may be entirely destroyed. It is doubtful, however, whether the so-called colloid cancer is really colloid, and not rather myxomatous. In interstitial nephritis colloid cysts are frequently found, though some writers are inclined to regard their contents as produced by coagulation of an albuminous substance, and therefore as being allied to hyaline.
Mucous CHANGES.
Mucin is a transparent viscid colloid substance, the chemical nature and properties of which are as yet insufficiently known. According to Landwehr, it is a compound of albumin with a carbohydrate body called animal gum, which on boiling with dilute mineral acids (sulphuric acid) yields a non-fer- mentable sugar. The mucin produced by epithelial cells differs materially from that derived from connective tissues, whilst again the mucin obtained from epithelium is not a constant substance. Thus the mucin found in ovarian cysts is not precipitated by acetic acid, while that formed by the columnar cells of the intestines is solidified by both alcohol and acetic acid.
Under pathological conditions, mucin may show itself (a) as a product of abnormal epithelial activity. The columnar cells of mucous membranes normally form mucin in a mucous catarrh the number of goblet cells becomes much
WASTING AND ATROPHY. n
increased, or every columnar cell may be distended with mucin. Again, the columnar cells lining the cystic spaces of an innocent tumour (such as an ovarian cyst), or of a malignant tumour (such as a columnar-celled carcinoma), may also produce an excessive amount of mucin, so that the cystic spaces become distended with mucus. On the other hand, (6) mucin may appear in connective tissue, bone, cartilage, and fat, or in the connective tissue tumours. There is then either a viscid gelatinous matrix, embedded in which are numerous reticular cells, or a more or less dense network of filaments (a reticulum). In myxoedema, in certain stages of the disease, the connective tissue of the skin becomes gelatinous. It must be remembered that embryonic connective tissue is myxomatous, and that, therefore, young connective tissue appearing under morbid conditions is also frequently mucous.
WASTING AND ATROPHY.
Atrophy, closely allied to degeneration, is a condition in which there is diminution in the size of an organ or part, or even a cell of the body. This is a purely morphological term, and was originally used to indicate macroscopic changes. When a liver rapidly decreased in volume, as the result of marked fatty degeneration, the process was called an acute atrophy ; but from histological observation it is now known that this is a degeneration followed or accompanied by necrosis, and not an atrophy proper. Arrested development (hypoplasia) must not be confused with atrophy, for here the organ has never attained its normal size. Hypoplasia may be due to intra-uterine changes, or it may be caused by forces acting at the seat of and during the period of growth, as in microcephalus, undeveloped thyroid, and stunted epiphyses of long bones following rickets or inflammation. After an amputation of a leg, during childhood or youth, the corresponding side of the pelvis remains small, whilst infantile paralysis of the upper extremity leads to arrested development of the clavicle and scapula on the same side. When development has not taken place at all, the term aplasia or agenesis is used.
Atrophy of an organ must be due (1) to diminution in the size of the component elements, (2) to a diminution in the number of these elements, or (3), and most commonly, to a combination of the two. At the same time, inadequate regeneration may play a most important part in this condition. Under physiological conditions cells continually dis- appear, but they are replaced by others. If, however, the regener- ative process does not at least balance the normal decay, the part must diminish in size, i.e., it must undergo atrophy, as when tissues become senile, e.y. the skin and the muscles of an old man are visibly atrophic, although there is no degeneration ; a cell, having played its part, disappears from the scene, and its place is not filled by another cell, — simple atrophy. In the atrophy of degeneration, on the other hand, the cells become fatty, hyaline, amyloid, or necrotic, and are then removed as dead matter or are replaced by fibrous tissue ; the part becomes smaller and many cells disappear, the diminution being due to degeneration and death, and the removal of the useless material. It may be held that as decayed tissue is replaced by fibrous tissue, which, contracting still further, diminishes the size of the organ, it is quite unjustifiable to speak of atrophy. The shrinkage in an atrophic cirrhosis of the liver, or an atrophic red kidney, is due to the condensation of the fibrous tissue, and it might be better to speak of a shrinking liver, and a shrinking or
1 2 GENERAL PA THOL OGY OF DISEA SE.
contracting kidney. On examining such a shrinking organ, e.g. kidney, it will be found that many of the epithelial cells pressed upon by the fibrous tissue become smaller and smaller, i.e., they atrophy, till eventually they degenerate, die, and are cast off.1
Simple atrophy may be observed — (1) under physiological conditions, e.g., when the thyrnus gland gradually disappears ; (2) as a senile change ; or (3) it may be due to morbid conditions, e.g., when, on account of diminished nutrition, an organ or a tissue becomes reduced in size. Thus during inanition the fat atrophies, the muscle becomes smaller, and the glandular cells disappear, there being in all three cases an impairment of regeneration on account of the inadequate food supply. It is doubtful whether the disappearance of the fat can be called an atrophy, except in the sense that it is not regenerated. Just as the plant stores up starch for future consumption, so does the animal body store up fat ; the using up of the fat is not atrophy, but the adipose cushions vanish, because there is no regeneration. The diminution of nutrition may be due (a) to general causes, such as starvation, or (b) to local circulatory disturbances or local pressure, but in the latter case there is also, as a rule, actual destruction of the cells by continued pressure.
In morbid conditions " simple " atrophy is rarely met with. When a paralysed muscle wastes, it generally becomes fatty, or is replaced by fibrous or fatty tissue, and similarly in starvation the cells in the wasting organs often undergo degeneration. Indeed, true and uncomplicated histological atrophy is rare ; either degeneration or fibrosis is also present, or the two processes may be combined. Atrophy, in the generally accepted sense of the term, is usually accompanied or preceded by degeneration, and may be due to shrinkage of newly formed tissue.
Atrophied tissue may be restored, as where a wasted muscle again increases in bulk ; in which case an active regeneration more than balances the normal loss. But if repair does not take place, then the muscle degenerates or dies ; should " repair " occur after this, as it may, it must be either by new proliferation of homologous cells, or by the formation of fibrous tissue. (See "Chronic Inflammation.")
NECROSIS AND NECROBIOSIS.
Death of the tissues may be — (a) Gradual (necrobiosis), when it is usually preceded by a chronic degeneration, such as fatty degenera- tion or a more acute form of degeneration, such as cloudy, hyaline, or coagulative changes, nothing of the original shape, form, or struc- ture of the tissue being left. In tuberculosis and syphilis, and even in carcinoma and sarcoma, it is generally maintained that a process of so- called coagulative necrosis, which is closely allied to cloudy swelling and to the hyaline or waxy changes, is first set up. The cell pro- toplasm becomes solid or coagulated, granular or hyaline, the nucleus disappears or becomes obscured, and both cell and nucleus refuse to stain. If this intracellular coagulation is followed by a breaking up of the cell into detritus or fatty debris, then the result may be caseation. Caseation, however, is quite independent of fatty metamorphosis, and may occur without it. Caseous matter, as a rule, is semi-solid or pultaceous, whitish or yellowish in colour, microscopically granular, staining indefinitely, or not at all (in certain stages of the process hrematoxylin gives a very deep stain); it becomes dry and cheesy;
1 Kanthack held that in a shrinking organ, cellular atrophy may be observed under the microscope, but that the shrinkage is not atrophy. It is well to remember, however, that atrophy is a mixed process, and received its name before pathological histology existed.
NECROSIS AND NECROBIOSIS. 13
it is dead matter, and therefore becomes easily calcified, and if present in any quantity cannot be absorbed, but must be removed, either by operation or by ulceration.
Death of the tissues, on the other hand, may be — (Z>) Acute, or sudden (necrosis), the tissues retaining their form for some time, and must be the result of either (1) a gross or fatal tissue injury, or (2) starvation of the tissues, due either to want of food or incapacity on the part of the cells to assimilate the food supplied. Thus a direct injury, e.g. a crush, a burn, or a caustic, may destroy cell life immediately, or it may lead to serious inflammation, which only later brings about the death of the part. Again, if the nutrition of the cell is suspended it must die, as when there is a complete or serious obstruction to the circulation, (1) arterial, (2) venous, or (3) capillary. Thrombosis, embolism, or obliterative eridarteritis may produce gangrene or necrosis, e.g. dry gangrene in the extremities, cerebral softening, infarctions. Complete venous obstruction, as for instance in a strangulated hernia, may cause absolute stoppage of the circulation, i.e. capillary stasis, which, if not relieved, must result in death of the part. A complete capillary stasis may also be produced by inflammatory pressure, due to the accumulation of exudation ; in dense hard tissues, as in bone, this often leads to necrosis.
It is evident that an injury leads to necrosis partly by favouring or producing inflammation, which in its turn favours capillary stasis, and partly by impairing the vitality of the cells directly, so that comparatively slight causes are sufficient to extinguish life altogether. It must further be remembered that in many forms of gangrenous or necrotic inflammation, such as diphtheria, cellulitis, phagedaena, etc., bacteria are concerned ; they keep up a continual supply of tissue poisons, which not only have a deleterious action on the cells themselves, but also excite the surrounding tissues to inflammation. A vicious circle is thus established ; the bacterial irritants predisposing or weakening the tissues, which then succumb readily to the inflammatory pressure, which latter in turn predisposes the tissues to the action of the bacterial poisons. Weakened or predisposed parts become necrosed more readily than vigorous and healthy ones, and causes which under normal conditions would only produce an inflammation or a transient retrogressive change, may be severe enough to destroy a debilitated organ or group of cells. Thus an incomplete arterial obstruction may cause gangrene in an individual suffering from cardiac disease, or in the old and exhausted ; necrosis of the bone is commoner in those who suffer from infective fevers, and infective emboli are more serious than simple ones. Chronic alcoholism predisposes to gangrenous cellulitis ; diabetes, anaemia, marasmus, general weakness, and a feeble circulation are also all powerful predisposing factors ; the tissues are already badly nourished under such conditions, and but little suffices to destroy life altogether. Sometimes the predisposing factors may be local, such as atrophy or serious lesions. Paralysis and anaesthesia are not direct causes of necrosis, but they favour its occurrence no doubt by influencing the nutrition of the part.
Gangrene and necrosis, therefore, are due to (a) a cutting off of nutrition from a part, (b) changes which exclude the assimilation of what is supplied, (c) predisposing causes, intensifying the effect of the two pro- cesses mentioned. Generally speaking, it may be said that the first change is a coagulation of the protoplasmic cell contents, i.e. a coagu- lative necrosis. If no moisture is supplied, or if that which exists is absorbed or evaporates, the result is a dry gangrene or mummifica- tion, but if the part is moist from osdema, whether passive or inflammatory, then a moist gangrene or colliquative necrosis results.
i4 GENERAL PATHOLOGY OF DISEASE.
The dead or dying tissues may putrefy if bacteria find an abode in them, and these bacteria may themselves cause a liquefaction of the decomposing matter.
Thus there may be distinguished — (1) dry gangrene, due as a rule to an obstruction or weakness of the arterial circulation ; (2) moist gangrene, which is due either to the same causes, oedema existing or appearing at the same time, or has its origin in a severe inflammatory condition; (3) traumatic gangrene, which includes (a) immediate death as the result, for instance, of a crush, or (b) inflammatory necrosis (cellulitis and phagedaena), or (c) special infective forms, such as noma, cancrum oris, acute spreading gangrene, or emphysematous gangrene, or rapid septic gangrene, or necrosis ; (4) symmetrical or idiopathic gangrene, the etiology of which is at present but little, known ; (5) gangrene accompanying infective fevers, such as ulcerative endocarditis, typhoid fever, etc. ; (6) the gangrene of anaemia and marasmus ; and (7), most obscure form of all, the gangrene of nervous origin, e.g. hysteria and Raynaud's disease. Any form of ulceration, or sloughing inflammation, bedsore after hsemorrhagic extravasations, from pressure or during osdema, or abscess, is accompanied by necrosis, which, however, may be so small as to escape detection with the naked eye.
In bones the death of the tissues shows itself either in the form of an extensive necrosis, — a sequestrum, or as caries. In the intestinal tract, gangrene of the bowel is observed in cases of hernia, intussusception, and strangulation ; necrosis occurs in the various forms of ulceration, such as are seen in typhoid fever, ulcerative colitis, and dysentery ; while in the pharynx and larynx, diphtheria offers the commonest example of necrosis. In the lungs large areas may become gangrenous, as for instance during or after pneumonia ; or as the result of the presence of a foreign body or an injury. Necrosis is observed with caseation or during the development of cavities in the lung. Sloughing and necrosis also occur in new growths, especially in those of a malignant type, of the bladder and uterus, liver and pancreas. The so-called fat necrosis, in which the omental and mesenteric fat more especially shows numerous dull white or yellowish areas, consisting of dead, solid, or saponified fat, generally accompanies sloughing or inflammation of, or haemorrhage into, the pancreas.
Necrosed tissue must be removed from the body, and whatever defect remains is subsequently made good by newly formed fibrous tissue, unless the necrosis was slight and superficial, when there may be homologous repair, as for instance when epithelium is cast off arid the gap is filled by
•iU T J
epithelium.
CALCIFICATION AND CONCRETIONS.
Calcareous changes generally appear in dead or dying tissues, never in perfectly sound and normal structures. Two main processes may be distinguished — (a) infiltration and (6) concretion.
Infiltration. — The deposition of calcium phosphates and carbonates, often with similar magnesium salts, occurs either in the cells or in the matrix binding the cells together ; these salts occur first in the form of minute granules which are soluble in hydrochloric acid, often with an evolution of gas if carbonate be present. The granules are readily stained by haematoxylin, and gradually fuse into homogeneous masses which may have a concentric arrangement.
Forms of calcareous infiltration.— (1) Normally it is observed during the formation of bone, when the lime salts may be deposited either in the cartilaginous
CALCIFICATION & CONCRETIONS — PIGMENTATION. 15
matrix or in the dense osteoid connective tissue substance. (2) It occurs in senile tissues, notably in cartilage, e./j. the laryngeal or costal cartilages, which may even ossify ; and in the vessel walls, especially in the intima or media, where it is generally preceded by a morbid lesion, such as atheroma or fibrosis, the tissue being in an impoverished condition on account of a weakened circulation. (3) In continually irritated or hyperplastic connective tissue, the result of so-called chronic inflammation. Thus in a thickened pleura or in tendons of muscles constantly exposed to pressure (e.g. from riding), calcareous changes are not rare, and in the adventitious fibrous capsule produced by the continued irritation of parasites, as in hydatid and trichina cysts; in this, subsequently, lime salts are deposited. (4) In tumours, such as fibromyomas or growths containing cartilage, calcareous changes are by no means uncommon. When cartilage is present, the process is almost physiological, while in the fibrous tumours those parts suffer which are furthest removed from the blood supply, or which, for some other reason, have their vitality impaired. (5) Calcareous changes are especially common in caseating or necrosed tissues, and wherever fibrin is present, as for instance in thrombi, infarcts, or endocarditis. Hyaline changes are also very common precursors of calcification. Generally speaking, then, calcareous infiltration occurs in connection with a dense matrix or tissue, dead or necrosing elements, and with impaired nutrition ; it is therefore intimately associated with degeneration and necrosis. Soluble calcium salts, lactate or glycerophosphate of lime in the blood, and lymph, may become converted into insoluble salts, the carbonate or phosphate ; while at the same time there is a diminution in the amount of fluids keeping the lime salts in solution.
Concretions are calcareous or earthy masses occurring in pre- formed or pre-existing cavities, in the lumen of vessels, tubes, or ducts. They may be found in serous cavities, when they generally develop in fibrinous masses, or they may present themselves as calculi. In the latter case the lime salts are generally combined with other substances, and they may be altogether of secondary importance. Calculi are found in the kidneys, the gall bladder, pancreatic and salivary ducts, the prostate and urinary bladder; concretions may also occur in the intestine, veins, or tonsils, as enteroliths, phleboliths or rhinoliths, the development of which is generally accompanied by — (1) stagnation of the excretion or secretion ; (2) a solid substance, it may be a small crystal, around which the incrustation or deposit takes place ; (3) changes in the chemical constitution of the fluids and in their solvent power, which are often due to bacterial activity and to an increase of albuminous, mucous, or colloid substances. Gouty concretions, which consist of urate of sodium mixed with carbonate and phosphate of lime, will be considered elsewhere.
PIGMENTATION.
Pigment may be of little or no importance, or it may be of the greatest significance in the diagnosis of disease. The pigment may be exogenous, having entered from without, or it may be endogenous, derived from the body itself. Examples of the former process are anthracosis, where carbonaceous matter is stored up in the lungs or lymphatic glands, the liver, diaphragm, and other parts; argyria, where, as the result of con- tinued ingestion of nitrate of silver, salts of silver are deposited in the connective tissue and vascular walls of the skin and kidneys; and tattooing, where insoluble coloured substances are rubbed into excoriated skin and its lymphatics, whence in part they are carried to neighbouring lymphatic glands.
16 GENERAL PATHOLOGY OF DISEASE,
|
Pigmentation. |
|
|
I. Exogenous — Anthracosis. Argyria. Tattooing. |
II. Endogenous — -, TT 1 extravascular. 1 . Haematogenous < . , ( mtravascular. 2. Overproduction. 3. Atrophic. 4. Hepatogenous. |
Such conditions are of little pathological interest. In anthracosis of the glands the black pigment occurs in the larger connective tissue or endothelial cells, but never in the lymphocytes themselves ; in anthracosis of the lungs the pigment is found in the epithelial cells of the alveoli, but chiefly in the inter- stitial connective tissue between the alveolar walls, where it lies in the same type of cell in the peribronchial or periarterial tissue (even media and intima may be affected), and on to the bronchial glands. The deposited pigment acts like other foreign bodies, and produces a hyperplasia of the connective tissue which becomes fibrous (fibrosis and induration). When the vessel walls are markedly infiltrated, they appear as rings of pigment. Anthracosis affects especially the bronchial, tracheal, cervical, portal, and mesenteric glands. Pass- ing along the lymph sinuses, this pigment is taken up by their endothelium, and is at first deposited around the periphery of the lymph follicles. Its presence produces a fibrosis of the reticulum just as it did in the lung, and many of the newly formed connective tissue cells become impregnated with pigment ; this gradually extends into the follicle, which becomes indurated, its lymphocytes disappearing before the proliferating endothelial or connective tissue cells. Tattoo pigments are taken up in the same manner. Where the pigment is of endogenous origin, it may have been derived (1) from the blood; (2) from over- production due to an increased functional activity of the pigment cells ; (3) from certain degeneration processes ; or (4) from the bile.
Hsematogenous pigmentation may be (a) extravascular, or (6) intravas- cular. In the former case it may result from a haemorrhage or an engorgement, with diapedesis and destruction of the red blood corpuscles. The pigment is brownish or yellowish in colour, and consists either of haematoidin or haemo- siderin. Haematoidin is crystalline acicular, or rhombohedral and free from iron. It is apparently identical with bilirubin ; but it, includes several substances, all iron-free derivatives of haematin, which are formed in and by the tissues as opposed to the cells. Haemosiderin, on the other hand, an iron- containing granular pigment, is manufactured in and by the cells themselves, which have taken up the destroyed red corpuscles. It may be taken to the lymphatic glands by the wandering cells. Haemosiderin and haematoidin often occur together, (b) When the pigment is formed inside the vessels (1) the blood may be stagnating, and there may be a thrombosis, when a state of things corresponding to that existing in a haemorrhage is present, or (2) the blood may be circulating. Certain poisons may cause a dissolution of the red corpuscles (a haemolysis), the dissolved haemoglobin being taken up by the blood plasma (hsemoglobinaemia), to be excreted by the kidneys as haemoglobin (haemoglobinuria), which may be present in such quantities that it may even cause a brown discoloration of the uriniferous tubules (haemoglobin infarcts). Experimentally, haemolysis may be produced by chlorate of potassium, arseniuretted hydrogen, and toluol-diamine, etc.
In other cases a living virus may attack the red corpuscles directly, as for instance in malaria, where an iron-free black pigment (melanin) appears in the spleen, liver, brain, and bone marrow, and is also deposited in the skin and tissues, generally together with haemosiderin. Quincke has described another
PIGMENTATION 17
process of haemal pigmentation which he calls siderosis ; this must be dis- tinguished from siderosis of the lung, which is produced by inhalation of iron dust, and causes a rusty brown discoloration of the lungs. In Quincke's siderosis there is a deposition of a ferruginous pigment in the liver, spleen, marrow, and often also in the kidneys ; this is derived from the red corpuscles which die in the circulating blood, and are then carried by phagocytic cells to the organs mentioned above ; from them a yellow haemosiderin is formed. This process is a physiological one according to Quincke, but under pathological conditions there is increased haemolysis accompanied by diminished regeneration of red corpuscles, as for instance in pernicious anaemia, when the presence of free iron can easily be demonstrated in the liver, spleen, and bone marrow by means of chemical reagents.
Overproduction of pigment. — (a) An excessive amount of brown pigment may appear in situations which normally contain such pigment, e.g. the skin, where, for some reason or other, the pigment cells become more active in the elaboration and excretion of pigment. Such overproduction may be physiological, as in the pigmentation of pregnancy ; and in freckles (due to exposure to sunlight) ; it may be congenital, in pigmented moles (naevi pigmentosi). Again, pigment (melanin) may occur in small innocent wart-like or mole-like new growths, or in malignant deposits, such as melanotic sarcoma. Melanin is free from iron, but contains sulphur. In Addison's disease, large areas may be pigmented, but as yet no sound explanation has been offered as to the origin of the pigment and the relation between the diseased suprarenal capsules and the bronzing. Histo- logically, wandering cells loaded with pigment can always be demonstrated in the skin and even in the lymphatic glands, but seldom in the blood.
(6) Under certain pathological conditions, a yellowish-green pigment may appear in morbid growths, more especially in sarcomas (chloromas), and in the so-called xanthoma (xanthelasma), which is occasionally associated with, although it may occur independently of, jaundice. This light pigment is probably a lipochrome.
Pigmentary atrophy. — With advancing age pigment appears in several organs, such as the heart, the liver, the kidneys, the testes, the suprarenal capsules, and the ganglion cells of the central nervous system. The origin of this pigment has not been satisfactorily explained. In the testes and liver it is ferruginous, and may therefore have been derived from the blood, but in the heart it is iron-free. Here it is found in the fibres of the myocardium, collected around the nuclei, obscuring the striation of the cells, and apart from senile changes may appear as the result of a cachexia or marasmus (Addison's disease), and may be so excessive as to produce a yellow or brown discoloration (brown or yellow atrophy) of the heart.
Bile pigmentation. — This is known as icterus or jaundice. Under certain pathological conditions, bile pigment, bilirubin, passes into the circulation by the thoracic duct from the hepatic lymphatics. In this condition the larger bile ducts, or the smaller ducts over a large area of liver tissue, are obstructed, or there is a regurgitation of bile into the smaller canaliculi and the hepatic lymphatics. It is always liepatogenous, that is, the pigment is formed by the liver and in the liver, and not in the blood vessels. The pigment appears in the tissues first as bilirubin, which is apparently identical with haematoidin; but if the jaundice persists, the bilirubin is gradually oxidised into biliverdin, the tint of the skin changing from yellow to dark green (black jaundice). Bilirubin absorbed from the liver appears in the urine as such, Avhile hsematoidin appears as uribilin. The icteric pigmentation is observed in the following tissues: — Skin, conjunctiva, most internal , organs, the intima of the _ larger vessels, the liver cells and the renal epithelium; it is also found in the various serous fluids and in sweat, but not in tears; the brain is always free. If the jaundice is of long standing, the bile canaliculi may be filled with inspissated bile.
The cause of the yellow discoloration in certain forms of anaemia (pernicious anaemia and leukaemia) is not known. VOL. i. — 2
1 8 GENERAL PATHOLOGY OF DISEASE.
ACUTE INFLAMMATION.
Numerous attempts to give a definition of acute inflammation have from time to time been made, but none of them have been altogether successful. Metchnikoff, studying inflammation chiefly in its relation to bacteria, builds up a theory upon phagocytosis as a foundation. He observes the reactions of the tissue of mammals, frogs, crustaceans, and amoebse in the presence of micro-organisms, and finds that phago- cytosis is the one phenomenon which is seen in all animals in the struggle, and therefrom argues that it is the primum movens of inflamma- tion. Such reasoning appears to be unsound mainly because the analogy is incomplete, and it is highly questionable whether it is possible, by going back to such simple animal forms as daphnia and amoeba, to analyse such an extremely complex process as inflammation, which, so far as it is known in its true form, occurs only in extremely complex animals. It would be as rational to study mental activity in man and the higher animals by examining an amoeba. A process occurring in an animal possessed of highly differentiated nervous and vascular systems, the tissues of which, moreover, are highly complex, cannot be compared with any process observed in an animal the structure of which is very simple, or is represented by a single cell. In defining inflammation, or in describing it, classes of animals homologous in structure, and known to react by what is recognised as inflammation, must be taken.
Adami gives as a definition of inflammation, " the local attempt at repair after an injury, actual or referred." This definition includes phenomena which no histologist would or could regard as inflammatory. The constant renewal of the cuticle would be inflammation. An injury — as, for instance, superficial epithelial lesions — may be repaired without what is generally recognised as inflammation, i.e. by regeneration and direct repair. Some low forms of animal life are capable of regenerating any part or parts of their body. Eegeneration is not the same as repair by inflammation, or indirect repair. There is no valid reason for extending the meaning of a term so as to make it answer the requirements of a definition. Inflammation is known by its phenomena and its appearances, and by the changes in the tissues, and unless all these are present there is no justification •for speaking of inflammation. A certain process or an attempt at repair in a low form of animal may in some or in many of its phenomena resemble inflammation, and still not be inflammation, which is a complex process and occurs in complex tissues, and whose criterion should be what is known to occur in such tissues, and nothing should be called inflammation that does not agree with observations on animals in which the recognised tissue reactions of inflammation may be met with.
Starting from this point, it will be found that acute inflammation is a reaction of mixed tissues, which occurs only in man and other vascular animals ; it is a uniform process, varying, no doubt, in its different types, but in degree only, not in kind ; there is a uniformity in the pathogenesis, progress, and morphological attributes of acute inflammatory conditions, which is so striking that nothing should be called inflammation, unless it presents all the essential phenomena which the study of disease in man and other vascular animals has revealed to us. To select phagocytosis, or chemiotaxis, or new formation and repair as essentials, and make them the corner-stones of theories of inflammation, is unjustifiable. Phagocytosis, chemiotaxis, and proliferation are concomitant, or it may be constant, phenomena of acute inflammation, and each one of them may be traced
ACUTE INFLAMMATION. 19
back from the highest to the lowest form of animal ; but surely it is not sound reasoning to evolve the whole process of inflammation from one or two of its phenomena, especially when such phenomena are very primitive protoplasmic properties. Evolution may teach how a property or a character has been acquired ; it may indicate something of the phylogenetic origin of an organ or a process ; but it nowhere teaches that a complex process in a higher animal type, which can be traced back to some property or function in a lower type, is identical with this property or function. In any appeal to evolution, the thread is often lost and many gaps cannot be filled. Inflammation, as it is known to the human pathologist, occurs only in certain higher animals in which there is a blood vascular system. This is the line of demarcation. A vascular animal reacts to a certain stimulus by inflammation, while the same stimulus in an avascular animal may produce some phenomenon which also occurs in inflammation, but of itself is not inflammation.
Analysing the process of inflammation, it is found that (1) without blood vessels there is no inflammation ; (2) it is a reaction of vascular connective tissue or of connective tissue, itself perhaps avascular, but in close relation with the vascular system. Inflammation of epithelium does not exist, and true inflammation in really avascular connective tissues, such as cartilage, has not been observed. Inflammation in avascular tissue is said to occur in the cornea, but here an anatomically avascular tissue is in close connection with the circulation by means of the vessels at its periphery and its numerous lymph channels. So slight a lesion of the cornea, in which there is nothing more than a limited destruction and proliferation of the corneal corpuscles, is not and does not end in inflam- mation ; there is simply direct repair ; any tissue that has life left after an injury or a loss of substance will at once repair itself or regenerate. As soon as the injury is severe enough to transmit its influence to the vessels around the cornea, all the changes of inflammation become evident. The cornea, therefore, is a connective tissue which is subject to inflammation if the stimulus be adequate ; if not, repair occurs without inflammation. An irritant may produce different effects according to its intensity and the method of application ; it may produce a slight injury, easily and directly repaired ; or a serious injury, followed by immediate death or slow necrosis, or followed by secondary inflammation ; or it may produce an acute primary inflammation. Now, because the same irritant is applied to a graduated series of tissue and animals, it is not justifiable to assert that the effect of its action is one and the same process in all cases. No doubt, if the different effects produced are compared, there is a gradual transition from one to the other, but so there is from an innocent to a malignant growth.
A smaller number of vibrations of the mysterious ether results in the subjective sensation of heat, while more rapid vibration of the same ether produces one of light ; yet heat is not light. The cornea experiments cannot be used as arguments against the view, originally supported by Cohnheim, that inflammation can occur only in vascular tissues, for as soon as changes which everyone would recognise as inflammation are set up in the vessels around the cornea, the tissue in which they lie has reacted, being, so to speak, drawn into the zone of irritation through the innumerable lymph channels. Inflammation, then, must be regarded as a series of changes, occurring only in vascular or vascularisable connective tissue, or in connective tissue in close connection with the surrounding blood vessels.
GENERAL PATHOLOGY OF DISEASE.
Causation. — It is only necessary to mention here that traumatic, chemical, or physical irritants, including foreign bodies and micro- organisms, are capable of reacting on the connective tissue in such a manner as to produce the phenomena and appearances of inflammation. These irritants must possess a certain relative intensity, otherwise inflam- mation may not set in ; or if the intensity is too great, necrosis may be the result. The intensity will, of course, vary with the general or local tissue resistance of the individual. In certain diseased conditions, inflammation is readily produced by conditions which are incapable of producing it in health.
Processes. — In acute inflammation, two main processes may be distinguished — (a) exudative, and (&) proliferative.
The exudative processes are, speaking generally, most evident during the earlier stages, and are concerned especially with the vessels. Fluid and cells may pass through the vessel wall, the fluid being coagulable lymph, which may or may not coagulate, the cells being leucocytes and red corpuscles. The proliferat- ive processes are observed in the connective tissue and endothelium, and in the vessels. The fixed and wandering connective tissue cells nmltiply, and so do the endothelial cells lying in the lymph spaces, and lining the capillary and lymphatic walls. These proliferative changes are best seen in the later stages of acute inflammation. It appears, therefore, that in the earlier stages, if many cells are present in the inflamed area, they are mainly leucocytes (leucocytic infiltration} ; while in the later stages the cells are mostly derived from the connective tissue or endothelium. The products of proliferation, if repair follows, become con- verted into fresh connective or fibrous tissue, but when this occurs inflammation is at an end. Speaking generally, it may be said that the more vascular a part is, the more evident are the exudative changes during the earlier stages ; and, conversely, the less Arascular a part is, the more marked are the proliferative changes during the earlier stages. In any process which is recognised as inflam- mation, both exudative and proliferative changes always occur.
Acute Inflammation (Connective Tissue Reaction).
EXUDATIVE PROCESSES.
PROLIFERATIVE PROCESSES.
Vessels.
Connective Tissue.
Vessels and Lymphatics.
Fluid (fibrin).
Cells—
(a) Leucocytes (leucocytic infiltration).
(6) Red corpuscles.
(a) Fixed cells.
(b) Wandering cells (small
round-cell infiltration).
Endothelium.
Repair — New connective or fibrous tissue and vessels.
If the process of acute inflammation in the frog's mesentery be carefully watched, it will be found that dilatation of the small arteries (inflammatory congestion) first makes its appearance, and reaches its height in a few hours. More blood flows into the part, and the veins not participating in the dilatation, the velocity of the blood flow is increased. Gradually, but more slowly, the veins and capillaries dilate, and arteries, capillaries, and veins become turgid, and there is a retardation of the blood flow, the leucocytes arranging themselves along the walls of the veins preparatory to their emigration. In the capillaries,
ACUTE INFLAMMATION, EXUDATIONS. 21
analogous changes are observed: in some the blood still travels onwards; in others there is merely a flow of plasma-like fluid ; while in many the current has ceased altogether (stasis), the capillary being filled with red corpuscles, or some- times with plugs of white corpuscles (white stasis). Emigration (an active process) of leucocytes follows, as in the veins; pseudopodia are sent out through the vessel wall, the whole leucocyte gradually following the extruded part. This is accompanied by a diapedesis of the red corpuscles, at times but slight, at other times very marked, but always present. Amongst and between the capillaries numbers of scattered or aggregated white and red corpuscles are to be seen at this stage. At the same time there is also a transudation of fluid (plasma), sometimes so considerable in amount that the part becomes oedematous (inflam- matory oadema).
Exactly similar phenomena are seen in the inflamed mesentery of warm- blooded animals, or in the irritated cornea, the vessels at the corneal margin becoming dilated, this being accompanied by a copious diapedesis and transuda- tion of fluid.
The following is a summary of these conditions : —
Dilatation of arterial vessels (inflammatory congestion and increased velocity).
Dilatation of capillaries and veins (retardation).
With retardation : marginal arrangement of leucocytes.
In the capillaries there may be complete stasis;
Followed by diapedesis of white and red corpuscles.
Transudation (inflammatory oedema).
Although the process of emigration must be regarded as an active one on the part of the white corpuscles, certain co-operating factors must not be lost sight of — (1) Changes in blood current : the quickened stream by centrifugal action drives the corpuscles, which normally travel centrally, against the vessel wall, where they are inclined to adhere on account of their stickiness during the retardation stage. When there is stasis, the marginal distribution of the leucocytes is entirely absent. (2) Increased capillary and venous pressure must to some extent assist diapedesis, especially when (3) the permeability of the delicate vessel wall is increased. That the vessel wall becomes more porous can hardly be questioned. (4) Lastly, the vessel wall must be in a suitable condition to allow the leucocytes to adhere. Before emigration can occur, it appears, therefore, that certain conditions must exist — (a) changes in the blood current, to allow of a marginal distribution of the leucocytes ; (b) a suitable state of the vessel wall, without which adhesion cannot take place; (c) amoeboid activity of the white corpuscles. Substances which paralyse the amoeboid movements of the white corpuscles completely stop diapedesis.
Amoeboid leucocytes outside the animal body, whenever they come in contact with the surface of a foreign body, attach themselves and become flattened out : and if the foreign body be porous, having attached them- selves, they send out pseudopodia into the pores. It is important to remember that this tactile sensibility of the amoeboid leucocyte is a natural property. When the corpuscle comes in contact with the vessel wall, it becomes flattened out, attaches itself, sends a pseudopodium through any pore there may be in the vessel wall, and then creeps into the surrounding connective tissue. If the irritant which causes the inflam- mation is such that it does not paralyse the protoplasm of the leucocyte, nor prevent the vessel wall from responding to its tactile sensibility of adhesiveness, emigration must take place.
2 2 GENERA L PA THOL O GY OF DISEASE.
The leucocytes, having passed out of the vessel, begin to wander — migration to the seat of irritation. This is also mainly a pseudopodial act, although it is no doubt favoured by concomitant conditions, such as the exudation currents and the diminished resistance of the tissues. This migration to the seat of irritation is due chiefly to an attraction of the leucocytes by the chemical products of bacterial activity or tissue destruction, i.e. chemiotaxis. Certain substances, amongst which are albuminous bodies contained in the bacteria (proteins), and the earlier products of decomposition or necrosis, attract leucocytes. That chemio- taxis, or rather the chemiotactic irritability of the leucocytes, is an important factor in the migration, cannot be questioned ; but it does not explain altogether why the cells collect in the inflamed area. In pneumonia, for instance, where a whole consolidated lobe may show all the alveoli full of leucocytes, it is difficult to explain such extensive aggregation on the principle of chemiotaxis. A local and circumscribed attraction may be so brought about, but matters are different when a whole organ is invaded. Moreover, if the aggregation of leucocytes in the inflamed lung were due to chemiotaxis, the blood in the peripheral circulation should be impoverished in white corpuscles. The contrary, however, is the case, for in most cases of pneumonia which run a favour- able course there is an extraordinary leucocytosis.
The various forms of leucocytes do not show an equal tendency towards diapedesis or migration. In circulating blood, the following general types of white corpuscles occur, viz. — (1) The lymphocytes; (2) the multinuclear ; (3) the large uninuclear ; and (4) the coarsely granular eosinophile cells. The small lymphocytes consist of scanty protoplasm, covering a round nucleus, and are indistinguishable from the small cells of lymphoid tissue. They may form up to 30 per cent, of the leucocytes present in human blood. The large uninuclear cells have a round or kidney-shaped nucleus and abundant protoplasm, and are rare in the blood (2 per cent.). The multinuclear or polymorphonuclear cells have a lobed or multipartite nucleus, and their protoplasm is beset with small granules, staining red with eosin. They are abundant in the blood (up to 70 per cent.), and are actively amoeboid and phagocytic. The coarsely granular cell shows large and numerous granules, staining deeply with eosin ; they are rare in human blood (up to 5 per cent.), are amoeboid, but not phagocytic. During the earlier stages of inflammation, when chemiotaxis is said to be most active, the multinuclear (neutrophile) cells leave the vessels in greatest number and migrate to the irritated area, forming the bulk of the pus corpuscles. Sometimes the coarsely granular eosinophile cells also appear in large numbers. This " selective attraction " proves that we must not take the process of chemiotaxis too literally. The cells which migrate to the inflammatory focus are the most plastic and amoeboid among the leucocytes, and this demonstrates the close relation which must exist between so-called chemiotaxis, tactile sensibility, and motility. These leucocytes, coming up, draw a cordon around the inflammatory zone, and prevent absorption of the toxic material. Moreover, the cells being phagocytic, they not only destroy the irritant, but assist in clearing away the tissue debris, so preparing the ground for the proliferating connective tissue. At times, however, they have to collect in such enormous numbers that suppuration appears.
A fluid transudation, differing but little in composition from ordinary plasma, also leaves the vessels. There is a normal process of lymph trans- udation, exaggerated as the result of inflammation, varying with the laxity of the tissues, the nature of the irritant and the animal, and inversely as the resistance of the tissues. There is thus a flushing out of the part
SER O US EFFUSION IN I NFL AM MA TION. 2 3
and a removal, or at any rate a dilution of the poisonous irritant. This may bring about an increase of the chemiotactic process, for it has been shown by experiments that strong solutions of certain substances may paralyse the tactile sensibility and the motility of the amoeboid leucocytes, while when diluted the same solution may produce an attraction for these corpuscles. This fluid may supply the proliferating tissues with nourish- ment ; on the other hand, however, it may prove harmful by impairing nutrition, by the tissues becoming water-logged, by pressure on vital organs, and even on the cells of tissues.
Transudation appears to be due to three chief factors, namely, (1) the increased permeability of the capillary wall ; (2) an increased lymph secretion ; and (3) a diminished lymph absorption. Some observers deny that there is a true lymph secretion, but regard the process as a mechanical one, i.e. a filtration under pressure, and, according to them, instead of increased lymph secretion, increased nitration must be due to raised intracapillary pressure.
The inflammatory exudation consists of plasma or a plasmatic fluid, various enzymes and toxins derived from bacteria, and certain germicidal substances, tissue cells, mucin, leucocytes, fibrin and its precursors, albumoses, and peptones. The exudation may or may not coagulate, according to the presence or absence of the fibrin-forming substance.
Fibrinous inflammation.— Under physiological conditions, plasma will coagulate outside the body, on the addition of fibrin ferment or leucocytes ; it may be argued, therefore, that in inflammation, wherever leucocytes are present, fibrin is formed. The absence of coagulation in the case of serous effusion requires explanation. It appears to be due largely to certain inhibitory influences, amongst which may be mentioned — (a) integrity of the endothelial or epithelial surface ; (b) absence of fibrin ferment and leucocytes ; (c) increased alkalinity ; and (d) the presence of certain toxic or chemical substances which, in small quantities, are capable of preventing coagulation. Thus, extremely minute quantities of cobra poison will prevent coagulation, and certain bacterial substances or tissue products appear to be possessed of similar powers.
Fibrin generally appears on free surfaces or in enclosed spaces (tonsils, pleura, and pericardium), especially when there is continued rubbing of the surfaces of organs (heart and lungs), or as the result of the action of chemical substances, as in diphtheria and pneumonia. It may be formed either immediately or after some delay, the exudation at first serous, later becoming fibrinous; it may form a true membrane lying on the free surface, as in fibrinous pericarditis, or it may form an inter- stitial deposit, as in diphtheria, where the fibrin appears between and among the epithelial cells, which undergo a so-called coagulation necrosis.
Serous inflammation. — If the exuded plasma does not coagulate, the inflammation is said to be serous. The fluid poured out, which varies considerably in amount, generally speaking exudes most copiously from a free surface, which may be lined by epithelium, columnar in the nose, larynx, intestine, or uterus, or squamous on the conjunctiva and vagina. A serous inflammation on such free epithelial surfaces is called a catarrh ; the exudation then contains much mucus. The effusion may exude from an endothelial surface, such as the pleura or peritoneum. It is possible that coagulation does not occur, because the epithelium or endo- thelium is intact, or because there are other inhibitory influences which prevent coagulation.
2 4 GENERAL PA THOL O GY OF DISEA SE.
Instead of escaping to a free surface, the exudation may collect in the tissue substance, e.g. as in interstitial serous infiltration, in the connective tissue (inflammatory cedema), or between layers of epithelium (vesiculation). An inflammatory cedema is often observed; extensive fibrin formation, as in croupous pneumonia, where, on cutting into the consolidated lung, fluid generally exudes copiously ; again, the serous effusion may subsequently coagulate either completely or in part, producing a so-called sero-fibrinous inflammation. In cellulitis and acute septic inflammations, the cedematous infiltration is, as a rule, well marked ; indeed, speaking generally, the weaker the local or general resist- ance of the individual, the more marked is the inflammatory oedema. The fluid which is poured out may be completely absorbed, or it may stagnate, then leading to a chronic or persistent effusion, or to necrosis and gangrene from the impair- ment of the nutrition of the tissues, which become softened and waterlogged.
Fluid Constituent of Inflammatory Exudation.
Coagulation = fibrinous inflammation.
(a) Interstitial = diphtheria.
(6) Free endothelial surfaces = fibrin- ous pleurisy.
(c) Free epithelial surfaces = mem- branous tonsillitis, croupous pneumonia.
( Destruction and removal = Result -j resolution.
( Organisation = induration.
fsero-
Alsence of Coagulation I fibrinous. = serous inflammation = I sero-
\ purulent.
(a) Interstitial = inflammatory cedema,
vesicles.
(b) Free endothelial surfaces = serous
effusion.
(c) Free epithelial surfaces = catarrh.
Result
Discharge = catarrh (restitu- tion).
Absorption = resolution.
Stagnation = chronic effusion.
Coagulation = fibrinous or sero- fibrinous inflammation (q.v.).
Purulent inflammation. — When emigration and aggregation of leucocytes are excessive, and there is no coagulation, the exudation becomes converted into pus. Microscopically, the so-called laudable pus of the older writers is a thick, viscid, light yellow, or yellowish fluid, with a faintly sweetish, sickly odour; on standing, it separates into two portions, a serous element, the liquor puris, and a whitish sediment, the pus corpuscles. Although pus consists of inflammatory plasma and leucocytes, it does not coagulate, so that there must have been influences or substances at work which, during the process of pus formation, inhibited coagulation. Micro- scopically, the most important constituents of pus are the pus corpuscles, which are mostly of leucocytic origin. In fibrinous inflammation, e.g. in pneumonia, where the number of white corpuscles present may be as great as in pus, the process cannot be compared to a suppuration, as has been done by some observers. The leucocytes, which constitute the pus corpuscles, are mostly actively amoeboid, and are usually of the so- called polymorpho-nuclear or neutrophile variety ; sometimes, however, the number of coarsely granular eosinophile cells present is striking. Young connective tissue cells are also often found amongst the pus corpuscles; many of the cells are degenerated or dead, but many are still amoeboid, well preserved, and phagocytic, as may be seen on placing fresh pus on the warm stage of a microscope.
FORMATION OF PUS. 25
Pathogenesis of suppuration. — In most cases micro-organisms are present, and it must be concluded that pus is usually of bacterial origin. It is possible, however, by means of nitrate of silver, turpentine, castor-oil, perchloride of mercury, and other chemical substances, to produce a suppuration without micro-organisms appearing (sterile suppuration). Similarly, continued irritation, e.g. the presence of metal in the anterior chamber of the eye and the products of necrosis, may call forth a suppurat- ive process. Chemical irritation, therefore, may be a cause of suppura- tion. Buchner has shown that castor-oil causes a necrosis of the tissues, and that the products of this necrosis have a positive chemiotactic action, i.e. they attract leucocytes, and that suppuration is thus set up.
Most cases, however, are of bacterial origin, a fact which the surgeon especially should remember ; and certain micrococci are so constantly found in pus, that they are regarded as pus-producing or pyogenetic organisms. The commonest forms are the following: — (1) Staphylococci : (a) Slaphylo- coccus pyogenes aureus ; (&) Staphylococcus pyogenes albus ; (c) Staphylococcus pyogenes citreus. (2) Streptococci : (a) Streptococcus pyogenes ; (b) Strepto- coccus erysipelatis ; (c) Pneumococcus. Each variety may occur alone, but mixed purulent infections are frequently met with. Other microbes may produce a suppuration, e.g. the bacillus of typhoid fever, the gonococcus and the bacillus of tuberculosis ; but they are so markedly specific in their action, that they are not included among the pyogenetic organisms. How do these germs produce suppuration ? Buchner has clearly shown that they act by chemical irritation, for the dead bodies or the protoplasmic sub- stances (proteins) of the bacteria produce suppuration as effectively as, or even better than, the living organisms. The chemical irritant is extremely chemiotactic, and stimulates the leucocytes to emigrate and to wander to the seat of lesion. There appear to be two necessary conditions, without which there can be no pus — (1) chemiotaxis and aggregation of leucocytes, and (2) inhibition of coagulation. A third factor is histolysis or tissue destruction. Under the influence of pus formation, the tissues are dis- solved and disintegrated, and, according to the law of repair, they react against this dissolution by proliferation and an attempt to form new cells. This may be observed at the margins of any suppurating focus, and it is for this reason that connective tissue cells are so frequently found in pus.
The fluid constituent of pus is serum devoid of fibrinogen, but contain- ing albumoses and peptones, toxines of bacterial origin, and various products of degeneration. The albumoses and peptones are in part due to the digestive or proteolytic action of the micro-organisms concerned, and partly to a similar action on the part of the pus corpuscles themselves; indeed, it is probable that the histolysis depends on this proteolytic property of pus. Pus forms a bad soil for the growth of bacteria ; it has, indeed, a distinctly germicidal action, and long pent up in the body becomes sterile, the pyo- cocci being gradually destroyed. The chief physiological properties of pus, therefore, are the following: — It is (1) bactericidal, (2) histolytic, (3) con- tains phagocytic elements, and (4) is a strong solvent, for Leber has shown that it is capable of dissolving such metals as platinum and copper, which require strong acids for their solution. There can be no doubt that sup- puration must frequently be a useful issue of the inflammatory process, assisting in the destruction of the irritant, and stimulating the tissues to react by proliferation. It is often, however, a source of danger, leading to the destruction of the tissues, laying open the vessels, and thus offering openings for serious complications, such as septicaemia and pyaemia.
26 GENERAL PATHOLOGY OF DISEASE.
It would be erroneous to suppose that pyogenetic microbes have an absolutely specific action, and are capable of producing suppuration only. Suppuration is merely the outward expression of certain inflammatory processes, and it is not even the most serious phase or variety of inflammation. As a matter of fact, it is found that the same species of organisms may produce a slight local inflammation or an extensive spreading inflammation, a small local suppuration or a large acute abscess, an erysipelas or a cellulitis, a pneumonia, a septicaemia, an infective endocarditis, or a pyaemia. Thus a small acne pustule may contain one or more varieties of pyococci. It may grow into a boil, the latter into a carbuncle, which, again, may be followed by septicaemia or pyaemia. The pneumococcus may be found in pneumonia, in suppurative otitis media, in angina Ludovici, in infective endocarditis, peritonitis, and pleurisy. Almost all vegetable micro-organisms possess the faculty of producing an inflammation, and those which are most fre- quently found in primary inflammatory processes are called pyogenetic, but whether they produce a benign form of inflammation, or a suppuration, an osdematous or a necrotic inflammatory lesion, will depend chiefly on the virulence of the bacteria, and the local conditions, the local or general resistance, on the quantity of bacteria introduced, and on the continuance of the supply of micro-organisms, i.e. whether there is a single or a continued invasion of micro-organisms. Under favourable conditions, i.e. if the virulence of the bacteria be reduced, or the resistance exalted, an innocent local inflammation may ensue ; as the virulence increases, or as the resistance decreases, suppuration makes its appearance; and if the virulence is excessive, and the resistance slight, an oedematous, necrotic, or gangrenous inflammation is produced. Septicaemia appears when the organisms enter the cir- culation and multiply in the blood. It is of the utmost importance to realise that suppuration is not a specific process : it is a clinical term for changes which can be recognised by the unaided eye.
The character of the pus varies considerably. (1) Thus it may be thick, creamy, light yellowish, or greenish in colour, possessing a characteristic faint odour (laudable pus, which is oftenest associated with staphylococci). (2) It may be serous and thin, when the streptococcus is also not uncommon. (3) Its colour may be blue or green, due to the presence of the B. pyocyaneus. (4) In typhoid suppuration the pus is generally thick and reddish in colour, (5) while gangrenous pus is usually associated with a mixture of organisms (mixed infection). It must not be imagined, however, that it is possible to recognise the bacterial infection from the appearance or character of the pus, which can only be gauged by means of the cultivation tube, all the more since usually two or more species of pyogenetic organisms occur together.
A suppurative process may be either primary or secondary, i.e. it may be the only lesion present, or it may appear in the course of or after the defervescence of an infective fever. Thus an abscess may be due to some injury followed by infection (primary suppuration); another may occur during or after an attack of enteric fever (secondary suppuration). In the latter case the suppuration may be due to the organisms which caused the fever, B. typhosus (homologous infection), or it may be due to an altogether different organism, a streptococcus or a staphylococcus (heterologous in- fection).
Anatomically, suppuration may be superficial, or interstitial; that is, pus may either be discharged from a free surface or it may collect in the deep tissues. When the process is superficial, it may appear (a) as a result of inflammation of a mucous membrane, — pyorrhoea, or (6) of a serous membrane, — empyema. Pyorrhoea may or may not be accompanied by superficial ulceration. The term emp-yema is now generally applied to
SUPPURATION— HSEMORRHAGIC EXUDATION. 27
suppuration of the pleura. In interstitial suppuration the pus may remain (1) localised, forming an abscess which may or may not be sur- rounded by a capsule, or (2) it may infiltrate the connective tissues. The purulent infiltration, by destroying the tissues bathed by the pus, may become converted into an abscess. If the pus infiltrates the epidermis, the result is a pustule, which in reality is an epidermal abscess.
Suppuration.
(a) Mucous membrane = pyorrhoea
± ulceration. (&) Serous membrane = empyema.
1. Superficial —
abscess ± capsule.
(a) Localised : Epidermis = pus-
tule.
(b) Infiltrating : may become an
abscess.
The pus which has been formed (if small in amount) may be reabsorbed on cessation of the irritation of inflammation. This is effected in part by phagocytosis, in part by the proliferation of the endothelial and connective tissue cells. Proliferative changes there always must be, because during sup- . puration there is always histolysis, and the destroyed tissue must be replaced by fibrous tissue (indirect repair). The pus may remain behind, and result in the formation of a chronic abscess, which may have a distinct fibrous capsule, and on cessation or abatement of the inflammation the capsule becomes smooth, and forms the so-called pyogenic membrane of older writers. In most chronic abscesses inflammation and suppuration con- tinue, micro-organisms flourish in the pus, and they, with their poisons, act as irritants. In some, however, all inflammation ceases, the micro-organ- isms perish, symptoms due to pent-up pus often being entirely absent (cold abscess). On the other hand, the unabsorbed pus may become curdy and inspissated, caseous, or even calcareous or cretaceous, as the result of a deposition of calcium salts ; calcification is always preceded by inspissation or caseation.
Ptis,
Reabsorption. Retention.
Liquid — Inspissated —
(a) Chronic abscess, (a) Curdy.
(b) Cold abscess. (b) Caseous.
(c) Calcareous.
Hsemorrhagic exudation.— Under certain conditions the diapedesis of red corpuscles may be excessive, the exudation becoming haemor- rhagic. In such cases leucocytes are generally scarce; there is a blood- stained serous exudation, but occasionally the red corpuscles are mixed with the leucocytes and round cells, which have been collected in large numbers at the inflammatory centre — blood-stained purulent exudation.
The excessive diapedesis of the red corpuscles is due mainly to the activity of the irritant, or to lowering of the resisting powers of the tissues. Virulent infec- tions, such as smallpox, malignant pustules, and acute necrosis, are frequently accompanied by haBmorrhagic exudation ; whilst in a debilitated subject, suffering from renal disease, inflammations readily become hsemorrhagic. In gangrene,
28
GENERAL PATHOLOGY OF DISEASE,
where the toxines are powerful and absorbed in large quantities, the vessels are injured, and haemorrhages, due to direct rupture, or indirectly to diapedesis, are common. Again, in the early stages of acute inflammation, heemorrhagic exuda- tions are common ; in the first stages of acute nephritis the urine is often red from admixture of blood (nephritis haemorrhagica). A mechanical injury may cause vascular lesions, gross or minute, by which the blood finds an outlet and mixes with the inflammatory exudation ; this, however, is a true haemorrhage, and is very different from hgemorrhagic inflammation, where the blood transudes by a process of diapedesis ; the former is a haemorrhage per rhexin, the litter a haemorrhage per diapedesin. Again, inflammation may occur in a part the venous circulation of which is laboured and obstructed, i.e. in an engorged area. Here there is considerable slowing of the blood stream, marked fulness of the venous channels, and grave disturbance of nutrition.
Hcemorrhagic Inflammation.
(1) Direct hcemorrhage
(per rhexin)
= lesion of vessel wall, gross or minute.
(2) Indirect haemorrhage (per diapedesin)
(a) Intense irritation.
(b) Early stages of acute in-
flammation.
(c) Venous engorgement.
(d) Loss of local or general
tissue resistance.
The proliferative changes of acute inflammation are best seen when the exudative changes are clearing away, but it is erroneous to imagine that in point of time they follow the exudative phenomena. They may be observed at the margins of the affected area, even at the earliest stage of inflammation, but they become more evident with the disappearance of the leucocytes ; the veil is lifted, and a clear view is obtained, and they persist, passing on imperceptibly to play a part in the stages of repair. Eepair is not necessarily a termination of inflammation, but proliferative changes are always present. An injured tissue which has any life left, is always ready to react by repair ; if there is loss of substance, the living cells multiply and proliferate; if there is no loss of substance and no necrosis, but merely damage to the cell, the cell itself may recover. There are, therefore, two processes by which an injury is made good — (a) recovery, (b) repair by proliferation. The latter may or may not be accompanied or preceded by inflammation. Thus an injury to a tissue may not be sufficient to cause proliferation of the connective tissue ; repair is then direct, the cells pro- liferating and producing homologous tissue ; if, however, it be sufficient to rouse the connective tissue to inflammatory reaction, repair is indirect: matter has to be cleared away, the resulting gap has to be filled up, and this can only be done by fibrous tissue, i.e. by heterologous tissue. It is the nature of things that reparative changes should appear in inflammation, the remain- ing living tissue tends to repair an injury ; that is a postulate of pathology. The least injured cells recover, the more injured ones die, but their places •are supplied by a new progeny. Since in inflammation there is always some necrosis, therefore some proliferation, proliferative changes are necessarily present in inflammation. These changes are observed — (1) in the connective tissue cells, (2) in the endothelial cells of the lymph spaces and capillaries. The connective tissue cells enlarge ; their nuclei become swollen, round, or oval, and karyokinesis (mitosis) is active; this is certain evidence of
REPAIR B Y PRO LIFER A TION. 29
proliferation. The leucocytic infiltration may be so considerable as to hide the proliferative phenomena altogether, but as soon as the leucocytic infiltration clears up, which it always does as the inflammation subsides, what has taken place may be clearly seen. There are many large protoplasmic cells, rich in cell substance, and with nuclei which stain but faintly, or are rich in chromatin and resemble epithelial cells, and are there- fore usually spoken of as epithelioid cells. Others are more fusiform in shape, with long darkly staining nuclei ; these gradually become spindle-shaped. It is generally believed that the spindle cells are merely a later stage of the epithelioid cells, i.e. that both are derived from the connective tissue cells, although some observers maintain that the spindle cells are derived from the fixed connective tissue cells, and the epithelioid cells from the endotheliiim. At this period, when the leucocytic infiltration has disappeared and the cells begin to proliferate, numbers of small uninuclear round cells appear, which possess a large round nucleus and resemble lymph corpuscles (lymphocytes). These small cells are collected in irregular groups or in distinct masses, which may be compared to adenoid or lymphoid collections, and they constitute the small round-cell infiltration (lymphocytic infiltration). These small cells appear to be derived from rapidly proliferating connective tissue cells, from the endothelium of the lymphatic spaces, and from the lymphocytes which are always present in the connective tissue ; but many of them may have been attracted by so-called " chemiotactic " influences. The free connective tissue cells, the lymphocytes, and the endothelium of the lymph spaces are all migrating, and may therefore be attracted to the seat of irritation.
The normal connective tissue possesses (a) fixed cells and (b) wandering cells ; but while only the latter are free and under the spell of chemiotaxis normally during inflammation, the fixed cells, as they divide and proliferate, may become free and wandering. Migrating to the seat of inflammation, they are at first mixed up with the emigrated leucocytes in the exudation, and assist the latter in clearing away the irritant, foreign and dead matter, haemorrhages and fibrin ; they also take up the remains of dead leucocytes, which have done their share of the work, and thus complete the cleansing process. When everything is cleared away, they either fall into their proper places, or they undergo further changes and form vascular cicatricial tissue. A croupous pneumonia, for instance, may clear up, the leucocytes disappearing, being in part discharged with the expectora- tion, in part taken up by the connective tissue cells and the endothelium ; these cells may then simply resume the places they ought to occupy, so that the result is a complete resolution without secondary thickening, or they may form vascular connective tissue, which gradually becomes fibrous and leads to a chronic indura- tion of the lung. Resolution then corresponds to homologous repair, induration to heterologous repair (cicatrisation). When cicatrisation occurs, the proliferated cells become spindle-shaped, arrange themselves in strands along the vessels, more and more interstitial substance appears between the cells, which have become still more fusiform, and are now called fibroblasts. The latter become gradually less protoplasmic, while the interstitial substance increases, and gradually typical fibrous tissue is formed, which in time becomes harder and less vascular.
It is during the earlier stages of repair that phagocytosis is best seen. The connective tissue cells take up the dead tissues, leucocytes, foreign bodies, etc., following the example set them by the leucocytes. If the material to be removed is copious or firm, giant cells — multinucleated cells with numerous nuclei, and often provided with branched processes — appear. They are both phagocytic and histolytic, devouring and dissolving the substances with which they come in contact.
During the process of heterologous repair new vessels appear. These are
30 GENERAL PATHOLOGY OF DISEASE.
formed from the original vessels, which throw out endothelial buds into the inflammatory area occupied by the proliferated cells, i.e. by the small round cells forming the lymphocytic infiltration. At a given point the endothelial cells divide and multiply, until a solid endothelial protrusion is formed. This becomes hollowed out, the blood extending into it from the old vessel. These newly formed A^essels are surrounded by numerous small round cells, amongst which are spindle cells, epithelioid cells, and large protoplasmic cells, and, under the above-mentioned conditions, giant cells. Such vascularised proliferating cellular tissue constitutes the so-called granulation tissue of the surgeon, which gradually becomes converted into cicatricial tissue. As the cicatricial tissue becomes more fibrous, the vessels gradually disappear, and a hard, dense, white or glistening fibrous tissue remains.
It should be remembered that as soon as resolution or repair sets in, inflammation is at an end, and further that cicatrisation may take place without the occurrence of preceding inflammation.
Abscess and ulceration. — Of the clinical results of inflammation, abscesses and ulcers require special mention. Abscess is a local collec- tion of retained or pent-up pus, buried in the depth of the tissues. If the early leucocytic infiltration is excessive, the inflammatory exudation assumes the characters of pus, being whitish in colour, when enough pus is formed to be detected with the unaided eye. The newly formed pus, acting destructively on the surrounding tissue, assists the original irritant. The inflammation thus progresses, more leucocytes are attracted, and the proliferating tissue and endothelial cells are compelled to withdraw, being destroyed by the spreading suppuration. A growing collection of pus is thus pent up in the tissues, and an acute abscess is the result.
Should the process last for some time, or the irritant be abated, the proliferating cells may gain the upper hand, and the granulation tissue, which may eventually become changed into fibrous tissue, is formed : the collection of pus is thus enclosed by a fibrous membrane, — a pyogenetic membrane. There may be all gradations of structure in this wall from a fibrous membrane to soft granulation tissue. In the latter case the granulations continue to discharge pus, and the abscess grows ; where a typical fibrous membrane is present, pus formation has ceased.
An ulcer, when acute, is merely an inflamed and suppurating surface of the skin or mucous membrane, accompanied by, or resulting from, necrosis. Necrosis, whether caused by inflammation or by any other cause, implies loss of substance, a loss that has to be made good. Inflammation follows upon necrosis, if it did not exist before, and as recovery takes place gradually, the proliferative changes become more and more apparent, the necrotic tissue being dissolved and absorbed, and granulation tissue developed. So long as the slough and the irritant cause remain, the granulation will discharge pus, but gradually, as the slough is cast off, the discharge of pus ceases, the granulations become fibrous tissue, and the cutaneous or mucous surface is restored. An ulcer may therefore be compared to an open abscess ; both when of some standing being lined by granulations, and when acute being marked off by typical inflammatory tissue. The necrosed tissue may show itself either as a coherent piece of dead tissue, a slough, or as a friable structureless mass.
Septicaemia and pyaemia.— Of the complications of inflammation the most interesting, if not the most important perhaps, are septicaemia and secondary infections. The commonest causes of inflammation, as already seen, are micro-organisms, and the complications here considered are
SEPTICAEMIA AND PYAEMIA. 31
closely bound up with the fate of these micro-organisms in the tissues. Whether one of the pyococci, or a specific bacillus such as the bacillus of typhoid fever, diphtheria, or tuberculosis, caused the initial inflammatory lesion, their future is governed by the most diverse circumstances.
1. They may remain localised at the seat of infection, where they produce simple inflammation, or its various modifications. Here they may soon perish, the phenomena of inflammation coming to an end, or they may be pent up or retained, together with some of the inflammatory products, and acting as a continual irritant, a chronic suppuration results. This leads to chronic abscess and chronic ulcera- tion. The micro-organisms continually irritate the imperfectly formed, immature, and delicate, vascular, connective tissue, and the inflam- matory exudation, generally in the form of pus, persists. The micro-organisms, growing quietly and undisturbed, produce their poisons or toxines, which being absorbed lead to chronic intoxication (toxcemia), the effect of which may show itself as fever of a remittent, intermittent, or hectic type. Thus, where there are abscesses hidden in the tissues, as for instance in the lung or liver, the thermometer often reveals the existence of a suppurative fever ; the same type of fever occurs with typhoid ulcers and with tuberculous lesions.
2. On the other hand, the organisms may not remain localised, but may be carried away from the primary seat of lesion. The paths by which they travel may be (a) either the lymphatics, (&) or the blood vessels. The pathogenetic organisms being mostly parasitic, i.e. capable of thriving in or on living tissues, may travel along the lymph channels into the surrounding tissues, and form fresh foci of inflammation or suppuration at some distance from the primary area (secondary infections). Thus, in croupous pneumonia, the pneumococcus may be carried into the pleura, the pericardium, or the peritoneum, by the lymph channels, and there produce inflammatory changes. Again, the lymphatics may transfer them to the nearest lymphatic glands, which in turn become inflamed or form fresh foci of infection. Thus, in typhoid fever, bacilli are carried to the mesenteric glands, or, again, streptococci, with or without diphtheria bacilli, find their way into the cervical or bronchial glands during an attack of diphtheria, or suppurating glands may appear in the groin as a sequela to an ulcer in the foot. In such cases the symptoms may be those of a serious and severe intoxication, the foci whence poison may be absorbed being or becoming numerous and extensive. An infected lymphatic gland may become the source of a general infection, if a communication is established between it and the blood circulation through the thoracic duct. Thus Weigert has demonstrated that in acute miliary tuberculosis the thoracic duct is frequently tuberculous, and by this path the tubercle bacilli reach the systemic circulation. They may then be carried away as bacterial emboli into distant parts, or they may multiply in the circulation, producing a haemic infection. It is a curious fact that most morbid anatomists are satisfied in cases of acute miliary tuberculosis when they are able to demonstrate a caseous focus somewhere in the body, but they do not attempt to find the actual point of entrance into the systemic circulation.
The diffusion of the organisms which are responsible for the primary infection may, however, be brought about by the blood vessels. Here two methods of dissemination must be distinguished.
32 GENERAL PATHOLOGY OF DISEASE.
(1) The venous channels being eroded or laid open during and by the process of histolysis, a few microbes may find an entrance into the blood stream, and then one of several things may happen.
(a) The blood may possess sufficiently strong bactericidal power to cope with and destroy the few organisms which have found their way into the vessel. This is the most fortunate termination of what might be a serious accident, for no evil will come of this haemic invasion ; (b) the micro-organisms may escape the deadly action of the blood, and, without multiply ing in the circulation, they may be carried away as emboli through the heart into the systemic, pulmonary, or portal circulation, till arrested at some narrow point. Here, if suitable conditions exist, they will gain a footing and form a fresh focus of inflammation or infection, i.e. a metastatic or secondary focus, due to the arrest of a bacterial embolus, is formed. If conditions at the point of arrest are not suitable, the micro-organisms may perish, but they may remain latent, and survive, inoffensive and harmless, until such conditions arise as will awaken them into dangerous activity. Thus, in typhoid fever, organisms are almost constantly found after death in the bone marrow ; there they have been carried from the seat of ulceration to the blood and through the heart. Here they enjoy an existence of inactivity, till perhaps an injury to the bone or a general tissue depression resuscitates them into aggressive virulence, (c) The micro-organisms may find the blood so impoverished that its bactericidal power has vanished, and they may then multiply in the circulation, and produce a general haemic infection, — a septicaemia. In septicaemia, micro-organisms are found in the circulation, where they multiply and thrive, and produce their poisons. Nothing should or must be called septicaemia, itnless there be general haemic infection (demonstrated by cultivation), whatever may be the clinical prejudice. Any inflammatory infection may end in this untoward manner, e.g. pneumonia, typhoid fever, sore throats, acute necrosis, erysipelas, cellulitis. When symptoms point to serious complications, a thorough examination of the blood for haemic infection renders it possible to pronounce upon a most serious prognosis, and, in these days of serum therapeutics, to adopt appropriate treatment.
A general haemic infection may, however, start in a roundabout way. A bacterial embolus may enter a venous channel, and may find its resting place on one of the cardiac valves, where, should the organisms find the conditions necessary for their growth, an infective endocarditis must result. From the infected valve micro-organisms may be poured into the circulation, till the haemic infection is complete. Again, a metastatic focus, produced in the following manner, may become the starting-point of a haemic infection, or an infective endocarditis which generally implies hsemic infection.
Infected fibrinous or tissue emboli may take the place of simple bacterial emboli. The veins at the seat of inflammation become plugged with fibrin, the thrombus is invaded by micro-organisms, and thus become infected. From this infected and contaminated mass, fragments may be carried off by the blood current to the right side of the heart, where they may become attached to the tricuspid valve and form the starting-point of an infective endocarditis. If not arrested there, the embolus is carried into the lung, and may become lodged in some arterial branch, producing an infected infarct. The embolus may, however, be carried right through the lung into the left ventricle, and thence may enter the aorta and the systemic circulation, or it may become fixed on the mitral valve. It is natural that, when an infective endocarditis appears, micro-organisms will readily find their way into the general circulation, and from the diseased valve bacterial or infected fibrinous emboli may enter the circulation and produce fresh metastatic foci or
SEPTIC INFECTION AND INTOXICATION.
33
general htemic infection. It stands to reason that the presence of metastatic abscesses, clinically called pyaemia, does not of necessity imply that micro-organisms are found in the blood, that is, that there is septicaemia. (2) The micro-organisms may be carried away from the seat of lesion by the arterial channels. A small artery, for instance, although the elastic coat is very resistant against infection of any kind, may be attacked and pierced by the micro-organisms, which are then carried away as bacterial emboli towards and into the capillary area.
In septicaemia an inflamed area becomes invaded by saprophytic and putrefactive organisms. These latter thrive on dead or dying tissues, but cannot grow on healthy or living tissues ; saprsemia, therefore, commonly accompanies gangrenous or ulcerated lesions ; and in childbed, with which there is much necrosis, the microbes produce their toxines, which are absorbed, and serious symptoms of saprsemia may result. When the necrotic area is removed, the bacteria, which cannot grow in living tissues, disappear; the symptoms of sapra3mia subside, and the patient usually makes a speedy recovery. Septicaemia, or hsemic infection, can obviously never be produced by true saprophytes. In the following table are tabulated the various paths of dissemination : —
Infection of an ulcerating or. necrotic area by saprophyticj organisms, accompanied by general intoxication, with their products
Infection of an inflammatory area by parasitic organisms, accompanied by general in- toxication, with their pro- ducts.
Recovery after radical removal,
Saprcemia. so long as the amount of
toxines absorbed are sublethal.
Lymphatic infection, direct re- tention (cellulitis) ; glands (buboes), septicaemia ; thora- cic duct, multiple emboli. Haemic infection = septicaemia. Metastatic in- I fection (py-
Bacterial emboli \ aemia) ; hae- mic infec- tion.
T £ LI £i> • ( Metastatic in- Infected fibrin- , , . /
, T -I fection (py- ous emboli I
Septic Infection
and Intoxication.
To give a few examples. In suppurative otitis media, the pyococcal infection may remain localised or may spread to the brain, leading to a temporo-sphenoidal or cerebellar abscess, or it may spread into the lateral sinus or into the jugular vein, and thence into the right side of the heart, producing an infective endocarditis and general haemic infection (septicaemia). This may be accompanied, or followed, by multiple embolism, with metastatic deposits in the lungs, spleen, and elsewhere (pyaemia).
In a case of typhoid fever with ulceration in the intestines, and in the ulcers besides the typhoid bacilli there are streptococci which may be swept away by the blood stream, and deposited in the bone marrow, where, under suitable conditions, they may produce a secondary lesion, an osteomyelitis. On the other hand, entering the blood stream they may multiply, and set up a general haemic infection or a septicaemia, in some rare cases with infective endocarditis, and secondary deposits in the body (pyaemia). Even the typhoid bacilli themselves VOL. I. — 3
34 GENERAL PA THOL OGY OF DISEA SE.
may be carried away by the blood stream, whence they may be thrown out in the urine, or they may be stored up in the bone marrow. There, under pro- vocation, they may produce a typhoidal osteomyelitis. Rarely they may multiply in the blood, and give rise to a true typhoidal septicaemia. In croupous pneumonia similar processes may be noted; the pneumococci may extend locally into the pleura or pericardium, the effect of such extension being a pleurisy or peri- carditis ; again, in endocarditis, a few cocci may be carried away by the blood into the meninges without the blood itself becoming infected ; or a hgemic infection may occur directly from the lungs or indirectly through the endocarditis. In the latter case pneumococci will be found in the blood, and there may be multiple inetastatic foci of a suppurative nature.
As regards the anatomical distribution of the metastatic or pycemic foci, even a casual observer will notice that when the primary focus is in the area of the pulmonary or the systemic circulation the liver generally escapes the metastatic dissemination. If a pulmonary infective lesion is followed by pyaemia, metastatic deposits occur mainly in the systemic, but frequently also in the pulmonary vascular area; if a systemic infective lesion is followed by pyaemia, metastatic deposits are found mainly in the pulmonary, but frequently also in the systemic vascular area. Pyaernic deposit in the liver (portal pytemia) is often observed in the post-mortem room ; the primary focus in such cases is always in the portal area. An embolus is carried up by a venous radicle of the large or small intestine, and, entering the portal vein, is finally arrested in the terminal distribution of this vein. Such a primary portal focus, however, may also produce a metastatic deposit in either the systemic or the pulmonary vascular area. A minute bacterial embolus may pass through the entire portal zone into the vena cava, and thence into the right side of the heart, to be deposited in the lungs or in the systemic peripheral area. Similarly, an embolus may be carried through the systemic circulation into the liver.
The following table will serve to summarise these considerations : —
Primary Focus. Metastatic Deposits.
T3 , f Systemic area.
.Pulmonary area . . . . . . -! /Ys i
((Pulmonary area.)
a • f Pulmonary area.
Systemic area - ,,
{( Systemic area.)
( Portal area.
Portal area ^ (Pulmonary area.)
[(Systemic area.)
General hsemic infection may owe its origin to a primary focus situated anywhere, whether in the pulmonary, systemic, or portal area; and when a general septicaemia has developed, metastatic deposits may appear in any region of the blood vascular system, because the arteries may carry the organisms indiscriminately over the body.
Septicaemia may occur without any recognisable local infection, i.e. idiopathic or, better, cryptogenetic septicaemia. No primary focus is found, yet pathogenetic bacteria are found in the blood and organs. These organisms must have obtained access to the blood from the respiratory or alimentary tract or from the skin, parts always in contact with bacteria. A slight loss of substance, such as an abrasion, is sufficient to open up the way, whilst it must also be remembered that the adenoid structures of mucous membranes are, even in the normal state, but scantily and incom- pletely covered by epithelium. A minute superficial lesion may easily
CHRONIC INFLAMMATION. 35
escape detection, when methods are used which, if the size of a micro- organism be considered, are very coarse indeed.
CHRONIC INFLAMMATION.
The term chronic inflammation covers processes which are essentially different, namely, chronic fibrous changes, chronic catarrhal conditions, and chronic suppuration. When pus is continually discharged, whether it be from an open ulcer or a closed abscess, or a large area healing by so-called second or third intention, there is always a granulating surface. In such pro- cesses, which is chronic, the discharge or the inflammation ? Undoubtedly the purulent discharge. Granulations are made up of extremely delicate, vascular, undeveloped connective tissue, which is easily irritated, becomes in- named and suppurates, and as new granulations spring up, they again become inflamed and suppurate ; or if the irritation, inflammation, and suppuration persist, more of the surrounding healthy tissue is attacked, and it in turn becomes inflamed and suppurates. Hence the irritation, acting ever on fresh tissues, sets up an ever repeated process of acute inflammation, affect- ing always different parts, or destroying one part and then attacking a fresh part, i.e. there is chronic irritation continually provoking inflammation, and producing a lasting suppuration of an ever-changing surface. The suppuration of these numberless foci of inflammation amounts to chronic suppuration ; it is only observed where there is granulation tissue. From the pathological point of view this is not chronic inflammation, but chronic irritation of such intensity as to produce suppurative inflammation of the delicate granulation tissue as it appears, or to destroy the superficial granulations, and to act on the freshly exposed tissues. The irritation is the constant quantity, but the suppurating surface changes. Removal of the irritant under suitable conditions will at once allow the granulations to advance to cicatrisation. In this country, therefore, continued suppura- tion, or a continued ulceration, or a hidden and lasting abscess, are not as a rule regarded as chronic inflammation.
Histologically, the various forms of so-called chronic inflammatory processes may be classified under several headings: — (1) In some there is hyperplasia or proliferation of the connective tissue ; or, if a mucous membrane be affected, a hyperplasia both of the epithelium and under- lying tissues, in which sometimes the glands also share; (2) in others, so-called catarrhal conditions, when the lesion occurs in a secreting tissue ; (3) or an interstitial fibrous change ; and (4), finally, in others a complete replacement of the primary elements by fibrous tissue.
In chronic inflammation of the vocal cords, there may be noticed chiefly — (a) proliferation and hyperplasia of the subepithelial connective tissue, i.e. fibrous hyperplasia, or, in more modern language, fibrosis; (&) proliferation and hyperplasia of the epithelium itself, which frequently becomes horny; and (c) proliferation of the capillaries and vascular elements. The proliferation may be so complete and uniform as to lead to a papillomatous growth or a pachydermia.
Compare and contrast with this chronic cervical catarrh, in which similarly there are — (a) proliferation and hyperplasia of the subepithelial connective tissue; (b) proliferation and hyperplasia of the secreting epithelium itself, leading to dilated and elongated, or even cystic follicles, lined often by several layers of columnar epithelium ; and (c) proliferation of the capillaries and smaller vessels. Here the proliferation may be so complete and uniform as to lead to a
36 GENERAL PATHOLOGY OF DISEASE.
beautifully papillomatous surface. The proliferated epithelium retains its secretory activity, hence the catarrhal flow. This is the only apparent difference between this affection and the laryngeal form ; the squamous epithelium is not secretory in the ordinary sense of the term, and there is no catarrhal flow. In one case the catarrhal flow, in the other increased formation of horny substance, mark the increased functional activity. In point of principle, there is no difference between these two processes, which at first sight appear to be distinct ; and therefore to the three factors mentioned, namely, hyperplasia of the connective tissue, hyperplasia of the epithelium, and slowly increasing vascularity, a fourth must be added, namely, increased functional activity. These changes are frequently, if not commonly, found in so-called chronic inflammation of mucous, muco-cutaneous, or cutaneous surfaces. But in the fibrous changes only is " fibrosis " an essential attribute of chronic inflammation.
In some cases, in place of hyperplasia, there is atrophy of the mucosa, as in atrophic rhinitis or gastritis. During certain stages, at least, firm fibrous tissue is formed, contracting from the surface, and, so to speak, smothering the glands. These for a long time remain functionally very active — teste the foetid secretion of ozaBiia, or the cystic dilatation of the glands in atrophic gastritis. Instead of a hyperplasia, there is an induration of the connective tissue, without proliferation of the surface epithelium or the capillaries. This induration could not have occurred without previous proliferation, the newly-formed fibrous tissue becoming condensed as soon as it is formed; it required a proliferative stimulus for induration or sclerosis to ensue.
Why do some newly formed fibrous tissues contract and others go on increasing? A scar will generally condense into hard fibrous tissue, but occasionally it becomes cheloid. Grawitz lays it down that the connective tissue " having once awakened," there is no limit, necessarily, to the energy of its waking hours ; it may go on unchecked, in a condition of morbid insomnia, but it usually stops at a certain point, where it may cease, or the tissue may become condensed, hard, or indurated. It must further be remembered that atrophy and polypoid hypertrophy (in the stomach, for instance) may occur together. Again, epithelial proliferation is frequently present in atrophic " inflammations" ; in ozaena the stinking mucosa may be lined by several layers of squamous epithelium, the product of a proliferative metaplasia, and papillo- matous cysts occur in atrophic gastritis. So that even in these conditions three of the four above-mentioned factors are present, although in modified form, namely — (1) induration of the subepithelial connective tissue; (2) partial or complete proliferation of the epithelium ; and (3) increased, though altered, functional activity, the increased vascularity being impossible on account of the induration.
Chronic inflammation of the serous membranes is characterised by either mere opacity or by thickening with or without contraction, i.e. fibrous hyperplasia with or without induration. There may also be distinct hyperplasia of the epithelium (or endothelium), which may even become converted into a kind of squamous epithelium. Increased vascularity is often present, and with this hydrops is frequently associated, which followers of Heidenhain would be inclined to regard as due to an increased functional activity of the endothelium. Here, then, all the four factors may be present, but the fibrous changes always.
When the lesions of chronic interstitial inflammation, e.g. interstitial nephritis, cirrhosis of the liver, interstitial myositis and myocarditis, are examined microscopically, the most striking feature is the marked fibrosis which has taken place — fibrous tissue, more or less well formed, and often of exceeding firmness, surrounds the active or organic structures, whether they be kidney tubules, liver cells, or muscle fibres ; the framework or secondary elements may altogether out- grow the primary elements. Increased vascularity is often present, but may be absent in advanced stages ; a hyperplasia of the epithelial tissues cannot of course take place in myocarditis or myositis ; but in the interstitial forms of chronic
IS CHR ONIC INFLAMMA TION AN IN FLA MM A TION1 3 7
inflammation it is generally absent, even in organs which are largely epithelial in structure, such as the kidney, liver, and pancreas. In an interstitial nephritis the renal epithelial substances become compressed and atrophied, the liver cells degenerate and disappear extensively in most forms of cirrhosis, and the pan- creatic cells share the same fate.
As the acute inflammation, the result of bacterial irritation, passes off, if it has caused no serious lesion to the muscle fibres themselves, practically no permanent change may be left behind. If, however, the acute injury has caused serious lesion, breaking up some of the muscle fibres, or producing partial or total necrosis, then repair is accompanied by formation of fibrous tissue, and the foundation for a fibrous hyperplasia is laid. This newly formed fibrous tissue, endowed with the progressive stimulus characteristic of all infant growth, may extend beyond the original seat of lesion, between the sound muscle fibres, so that on transverse section at this stage small and compressed muscle areas, surrounded by rings of fibrous tissue, are seen, — " chronic interstitial myositis." The effect of this compressing fibrous tissue is to cause further degeneration of the muscle fibres, and, as these disappear, more fibrous tissue appears — the " vicious circle " is established. (2) Another cause of chronic interstitial changes in muscle is atrophy. When a muscle atrophies as the result of a central or peripheral nerve lesion, fibrous tissue may soon appear and take the place of the muscle fibres. "Tissue degeneration, if not repaired, leads to fibrosis " ; degenerated muscle fibres are replaced by invading and proliferating connective tissue. Adami has spoken of this form of fibrosis as " a replacement fibrosis." It seems, therefore, that an important cause of progressive chronic interstitial myositis is the degeneration of the muscle fibres, which may be due (a) to an acute interstitial inflammation, or (b) to myotrophic or neurotrophic lesions, and which (c) may be kept up by, or progress with, the appearance of the fibrous tissue.
Similar conditions are met with in the so-called peripheral neuritis of diphtheria or lead poisoning. Sidney Martin and others have shown that the earliest stage in the process is a degeneration of the nerves ; this is followed by a proliferation of the connective tissue, which may go on to fibrosis. In the spinal cord the degenerated tracts and areas are replaced by fibrous tissues. In these cases there is no sign of acute inflammation, no dilatation of the vessels, no appearance of new vessels, no leucocytic infiltration, but merely a degeneration which excites the connective tissue to proliferation, that it may replace the lost tissue. This is not inflammation, but a different process altogether.
In cirrhosis of the liver difficulties arise, since the intercellular, lobular, and biliary types differ so widely, and are so diverse in their etiology and histology ; it seems impossible to explain them all in the same manner. When, however, any form of cirrhosis is so far advanced as to cause so marked a degeneration of the liver cells that recovery is impossible, then the degenerate cells may act as a further stimulus for progressive fibrosis. It appears that the primary cause of cirrhosis is ahcays a degeneration of the hepatic cells caused by some toxine, such as owes its origin to alcoholic or syphilitic poisoning; and it appears that, when the process of cirrhosis has once begun, the degenerated cells are replaced by fibrous tissue, and that the degeneration is to some extent responsible for a continuity in the cirrhotic process. Obviously the connective tissue must be in a position to respond by proliferation before a fibrosis can result. If its activity be impaired, either because the whole individual is atrophying, or because it is itself hopelessly badly nourished, fibrosis cannot possibly take place.
Venous engorgement occasionally, though rarely, leads to induration ; this induration is probably due to the engorgement, which causes degeneration of the organic cells ; these cejls are then replaced by proliferated connective tissue. Generally, however, the tissues are too badly nourished to respond by proliferation. Where general debility or impairment is absent, a fatty or waxy
38 GENERAL PATHOLOGY OF DISEASE.
metamorphosis of the liver may be accompanied by fibrosis, as in true fatty cirrhosis. Cirrhosis of the liver is always due to proliferative changes in the interstitial, portal, or lobular connective tissue, appearing to respond to cell degeneration, which promotes the progress of the fibrosis.
Ordinary interstitial nephritis (red atrophic kidney) may be produced by primary hyperplastic changes in the interstitial connective tissue; but it has yet to be proved that it is a primary hyperplasia, and not a hyperplasia called into existence by degenerative changes in the renal tissue. The chronic interstitial changes in a white kidney are certainly due to several factors — (a) the repeatedly recurring attacks of acute or subacute inflammation ; (b) the organic destruction resulting therefrom, which awakens the connective tissue ; and (c) the proliferative energy of the connective tissue.
The various forms of chronic inflammation may be reviewed shortly as follows : — (a) Processes which begin primarily in the connective tissue ; fibrosis appears and progresses, the process being in part maintained by the destruction of the organic elements (productive fibrosis of Adami) ; (b) processes which begin with an atrophy of the organic elements, the latter being replaced by hyperplastic con- nective tissue (replacement fibrosis, Adami) ; (c) processes which, occurring on free surfaces, involve all structures concerned, but where again the most striking phenomenon is the fibrous hyperplasia, included under 'productive fibrosis, by Adami.
The important law is that " tissue degeneration, if not repaired, leads to fibrosis," provided of course that the connective tissue is capable of further growth — for if it be half dead itself, it cannot possibly assume fresh vigour — and provided also that the stimulus for proliferation is sufficient, or, adopting Grawitz's metaphor, that the connective tissue has been sufficiently roused and awakened.
" Is chronic inflammation an inflammation at all ? " Inflammation is recognised by its appearances and phenomena, and inflammation is not synonymous with repair.
In microscopical specimens of tissues and organs undergoing so-called chronic inflammation, the appearances of inflammation are not found, but appearances characteristic rather of repair by fibrous tissue. True, at the outskirts of a chronically inflamed area, there may often be detected a few dilated vessels surrounded by clusters of round cells, but the bulk of the specimen shows nothing that could be called inflammation. Chronic inflammation, exhibiting all the changes of repair, cannot possibly be inflammation, for inflammation ceases where repair begins, and chronic inflammation is a term which has been given to conditions which already show completed repair, or which show excessive repair. This excessive repair — the hyperplasia and hyperplastic tendency of newly formed fibrous tissue — is an important element in some forms of "chronic inflammation."
An acute inflammation, in the language of the surgeon or physician, is fre- quently followed by a chronic inflammation. What does this signify ? Merely this, that the effects of the acute process have been repaired by fibrous tissue, developed from the proliferating connective tissue ; but the latter, once awakened to increased growth, in the full enjoyment of renewed vigour, continues to develop further and further on the slightest provocation. An acute inflammation is often the precursor of a fibrosis, but surely that is no justification for calling the resulting fibrosis a chronic inflammation.
An acute nephritis may at once pass into gradual and progressive induration (contracting white kidney) on account of such excessive repair. But in most cases where a fibrosis has followed upon an acute inflammation, there is an injured and dying tissue left behind, which acts as the proliferative stimulus upon a responsive and awakened connective tissue. And, what is still more important, in most cases the acute inflammation recurs from time to time, and rouses
REGENERATION AND REPAIR. 39
the connective tissue to continued repair, when it is already in a condition of initial fibrosis, ready to proliferate, so that every fresh acute attack only makes matters worse. A fibrosis may therefore result from a single acute inflammation, or from repeated attacks of acute inflammation, but on this account it is not necessarily to be looked upon as an inflammation.
Instead of repeated attacks of inflammation, there may be repeated or con- tinued irritation, which does not necessarily produce, or may stop short of producing, an inflammation. In most cases, no doubt, repeated irritation does lead to repeated attacks of inflammation, so localised and so slight that they are not recognised, subjectively or objectively, but are neverthe- less sufficient to awaken the connective tissue to hyperplasia and fibrosis, and also to cause a hyperplasia of the epithelial elements, and an increased functional activity. But even then the inflammatory attacks themselves do not constitute the chronic inflammation ; they simply incite to hyperplasia and hypertrophy.
In interstitial processes, especially cirrhosis of the liver and kidney, there is nothing suggestive of the presence of an inflammation ; but there is fibrosis. It may be said, there is no evidence that this is the outcome of a previous inflamma- tion, the processes appearing in the interstitial tissue, which has been awakened either by irritant substance, or by degenerating cells, or by a combination of the two stimuli. Possibly here and there an acute hepatitis or nephritis may have existed to begin with, but then it merely acted as the initial stimulus. The essence of the cirrhosis is the progressive fibrosis, which appeared either independently of an inflammation, or in the wake of an inflammation as excessive, or hyperplastic repair.
But it may again be objected that necrobiosis and necrosis in myositis produce inflammation, and that therefore tissue degeneration leads to in- flammation, and that the term chronic inflammation is justified. That is only true to a certain limited extent, where large necrotic areas, infarcts, haemorhages, and such like lesions are concerned, but is assuredly not true of progressive degeneration. Even infarcts and necrotic areas may disappear in a scar, without any actual or real inflammation ever having existed. The necrosed elements must first be removed. This may be done by a process of absorption or phagocytosis, with or without inflammation. The dead tissue having been removed, then the fibrous tissue tills up the gaps. If there is only one gap to fill up, a cicatrix is formed — repair — but that is not chronic inflammation ; if, however, the necrosis or degeneration be both extensive and progressive, and is responded to by equally progressive reparative proliferation, then fibrosis ensues, or, in ordinary language, chronic inflammation.
Chronic inflammation, then, may be regarded as a hyperplastic change of the connective tissue, occasionally accompanied by hyperplasia and hypertrophy of the epithelial and glandular elements, produced either by repeated or continued irritation (extrinsic or intrinsic), or by a single and more often by repeated attacks of inflammation ; it may be called into existence by progressive tissue degenera- tion, when the epithelial and glandular elements, of course, do not share in the hyperplastic process. An inflammation it is not, because, histologically, it is a process which is solely concerned with tissue elements which are considered characteristic of repair ; inflammation is not even a constant precursor. It would therefore be well to abolish the term chronic inflammation from morbid anatomy and histology, if not from clinical medicine and surgery.
Chronic Inflammation (so called).
I. CHRONIC SUPPURATION (abscesses or ulcers). — Granulation tissue and con- tinued irritation.
II. CHRONIC CATARRH. — Proliferation and increased functional activity.
4o GENERAL PATHOLOGY OF DISEASE.
( Result of degeneration.
III. INTERSTITIAL INDURATION I ^ continued irritation.
(cirrhosis and sclerosis) | ^ cicatricial hyperplasia.
IV. SUPERFICIAL INDURATION j Result of continued irritation.
(mucous and serous S cicatricial hyperplasia.
membranes) /
EEGENE RATION AND EEPAIR.
Tissues which are used up during ordinary normal wear and tear, or which have been destroyed by injury or other pathological processes, must be replaced or repaired if life is to continue, or if a cure is to be effected. Eepair may be either direct and homologous (regeneration), or indirect and heterologous. Thus the cuticular cells, the epithelium of mucous surfaces, are constantly reproduced, new cells being developed to take the place of the old ones. This regeneration is purely physiological, and is a continuous process. Physiological repair is always homologous.
Under pathological conditions repair is more rarely homologous ; as a matter of fact, it is more commonly indirect or heterologous. Still, it must be borne in mind that a tissue defect, whether due to injury, degener- ation, or any other cause, may be made good by regeneration. Thus connective tissue, nerves, and vessels may be regenerated; but the power of regeneration varies considerably for the different tissues, and also for different animals. Thus, while certain low forms of animals are capable of reproducing whole complex organs, man and most warm-blooded mammalia are most restricted in their recuperative powers. Whole organs are never reconstructed in man, but only certain tissue elements. Epi- thelium and connective tissues, if the defect be limited, may be regener- ated, the regenerative power being always most marked in the least specialised and differentiated cell elements. Thus ganglion cells are never reconstructed, and muscle fibres only rarely when there has been complete destruction; but when only a portion of a cell has been destroyed, the fragment may be restored, as e.g. the process of a ganglion cell. Again, tissues which have become mature and are permanent are less capable of regeneration than tissues which are more or less temporary and con- structive. Thus the periosteum is more readily re-formed than carti- lage. The regenerated tissue is always derived from homologous tissue, i.e. epithelium is derived from epithelium, connective tissue from con- nective tissue, muscle from muscle, etc. ; connective tissue cannot produce epithelium. Regeneration obeys rigorously the law of specificity, omnis cellula e celluld (epigenesis). Where homologous repair is absent, the defect is made good by the development of fibrous or cicatricial tissue — the common form of repair. Injured or degenerated tissues, if not regenerated, are replaced by fibrous tissue, unless the organ is in such a condition that it is incapable of further proliferation. When an inflam- mation ends in resolution, there is direct repair or degeneration ; when it ends in induration, indirect repair by fibrosis ; when a degeneration such as is observed in peripheral neuritis passes off, and the affected portions recover themselves, true regeneration takes place; while, when the degenerated elements disappear, and their place is taken by fibrous tissue, there is an indirect repair, a patching up. It is erroneous to suppose that indirect repair is always accompanied or preceded by inflammation, or to define any attempt at repair, whether direct or indirect, as inflammation.
METAPLASIA — HYPERTROPHY. 41
Since pathological repair implies increased proliferation, it will be readily understood why reparative tissue is so liable to hypertrophy; the pro- liferative stimulus may produce a more or less lasting effect or impression.
Repair.
I. DIRECT OR HOMOLOGOUS —
f Cuticle ^j
(a) Continuous = physiological -j ^P1 ,e l )- Wear and tear.
I Periosteum J
/ Epithelium \
Connective tissue \ T • j
(b) Discontinuous = pathological - Periosteum 1. J J
Nerves I generatlon-
[ Muscles
f Mature and permanent tissue,
TT ,, , . , I large areas of injured or
II. INDIRECT OR HETEROLOGOUS = pathological J. , & , , ,. d , . •, ,
* ° \ n ormn QTarofl riacnoo nirfh \\r
1 degenerated tissues, highly
specific tissues.
Eepair must not be confounded with recovery. Homologous or direct repair is true recovery ; there is a complete restitutio ad integrum. Indirect repair is something entirely different from recovery. First of all, it is not a restitutio ad integrum, ; secondly, it may not even be a cure. Often, no doubt, new-formed tissue acts as a barrier against the noxious agent, and encapsules the dead matter and entraps the materies morbi without doing harm to the organ and its function. Frequently, however, the elements of the organ suffer, its function becomes impaired, and the attempt at cure is as bad as the disease. Take, for instance, a fibroid heart, the fibrous tissue having resulted, let it be assumed, from a patching up of an interstitial myocarditis, still, the newly formed tissue weakens the heart, and serious symptoms, nay sudden death, may result. In physio- logical repair there is a limit beyond which matters do not progress in pathological repair, and especially when it is heterologous, the patching up may be carried to excess. (See " Chronic Inflammation," p. 35.)
METAPLASIA.
Metaplasia is a change of tissue type — a change limited and following certain laws; it is specific, but not generic, i.e. a connective tissue may change to another form of connective tissue, but never into epithelium, and an epithelium changes to another form of epithelium, but never to connective tissue. Metaplasia is naturally commonest in the pleomor- phic tissues ; therefore it is most frequently met with in the connective tissues. Physiological metaplasia may be seen in the development and growth of bone, in the formation of fat, and in the keratinisation of epidermal epithelium. In these instances the metaplasia is a continuous process ; in some cases, however, it is discontinuous, called forth by certain stimuli. Thus, when the breasts become active, there is a metaplasia from cubical or short columnar epithelium to a secretory or glandular type.
Under pathological conditions the metaplasia of the connective tissue may be retrogressive or progressive. Cartilage may change into myxomatous tissue, and
42 GENERAL PATHOLOGY OF DISEASE.
fatty tissue into a fat-free oedematous or mucous tissue. These are instances of a retrogressive metamorphosis. On the other hand, cartilage may become bone, mucous tissue cartilage, or fibrous tissue bone ; these are instances of a progressive metamorphosis. Tissue which has resulted from repair is extremely liable to metaplasia, and so is the tissue of certain new growths, namely, sarcomas. The delicate connective tissue which appears after pleurisy may change into dense and hard fibrous tissue, and the latter into bone or cartilaginous tissue.
As far as the metaplasia of the epithelium is concerned, under the influence of irritation, (a) columnar epithelium changes into squamous epithelium, and (b) squamous epithelium may become horny. But squamous epithelium never Incomes columnar or ciliated. Examples of a metaplasia of columnar epithelium may be looked for in the larynx, nose, or uterus, where, as the result of so-called chr-onic catarrh, the columnar or ciliated cells change into the squamous type, and the latter may even become keratinous. This metaplasia of the epithelium is most important in connection with carcinoma. A cancer developing in trans- formed epithelium always adheres to the new type of epithelium, and does not revert to the original type.
I. PHYSIOLOGICAI
Metaplasia.
II. PATHOLOGICAL —
(a) Continuous. — Ossification, ker-
atinisation, fibrosis. (1) Discontinuous. — Change in
breast from resting to active
state.
(a) Connective tissue. — Retro-
gressive— cartilage to myx- omatous tissue. Progressive — cartilage to bone.
(b) Epithelium. — Columnar epi-
thelium to squamous — squamous epithelium to horny epithelium.
HYPERTROPHY.
Tissues of organs and limbs may increase in size or enlarge under certain conditions, which may be either physiological or pathological. The increase in size, without structural changes, constitutes hyper- trophy. Under physiological conditions, and with continued exercise, a muscle, or a group of muscles, may enlarge ; the fibres increase both in number and in size. Similarly, the heart of an athlete may become slightly enlarged. It must be remembered that the body is so constructed that in health the organs are not worked to their utmost, and that they are capable, under exertion, of doing an increased or even an enormous amount of work ; if these demands on the functional activity of the organs is kept up, they are capable of adapting themselves to the new requirements. Physiological hypertrophy is therefore a process of adaptation.
Under pathological conditions hypertrophy may show itself as the result of two altogether different processes — (a) it may be due to adapta- tion, i.e. compensatory hypertrophy ; or (&) it may be due to an abnormal proliferative stimulus, the tissue or tissues growing and expanding without any extra demands being made upon them.
Compensatory hypertrophy is the more interesting and important form. On this power, which the body and portions of the body possess to adapt themselves to altered conditions, life, in health and disease, greatly depends, and when in disease the limit of compensation has once been reached, death soon supervenes. Compensation or adaptation may be so
PATHOLOG Y OF BACTERIAL INFECTION. 43
complete that an individual seriously maimed may be able to live a long and useful life. Compensation is not exclusively hypertrophic. It may be merely functional or vicarious, one organ supplementing another. Com- pensatory hypertrophy may be — (1) Supplementary, upon an increased demand for work ; (2) vicarious, affecting a whole organ after loss of one of a pair of organs, or a portion of an organ after a partial loss of substance ; (3) systemic, where a lesion is counteracted by a complete readjustment of several or even numerous organs or tissues. Thus, if there is obstruc- tion to the outflow of urine, the bladder wall may become considerably thickened, this being due to an increase of its muscular substance; or, again, if there is an obstruction of the aortic valve, the left ventricle becomes thickened, more force being required to propel the blood through the narrowed opening. So long as the hypertrophy is adequate, matters may progress so well that all symptoms of disease are practically absent. A good example of vicarious hypertrophy is the enlargement of one kidney after removal or total obstruction of the other, or enlargement of a part of a kidney after atrophy of the remainder. The best example of systemic hypertrophy is also found in renal diseases, as with granular kidney when the left ventricle of the heart hypertrophies and the tunica media of the arterioles in- creases in thickness.
The increase in size is due chiefly to proliferation of the tissue constituents, without change of structure, but they may also become enlarged. It is customary in theory to distinguish between hypertrophy and hyperplasia. In either case the type and structure of the tissue remain unaltered ; in hyperplasia there is a numerical increase of the tissue elements, in hypertrophy an increase in volume. Since, however, hypertrophy is always accompanied by hyperplasia, it is best to call any increase in size without histological change hypertrophy, even though this may not be quite accurate, for it is impossible to draw a hard and fast line between the two processes.
Hypertrophy or overgrowth may be either primary or secondary. Primary overgrowth may be due to irritation, or possibly to long-continued hypersemia and certain nervous changes (pseudo-hypertrophic paralysis), but its cause may be altogether obscure ; again, it may involve a whole organ, i.e. all its components, or only some of them. A whole extremity or a finger or toe may overgrow, and then all the components are hypertrophied ; on the other hand, as in elephantiasis, the skin and subcutaneous tissue only may increase. Again, a breast may hypertrophy generally, or only its fat or glandular substance may develop abnormally. When the cause of the overgrowth is obscure, there may have been (1) congenital in- fluences (moles, naevi, ichthyosis) ; (2) disease (nails and teeth) ; or (3) arrested involution (uterus and breast), but often even then no explanation can be found (lymphadenoma and goitres).
In secondary overgrowth a new tissue is first produced, either as the result of irritation, inflammation, or atrophy, metaplasia or heteroplasia, and this new tissue then overgrows. As examples, the formation of keloids and exostoses, developing in common with muscular and tendinous insertions, may be mentioned ; again, fibrous tissue may appear as the result of atrophy (cirrhosis of the liver, senile changes in the breast), and this tissue may undergo considerable proliferation, a so-called hypertrophic condition being produced.
PATHOLOG-Y OF BACTEEIAL INFECTION.
In the causation of diseases and morbid lesions, minute vegetable organisms play an important part.
44 GENERAL PATHOLOGY OF DISEASE.
CHARACTERS OF BACTERIA.
Classification.— The pathologist, awaiting the final classification of the botanist, temporarily arranges the vegetable bacterial organisms in morphological groups, and he uses terms which, from a botanical point of view, may be objected to, but which have become customary, and will probably be adhered to until the botanists have settled their dis- putes. Vegetable micro-organisms are roughly divided into (1) fission fungi, or bacteria, (2) sprouting or budding fungi, and (3) mycelial fungi, of which the bacteria are the lowest and simplest forms, and the mycelial fungi the highest and best developed. Most disease- producing organisms belong to the first group, a few only to the third. The budding fungi include the yeasts which are responsible for certain processes of fermentation, and are also said to cause tissue irritation.
The fission fungi, according to their shapes, are again divided into three main groups : —
1. Cocci.— Globular, subglobular, oval, ovoid, or reniform.
(1) In chains (Pyogenes and erysipelatis.
(a) Streptococci . . . (pneumonice.
(2) In pairs— - (Pneumonia (meningococcus).
(6) Diplococci ^ . (Gonorrhcece.
(3) In tetrads —
(c) Tetracocci . .. *•• • ;-•; . Micrococcus tetragenus.
(4) In three dimensions- (Pulmonalis.
• \Ventriculi.
(5) In irregular dusters- (Pyogenes aureus.
(e) Staphylococci '.' . . < albus.
{citreus.
The streptococci are arranged in chains, varying considerably in length, the diplococci in pairs, the tetracocci in fours, the sarcinse in groups of fours, and the Staphylococci in irregular masses. This classifi- cation, based on the method of division, though useful, is extremely imperfect, because it is not exclusive. Thus the diplococcus is at the same time the simplest form of streptococcus or of staphylococcus. The pneumococcus, which in pneumonic sputum generally occurs in encap- suled pairs, in artificial media grows as a streptococcus ; the Micrococcus tetragenus, which in phthisical cavities is found in fours, surrounded by a capsule, in artificial media becomes a staphylococcus ; so also do most sarcinse.
2. Bacilli include all rod-shaped organisms. They are generally long or short straight cylindrical cells with rounded, pointed, or straight ends, but some of them are clubbed and evince a ten- dency towards branching. The latter, strictly speaking, should be taken out of the group of bacilli, and placed amongst the mycelial fungi in a class by themselves; they are, however, as a rule kept in this group. The following bacilli are found in association with disease in man : —
INVOLUTION, PLEOMORPHISM, AND VARIABILITY. 45
(1) The straight bacilli — (2) The clubbed or branched bacilli —
Bacillus of anthrax. Bacillus of tuberculosis.
„ glanders. „ „ leprosy.
„ typhoid fever (motile). „ „ tetanus (motile).
coli communis (motile). ,, ,, diphtheria,
of malignant O3dema ,, „ xerosis.
(motile).
blue pus (motile).
tetanus (motile).
influenza.
plague (motile).
Friedlander (motile).
Bacilli may be motile or non-motile. When motile they possess flagella, which may be distributed all round the organisms, as is the case with the typhoid and tetanus bacilli ; or they may be fixed at one or both poles, e.g., bacillus of blue pus. There is no correlation between the rapidity of movement and the number of flagella, but it is generally held by botanists, who divide the bacilli according to their flagellation into Monotricha (a single termal in flagellum), Amphitricha (a single flagellum 'at each pole), Lophotricha (a bundle of flagella at one pole), and Peritricha (surrounded by flagella), that the arrangement of the flagella is a specific character.
Bacilli always divide by transverse fission into (a) paired bacilli, and (b) filamentous forms, of which the anthrax bacillus is a good example. Many bacilli are capable, before they die, of producing endogenous spores, which are highly refractive bodies, spherical or ellipsoid, developing in the interior of the cell substances. These spores are highly resistant to the action of physical and chemical agents, and may be (1) central (anthrax bacillus), or terminal (tetanus bacillus), or indefinite. The spore placed in favourable conditions again grows into a bacillus. The following pathogenetic bacilli are sporogenous: — (1) Anthrax (central sporulation). (2) Tetanus bacilli (terminal sporulation). (3) Malignant oadenia. None of the pathogenetic cocci or spirilla which occur in man, sporulate.
3. Spirilla.— The third morphological group consists of the vibrios — short, small, comma-shaped organisms, and the spirilla of longer, tortuous, or screw-like threads. The vibrios may be linked in such a way as to produce a jointed spirillum or an S-shaped curve, or they may grow into true spirilla. They are mostly motile and flagellated. The most important vibrio or spirillum, from the pathogenetic point of view, is that of Asiatic cholera ; spirilla and vibrios, however, occur commonly enough in the intestinal contents, the mouth, tonsils, and nose, and are often found in diarrho3ic stools.
Involution, Pleomorphism, and Variability. — Bacilli, cocci, and spirilla, when kept in or on artificial media, or even while growing in the animal organism, frequently show changes in their morphological appearances. In young cultures of an organism the different individuals resemble each other very closely, but as the culture becomes older, irregular and typical forms appear ; this is degeneration or involution. Such degenerate forms, transplanted on good and fresh soil, will again resemble the true or original type. Vibrios when grown on agar-agar or in other media frequently become coccoid ; other organisms swell up with age or become segmented. In other cases, e.g. diphtheria and tubercle bacilli, there may sometimes be noticed in young and perfectly fresh cultures
46 GENERAL PATHOLOGY OF DISEASE.
curious clubbed or branched forms. These organisms are therefore supposed to be closely related to the streptothrix forms, the appearance of branched forms afford- ing an example of a progressive metamorphosis. Pleomorphic organisms even in young cultures show variety of shape, the pleomorphism being a distinctive character of the species.
Pleomorphism and involution must not be confounded with variability. On changing the external conditions and soil an organism will vary somewhat, not only in its morphological, but also in its biological characters ; a short bacillus may become long, and a pigment-producing organism may lose its chromogenetic power. Variability is possible only within very narrow limits. Morphologically an organism may vary in shape, but the limit of its variability is fixed by its genus; thus cocci remain cocci, bacilli remain bacilli, and spirilla remain spirilla. Pleomorphic organisms retrogress or progress to a higher or lower class, i.e. an irregularly-shaped bacillus may become clubbed or branched. We still speak of diphtheria, leprosy, or tubercle bacilli, but it is questionable whether these are bacilli at all, and do not rather belong to a special genus. Singling out the established genera amongst the vegetable organism, the constancy of form upheld by Cohn and Koch must be accepted ; cocci, bacilli, and spirilla do not change one into the other, and even amongst the cocci such main divisions as streptococci and staphylococci are not interchangeable.
Variation can be achieved by artificial cultivation, and the result may be (1) a temporary, (2) a more or less permanent, and (3) an absolutely permanent variety. If a variety is temporary, on restoring the old condition, reversion to type quickly follows, while, as the endurance of the variety increases, the liability to reversion diminishes. Variation is generally due either to degeneration or to adaptation to a richer or better soil : in the former case variation is an easy matter, but in the latter variation is much slower and can often be produced only by a process of selection, that is, by constantly selecting colonies presenting the features which it is wished to emphasise. Variability shows itself generally in the following directions : — (a) Mode of growth, namely, changes in rapidity of develop- ment, in the amount of liquefaction, in the size of the colonies, and in the amount of mucilaginous material ; (&) temperature — organisms may become accustomed to a higher or lower temperature than that at which they grow best; (c) oxygen requirement — aerobic organisms may be trained to grow under anaerobic conditions, and conversely anaerobic organisms may be accustomed to aerobiosis ; (d) resistance to antiseptics ; (e) bio-chemistry — an enzyme may be lost or acquired by change of medium, a pigment lost or acquired, and a toxine increased, diminished, or lost altogether; (/) sporulation—an organism may be so modified that it loses its power of forming spores. It is important to note that, in the instances given, variability mostly implies loss of something, rarely the acquisition of a higher function. Again, variability is far oftener physiological and biochemical than morphological. It is quite easy to alter the shape of a bacillus or spirillum and the grouping of bacteria by a change of medium, but then this change is almost always temporary, and it affects only a larger or smaller proportion of the organisms growing on or in the medium. Taking it altogether, there is as yet no reason to give up the belief in the constancy of form. Physiological and bio- chemical properties do vary considerably, not only under artificial conditions, but most probably also in nature, and it is more than possible that an organism may for some reason or another suddenly acquire pathogenetic properties.
EEQUIREMENTS OF BACTERIAL LIFE.
Bacteria require oxygen, nitrogen, carbon, hydrogen, oxygen phos- phorus, and salts, which may be supplied in various ways. Nitrogen may be supplied in the form of diffusible albumins and peptones, or in the form of non-albuminous substances containing an NH2 or NH group
REQUIREMENTS OF BACTERIAL LIFE. 47
(leucin, asparagin, etc.), or even in the form of nitrates. It is important to remember that pathogenetic germs may be cultivated in non-albuminous solutions, because this proves that organisms work up their poisons in their own substance, and not by splitting up the solution in which they grow. Carbon may be supplied either with the diffusible albumins and peptones, or in the form of sugar or other carbohydrates, glycerin or fat ; it is obtained from the above substances. Phosphorus may be given as phosphates, but is generally present in the ordinary albuminous substances used.
The oxygen requirement. — The pathogenetic organisms may be divided into three groups, according to their behaviour towards oxygen. Some organisms, e.g. bacillus of tetanus or bacillus of malignant oedema, grow in an atmosphere devoid of oxygen, and, so far as the best evidence goes, cannot grow in the presence of free oxygen, they are therefore obligatory anaerobes. Others require the presence of free oxygen, and are obligatory aerobcs ; but the majority of bacteria are facultative anaerobes, i.e. they are capable of growing in an atmosphere devoid of oxygen, and also in the presence of free oxygen, some growing better without — others better with it. Most pathogenetic organisms which in the laboratory grow as aerobes, in the body produce their lesions and diseases as anaerobes, for in the tissues there is no free oxygen. Pasteur thought that bacteria and yeasts developed their fermentative and chemical activity best in the absence of oxygen. This does not appear to be an absolute law, although it cannot be denied that the absence of oxygen often provokes a more intense fermentation, further, many of the organisms which in the tissues are anaerobic can, outside the body, be grown without oxygen only with difficulty or not at all. This shows how imperfectly the test tube supplies the conditions existing in the living body. (2) The range of temperature at which bacterial life is possible varies considerably. There are organisms which grow at a low tem- perature, under 15° C., others which can only grow at a temperature of the human body and up to 40-420-5 C., and others again which grow at any temperature between 10° C. and 42° '5 C. The most extraordinary are the thermophilic organisms, found in faeces, which only develop at tem- peratures above 45° and up to 60° C. ; they appear, however, to be of no pathological importance. All pathogenetic organisms are capable of growth at blood temperature ; some readily perish if kept below this temperature ; others, however, persist either in a vegetative form, or as spores, or in a dormant and latent condition, often retaining their full virulence. Thus the staphylococci of suppuration thrive well at low temperatures, as does the typhoid bacillus ; the bacilli of anthrax and tetanus form spores ; while the tubercle bacillus and streptococci retain their vitality, the latter even when kept in an ice chest. Again, higher temperatures may be borne by many organisms, either by virtue of their own natural resistance or by their power of sporulatiou. Many pathogenetic organisms, then, possess a strong vitality, the far-reaching importance of which fact will be evident. (3) Light, generally speaking, is harmful to most pathogenetic organisms, either destroying them outright, or at least attenuating them, or modifying them. Direct sunlight is infinitely more potent than diffuse light, and the actinic more powerful that the heat rays. Apparently con- tact with free air is necessary for the perfecting of this action, and it is believed that the sunlight in the presence of free air produces either ozone or H202, and that the bacteria are destroyed by these substances.
48 GENERAL PATHOLOGY OF DISEASE.
(4) High altitudes and great atmospheric pressure are inimical to the development of pathogenetic germs.
It is important in all cases to study the effect of surroundings and physical conditions on disease-producing organisms, because it is evident that a resistant germ is a much more difficult foe to grapple with than one which is very sensitive.
VITAL MANIFESTATIONS OF BACTERIA.
It is evident that chemical changes take place during bacterial growths, for nutrition depends on them ; energy is developed as a result of such growth. Nutrition has two objects to fulfil — (a) to supply the bacteria with food material for their own development and proliferation ; (b) to supply the substances required for the development of energy. For mere vegetation plastic nutriment alone is necessary, i.e. simple substances ; but for the display of energy, additional food material, and additional chemical substances are required.
A change of medium or surroundings may alter the activity of an organism ; virulent bacteria after their removal from the body may become attenuated, and organisms which generally merely vegetate on the mucous or other surface of the body may under certain conditions acquire marked virulence. A virulent strepto- coccus can be kept for a long time in vegetative form on gelatin in a refrigerator, so that when again injected into the animal body it once more gives unequivocal evidence of its virulence. The pneumococcus on a mucous membrane, so long as it is merely supplied with plastic food material, simply vegetates in a harmless way, but a change of conditions which implies a change of medium will cause it to display an unexpectedly virulent activity. Nutrition, whether for the purpose of vegetative growth or for the purpose of developing energy, is a process of assimilation, i.e. of synthesis, but this must always be accompanied by an output of certain substances. The latter includes (a) waste products, and (b) the pro- ducts of intracellular chemical activity, i.e. secretions, which are often capable of calling forth fresh chemical processes.
Bacterial products. — By these are understood, generally, the sum total of substances which are found in a medium in which the bacteria have grown for some time. Hence they evidently include both the excreta and the secretions of these organisms. The medium may be altered in many ways — (1) organisms, growing in broth, use up certain substances, and hence alter the chemical nature of the broth, by removing them ; (2) they may destroy others by splitting them up ; (3) the excreta may form new compounds with substances . found in the broth ; (4) the secretions, especially if of the nature of enzymes, may by their action lead to the formation of a new series of molecular changes, which will greatly alter the medium ; and (5) the organisms may act as ferments, and still further alter the medium. Hence the chemical activity of an organism is extremely diverse, and depends on a number of often highly complex processes, our knowledge of which must necessarily be at present both limited and crude.
Amongst the numerous so-called bacterial products may be found the following substances: — (1) Gases, (2) water, (3) nitrates and nitrites, (4) sulphur, (5) vola- tile bodies, (6) oxy-acids, (7) sulpho-acids, (8) amido-compounds, (9) aromatic bodies, (10) indol, (11) pigments, (12) carbohydrates, (13) peptones and albumoses, (14) ptomaines and so-called alkaloidal substances, (15) toxines and toxalbumins, (16) enzymes, (17) the extracts of the dead bodies of the bacteria, and (18) other
FERMENT A TION—ENZ YMES. 49
products of fermentation. All these substances are not found at once in the chemical products of one and the same organism, but this extraordinary multitude and diversity of the bacterial products must be borne in mind, because they show what the organisms may do, and how diverse, in disease, the phenomena due to bacterial intoxication may be. A few chemical processes, which have some bear- ing on health and disease, may be instanced: — (a) Organisms may be strong reduc- ing agents, and may thus assist complex physiological processes. Thus putrefac tion is essentially a reducing process, and whether it is absolutely necessary or not, putrefaction certainly assists digestion and absorption, and prevents intoxica- tion from the intestinal tract, (b) Nitrates are reduced to nitrites, an indispens- able preliminary process in nitrification, which, if not absolutely necessary for some forms and phases of vegetable life, yet is of great use to them. By nitrifi- cation ammonia is changed into nitrates ; this process is a double one — (a) one group of organisms changes ammonia to nitrites, and (b) a second group changes the nitrites into nitrates. The nitrifying organisms are frequently associated with the leguminous plants, which use them for their own development. They can, however, do without them when ammonia or nitrates are present in sufficient quantity. This shows that, although not essential to life, these organisms, under ordinary conditions, are of the greatest use. It may be that bacteria are not essential for subsistence and growth, but by a process of adaptation the animal organism may, for the purpose of nutrition, have learnt to avail itself of the assistance of bacteria. Putrefaction, which normally takes place in the intes- tinal tract, and may reasonably be regarded if not as an essential as a useful process, as aiding in the splitting up of complex bodies, and in the destruction of poisonous bodies, is of course due to bacterial action, and is a complex chemical process resulting from bacterial fermentation, i.e. not a simple fermentation, but a compound fermentation. The following steps may be distinguished : — (a) The albuminous substances are changed by some bacteria into peptones and albumoses, by what appears to be a process of hydrolysis ; (b) these peptones and albumoses are then split and changed into amido-acids and amides, nitrogenous aromatic bodies and sulpho-acids (such as taurin) also making their appearance ; (c) the amido compounds are then decomposed into ammonia and fatty acids ; (d) the ammonia is then altered by bacteria, as described under nitrification, and the fatty acids are split into CO2, H2, and CH4. The products of putrefaction vary with the bacterial flora, and also with the presence or absence of oxygen. If oxygen is absent, true putrefaction takes place ; if it is present, decomposition characterised by an absence of the bad and offensive odour, and frequently accompanied by reduction of the nitrates (dentrification), by which N2 may be split off.
Fermentation may be brought about by (a) non-organised substances, the products of secreta (excreta) of bacteria, the enzymes, or (V) b}7 the living bacteria themselves, which then act as true ferments. The enzymes may be isolated from the living bacteria, of which they are the products, and are characterised by the following points : — (a) They are capable of splitting up H.202 ; (b) they are extremely sensitive to external influences — in the moist condition they are readily destroyed by heat, in the dry state they resist 100°-160° C. ; (c) certain salts, such as aluminates and phosphates, and nitrogenous substances — asparagin — assist the enzymes in carrying on their fermentative activity; (d) they are more resistant to external influences while active, especially in the presence of neutral salts (sulphates) ; (e) they set up hydroly tic action, during which one or more molecules of H2O are taken up, and a molecule of the fermenting substance is split into two or more molecules of a simpler substance ; (/) they act on certain special substances only, and show a selective power as striking as that shown by the living micro-organisms ; (g) their quantitative action is considerable, but by no means unlimited, the enzyme apparently forming VOL. i. — 4
5o GENERAL PATHOLOGY OF DISEASE.
an unstable compound with the products of decomposition, which is easily split up, and the enzyme again set free on the addition of fresh material. The enzymes are closely allied to the toxines of disease-producing organisms, and for that reason they deserve special consideration. The following enzymes have been isolated from living bacteria :—
Amylase, which converts starch into sugar (diastase), found in anthrax bacilli, and the vibrios of cholera and of Finkler-Prior.
Invertase, which converts cane sugar into dextrose (found especially in yeast
cells).
Glucoside enzymes, splitting glucosides into dextrose, and a body of entirely
different composition.
Cellulose enzymes, capable of dissolving cellulose.
Peptonising enzymes, converting albuminous substances into peptones and albumoses (found in all organisms which liquefy gelatin).
Milk curdling enzymes, found notably in the Bacterium coli.
Urea enzyme, found in the Micrococcm urece, which converts urea into ammonium carbonate, hippuric acid into glycocol and benzoic acid.
Fat-splitting enzymes, splitting neutral fats into glycerine and fatty acids.
All these enzymes may be obtained from the bodies of micro-organ- isms. Thus, on destroying yeast-cells in a watery suspension by shaking them up with chloroform, invertase remains in suspension. The enzymes may display their activity either outside the cell (extracellular), or in the cell (intracellular) enzymes. An extracellular enzyme is secreted or ex- creted by the cell, and then works upon the material in which the cell is suspended, while an intracellular enzyme acts upon the material taken into the cell substance, splitting it up by a process of hydrolysis. The opinion is gaining ground that under normal conditions the enzyme action takes place in the interior of the living cell. Thus living and normal yeast cells do not give off invertase, but the inversion takes place in the cell body ; only when the cell dies is the inversion given off, just as in fermenta- tion, where the process is assumed to be a vital one, i.e. an intracellular one, although in other respects it closely resembles zymotic action. Thus a few organisms will produce an effect out of all proportion to the number of living organisms used; in both cases a definite medium of a certain chemical composition is required. Ferment action and enzyme action are so closely allied that it may be doubted whether they are really two distinct processes. Hitherto, for instance, it has been believed that the yeast cell, by some vital process, changes glucose into alcohol. Recently, however, an extract has been prepared of yeast cells, which, in the absence of all living cells, is capable of fermenting sugar solution. The great difficulty has been to separate this substance from the cell. We must therefore believe that the yeast cell takes up sugar, and, by means of an enzyme-like body in its substance, splits it up into alcohol and other substances, just as inver- tase in the cell substance inverts cane sugar. The yeast cells therefore build up two enzymes — (a) invertase, and (&) alcoholic enzymes, of which the former is easily given off, while the latter is obtained with much greater difficulty. Sugars are taken up by the living cells, and cane sugar inverted by the appropriate enzyme in the substance of the living cell, and either given off again as glucose or at once changed into alcohol by the other intracellular enzyme. It is legitimate, in the present state of our knowledge, to assume that the processes which are brought about by patho- genetic bacteria are comparable to those of the yeast cell.
PTOMAINES, TOX ALBUMINS, TOXINES. 51
The yeast cell (a) will only develop its fermentative power on suitable media : on others it will merely vegetate without giving evidence of its energy, (b) In a suitable medium its energy depends upon and varies with such conditions as absence of oxygen, concentration, accumulation of the products of fermentation and of waste, (c) Although fermentation varies with the rapidity of proliferation on the part of the yeast cell, alcoholic fermentation will still take place, when the cells have ceased to multiply ; it appears that first the cell reaches its maximal vegetative energy, and then unfolds its maximal fermentative energy, (d) The yeast possesses two fermenting substances, of which one is of nutritive or plastic importance, namely, the invertase, which the cell will only use when it is placed in an unsuitable sugar solution ; whilst the other is of specific importance, is firmly fixed in the cell substance, and is only separated with difficulty. This latter substance acts on certain chemical bodies absorbed into the cell, and then the latter give off an elaborated product, which may be regarded as the specific toxine of the yeast cell, namely, the alcohol. By way of an example, take the diphtheria bacillus. The latter may vegetate on the tonsil as a saprophyte, without producing any lesions ; under certain conditions it becomes virulent, multiplies rapidly, and then displays its energy. It forms, if necessary, albumoses by an enzyme, and at the same time takes up substances from the nutrient material, and elaborates these into the diphtheria toxine, which is the specific product ; the albumoses are of secondary importance, and will not appear, for instance, when the bacillus is grown in a solution of asparagin. Disease-producing organisms elaborate poisonous substances, which call forth certain symptoms, of which s.ome are specific, and belong exclusively to a particular species, while others are general and shared by many organisms. The poisonous substance obtained from a tetanus culture, for instance, which, when injected into an animal, produces tetanus, is the specific poison; other poisonous substances, which merely produce fever and other general symptoms, are not specific, and may be found in many other organisms. It is a matter of the greatest importance to keep in mind this twofold nature of the poisonous substance of disease-producing organisms.
Ptomaines. — The ptomaines are nitrogenous bases, which bear some resemblance to the vegetable alkaloids ; they are frequently described as cadaveric or animal alkaloids. Brieger divided them into two groups — the toxic and the atoxic ptomaines. He succeeded in obtaining from putre- fying material and from pure cultures of bacteria on meat, both forms of ptomaines. Most of the atoxic ptomaines are amines — cholin, neuridin (putrefying meat), gadinin (putrefying fish), putrescin, and cadaverin, but the toxic ptomaines are also closely allied to the amines ; the best known of these are neurin, rnuscarin, mytilotoxin, and tyrotoxicon. Brieger obtained poisonous ptomaines from cultures of the B. typhosus, the cholera vibrio, and the bacillus of tetanus, and at one time believed that the specific toxines were ptomaines ; but ptomaines have not been found in all patho- genetic cultures, whilst quantitatively they are present in such a small amount in others, that it is impossible to regard them as being the specific toxines. During putrefaction ptomaines appear, and since this takes place both outside and inside the alimentary tract, poisoning may be produced either through ptomaines ingested with food, or through ptomaines developed in the alimentary tract after the ingestion of food. The term "ptomaine poisoning" is often employed without there being sufficient evidence to justify its use, and it must also be remembered that the process
5 2 GENERAL PATHOLOGY OF DISEASE.
of analysis offers numerous sources of error arising from the extremely complicated nature of the chemical manipulation.
When Hankiu and Sidney Martin discovered toxic albumoses in anthrax cultures, the specific poisons were thought to be albuminous substances which were called toxalbumins. In diphtheria cultures a poisonous body resembling serum albumin was found, and separated by Brieger and Frankel ; in other cultures, globulin-like substances; in others, again, toxic peptones, so that dis- tinctions wore, made between toxalbumoses, toxoglobulin, and toxopeptones. All these substances were included in the term " toxalbumins." The latter un- doubtedly contain specific toxines, since, on injection, they reproduce the specific lesions or symptoms of the infection ; but the question which was soon raised was, whether these toxalbumins were pure substances or a mixture of albuminous bodies with the toxine. Thus Roux and Yersin separated from diphtheria cultures a specific toxine which appeared to be an enzyme. Previously chemists had pointed out that it was necessary to work with culture fluids containing known substances, and to free the bacterial products as thoroughly as possible from albuminous substances. Recent work has shown that when an attempt is made to precipitate the toxines from albuminous solutions, the toxines are carried down mechanically with the globulins, albuminoses, or peptones ; and therefore, accord- ing to the constitution of the culture medium, the same bacterial toxine at one time may appear to be a globulin, at another time an albumose, and that, as a matter of fact, the worker has usually, if not always, to deal with mixtures of toxine and albumose or toxine and globulin. When diphtheria bacilli are grown in an albuminous solution, there appears, as shown by Sidney Martin, a mixture of albumoses, but, as shown by IJschinsky, in a medium free from albumin, a toxine free from albuminous matter is obtained, whilst Brieger and Cohn have succeeded in purifying the toxines of tetanus and diphtheria from all albuminous admixture, and Dr. Martin has extracted from the tissues of animals dead of tetanus, a toxine which is certainly not an albuminous substance.
These purified 'toxines undoubtedly resemble the enzymes in some respects, but they cannot be grouped with the enzymes, because their activity is essentially diffused and their action narrowly limited by the dose employed, while zymotic action is out of all proportion to the dose of enzyme used. It may be assumed, however, that the specific toxines are products of the bacterial cells, which take up certain substances, work them up into toxines, which are then excreted or secreted, and that the albumoses, globulins, etc., are merely secondary products due to the action of accessory enzymes.
Amongst the non-specific bacterial products the most important are the proteins of Buchner, apparently identical with Klein's intracellular poison, while the latter's extracellular poison is practically the same as the specific toxine. The proteins are the protoplasmic substances of the bacterial cells, and may be obtained by taking masses of bacterial cultures grown preferably on solid media, such as potatoes, agar-agar, and gelatin, destroying them by heat, and extracting them by alkalies or other chemicals. The nature of these proteins is uot as yet clearly understood ; some observers believe that the proteins of the different bacteria are identical in nature. This, however, is certainly erroneous, because the immunity produced by injection of the so-called proteins is strikingly specific, and it is probable that what are usually called proteins are mixtures of different bodies, amongst which even the specific toxines in small quantities may occur. It seems, however, that there are also other substances, found in many bacteria, which are non-specific in their action, and are capable of producing febrile symptoms, leuco- cytosis, inflammation, and other general changes. It must be clearly borne in mind that the pathogenetic bacteria, besides secreting toxines, are themselves poisonous, and that this coexistence of specific and non-specific poisons explains the difference and diversity of symptoms in infective lesions, of which some are
PARASITIC AND SAPROPHYTIC ORGANISMS. 53
specific and others general and non-specific. The chemical changes that go on in a test tube are extremely complex, and those in the body must be equally, if not more so.
INFECTION.
There are a number of infectious diseases or lesions which never occur without the presence of micro-organisms in the tissues or in the body cavities. An infection must be defined as a morbid change pro- duced in the body by bacteria, and a disease or a lesion is infective or infectious if it be thus produced. An organism capable of manifesting its presence by infection is a pathogenetic organism. Bacteria may be roughly, but not absolutely, divided into pathogenetic and non-pa thogenetic. Every organism, even the most harmless, when injected subcutaneously in sufficiently large doses, will produce an inflammatory lesion. Again, an organism may be harmless to one species of animal and virulent to another ; harmless to one individual and virulent to another ; or in the same individual harmless under certain conditions, virulent under others. There are organisms which, when injected into an animal, in reasonable quantities, make no attempt at proliferation, but from the moment of inoculation steadily decrease in number without producing any symptoms of intoxication. Such organisms are non-pathogenetic.
Nature of infection. — The following are the known and recognised pathogenetic organisms capable of infecting man: — Bacilli of anthrax, diphtheria, glanders, tubercle, leprosy, typhoid fever, tetanus, malignant oedema ; and of Baltic fever — the pyogenetic cocci, including the pneumo- coccus and gonococcus, the vibrio of cholera, besides others whose exact position is as yet more or less ill defined. For a number of diseases which are probably infective, the bacteria have not as yet been discovered, e.g. syphilis, measles, scarlatina, variola, and certain other exanthemata.
Organisms in general, and especially the pathogenetic species, may be divided into parasitic and saprophylie organisms. The former are such as are capable of growing in living tissues ; the latter thrive in or on dead or devitalised matter. Amongst the parasites, some, under certain conditions, may do well in or on dead matter, and conversely amongst the saprophytes there are some which, under certain conditions, are capable of growth and proliferation in living tissues ; these organisms are the facultative sapro- phytes and facultative parasites respectively. Since most pathogenetic organisms grow in ordinary laboratory media, it is evident that they are mostly facultative saprophytes; but there is great diversity of opinion regarding their ability to thrive on such soils. An organism which cannot grow on dead matter is an obligatory parasite, and one which can- not grow on living tissues an obligatory saprophyte. There are but few obligatory parasites. However relative the terms saprophytic and para- sitic necessarily must be, it is of importance to adhere to them. Many organisms may grow on the different mucous membranes, or on the skin as saprophytes, i.e. they there vegetate on the secretions or dead cells, but do not penetrate into the living tissues, and for the time being are not parasitic. Thus the pneumococcus is frequently found on the buccal or tracheal mucous membrane, where it grows as a saprophyte in the saliva or mucus without producing its active toxine, or evincing any tendency to infiltrate the underlying tissues. Similarly the Strep- tococcus pyogenes is found on the tonsils and elsewhere as a harmless inhabitant, Staphylococci albi and aurei vegetate on the skin, and in the
54 GENERAL PATHOLOGY OF DISEASE.
sebaceous follicles ; and all sorts and conditions of micro-organisms lead a saprophytic and atoxic existence in the cavity of the alimentary canal. Some change occurs, either in the micro-organism itself or in its surround- ings, which" causes it to manufacture its toxine, and possibly at the same time to invade the underlying tissues. This change may be an alteration of the medium in which the organisms grow, for we know that the yeast cell, for example, can grow on gelatin without manifesting its fermentative activity; it merely vegetates; but on transferring it to a glucose solution, it at once begins to form alcohol. Again, organisms capable of secreting diastatic enzymes will often refuse to do so if albumin be present in the medium in which they grow ; they require for their diastatic activity free oxygen and carbon in the form of carbohydrates.
An organism may therefore for a long time simply vegetate harm- lessly, and then suddenly, by a process which may be compared to fermen- tation, it may produce toxine ; and the latter, on being absorbed into the lymphatic and hsemic circulation, will produce symptoms of disease, i.e. the organism becomes pathogenetic. The organism in its new character may invade the tissues and become parasitic, or it may remain sapro- phytic, and grow on the surface of the skin or mucous membranes. Saprophytic organisms may therefore be exquisitely pathogenetic if they multiply rapidly enough and manufacture toxines in sufficient quantity to produce either local changes or general intoxication. Thus it may be granted that the Bacillus coli communis and anaerobic organisms of certain kinds are normally present in the intestinal tract in limited numbers ; these may for some reason or another increase enormously in number, and while still remaining in the lumen of the intestine elaborate a large amount of toxine, this leading to grave symptoms of collapse and prostration, and to diarrhoea and enteritis. On the other hand, organisms may find their way into the intestines from without, as for instance the cholera vibrio, which may grow and multiply on the mucosa without invading it, and as a saprophyte produce a copious amount of poison, which, on being absorbed, leads to the most serious symptoms.
Streptococci which vegetate on the tonsils in a harmless form, or as atoxic saprophytes, may become exquisitely parasitic, and invade the tissues of the tonsil ; their toxines may be absorbed, and fever with other grave symptoms result ; nay, they may find their way into the lymphatics and the general circulation, and produce a general septicaemia. Pneumo- cocci, through the changes produced by cold and exposure, may change from harmless saprophytes to most virulent parasites, produce remote and secondary inflammatory foci and even septicaemia and ulcerative endo- carditis. Pathogenetic organisms, indeed, act either as saprophytes or as parasites, according as they lie on or in the tissues of the body.
It is a common error to suppose that because an organism is found inside some space, cavity, tube or duct of the human body, it lives in the tissues or in the body. In all cavities or spaces in direct communication with the outer world, the same organisms as occur in the outer world may be found. Indeed, unless there exist special preventive measures, those body cavities which are in direct communication with the outside must always contain bacteria. The mouth, the alimentary and respiratory tracts, and the pores of the skin are all in direct communication with— in fact, from a bacteriological point of view, they represent simply — the outer world, and organisms existing outside must often find their way into these body spaces. It is impossible to prevent the entrance of bacteria to the mouth, even if none but sterilised food be taken. The air con-
A CTION OF INFE CTIVE BA CTERIA. 5 5
tains organisms, both such as are capable of producing disease, and such as are harmless. The organisms which find their way into the nose, mouth, and larynx include some undoubtedly pathogenetic forms, as for instance the micro- organisms of pneumonia and suppuration ; but though they enter the body, they remain there as a rule without causing any lesions ; pathogenetic bacteria are frequently inhaled, but the diseases which they are capable of producing do not ensue. These organisms enter the body, not its tissues, and they thrive in the secretions and on the mucous membranes lining the various body cavities. The resistance of healthy tissues, and the absence of predisposing influence, prevent the pathogenetic organisms present leading anything more than a harmless vegetative existence. The bacillus of tuberculosis in rare cases has been found in the nasal mucous membrane of individuals attending upon consumptives, giving rise, however, to no harmful results, so long as it was outside the tissvies on the mucous membrane. But, on the other hand, the micrococcus of pneumonia, which lay harmlessly on the mucous membrane, after a drenching or a chill may assume a virulent character, invade the lung tissues, and in some cases even the circulation.
Action of infection. — Infection may therefore be parasitic or saprophytic, according as the disease -producing organisms live in the tissues or upon the tissues in dead or dying matter. Bacteria manu- facture their toxines wherever they grow, i.e. infection is accompanied by intoxication, and it is the latter which produces the really serious changes and symptoms. The results of intoxication may be local or remote, or both. Thus in diphtheria the local changes in and on the tonsils are accompanied by the symptoms of diffusion of the diphtheria poison over distant parts of the body. This remote intoxication again may be general or selective. Thus in hectic or suppurative fever there is a general intoxication, while in tetanus the specific toxine singles out the motor cells of the spinal cord, and in diphtheria the toxine particularly selects the peripheral nerves and their trophic centres. The infection itself may be (a) local or (&) progressive. If local, the bacteria remain at the seat of infection, where they may or may not multiply. Examples of local infections are tetanus and diphtheria. If the infection be progressive, it may spread (a) by continuity, as for instance in a spreading erysipelas, or it may spread (&) by metastasis, which again may be (1) haemic or (2) lymphatic, i.e. the organisms may be carried to distant parts by the blood stream or by the lymph channels. When organisms enter the blood stream, after the manner of-emboli, they may be deposited, and so lead to a secondary focus, or they may multiply in the blood and cause a general blood infection, i.e. a septicaemia. In many infective diseases, such as typhoid fever, small masses of bacteria may invade a blood vessel, through an ulcerated