Pharmaceutical pathology Livia Vida 2018 1. Necrosis, types, examples. Apoptosis. 2. Adaptations I. Degeneration, atrophy. 3. Adaptations II. Hypertrophy, hyperplasia. 4. Pigments. Calcification. 5. Inflammation I. Acute inflammation. 6. Inflammation II. Chronic inflammation. 7. Circulation I. Thrombosis, embolisation, heart failure, shock. 8. Circulation II. Hypertension. Atherosclerosis. 9. Circulation III. Bleeding diatheses. Oedema, congestion. 10. Immunology I. Immune deficiencies. Hypersensitive reactions. 11. Immunology II. Autoimmunity. Transplantation immunity. 12. Infectology. 13. Oncology I. Nomenclature. Caracteristics of neoplasms. 14. Oncology II. Molecular basis of cancer. Autoimmunity Autoimmune diseases are caused by an immune reaction against self-antigens. They mayinvolve a single organ or be multisystemic. How does autoimmunity develop? Failure of peripheral tolerance Release of sequestered antigens Genetic predisposition may take several forms. Infections by viruses and other microbes may cause autoimmunity because of cross-reactivity. 1
SYSTEMIC LUPUS ERYTHEMATOSUS Lupus usually manifests as arthritis, skin changes, kidney damage, inflamed serosal membranes, fever, and mental changes. Most lupus victims look healthy, but they are very sick. Lupus is mostly a disease of young women. At least one woman in 1000 in the US and worldwide has overt lupus. Lupus is a disease of many autoantibodies directed against antigens that are common to most or all cells. Most lupus patients make antibodies against their own DNA. Lupus patients make many other weird antibodies. For example, they tend to develop false-positive syphilis tests. 2
SLE Blood vessels: Lupus vasculitis typically involves the small arteries and arterioles. Type III immune complex injury is usually implicated. When acute vasculitis is bad, plasma proteins that have gelled in the walls are called "fibrinoid". If the walls are dead, "fibrinoidnecrosis" is said to be present. More chronic vasculitis leads to fibrosis and narrowing of vessels. Kidney: The glomerulus traps antigens or pre-formed immune complexes as the strainer does in a sink. Several different glomerular syndromes can result. Skin: Patients must avoid sunlight. The famous "butterfly rash" ("acute cutaneous lupus") results from sunlight on the malar area of the face. SLE Joints: Arthritis (inflammation of joint tissues) is common in lupus. It resembles rheumatoid arthritis, though it is seldom mutilating. It is probably due to typeiii immune injury. The histology is acute and chronic synovitis. Heart: The best-known and most typical change is "nonbacterial verrucous endocarditis" (verrucous means warty), also called "Libman- Sacks endocarditis". 3
SLE Blood: Patients with lupus have increased total serum gamma globulins("polyclonal gammopathy"; a lab test result). Antibodiesagainstredcells, neutrophils, and platelets can cause the corresponding cytopenias. Patients with"lupus anticoagulant tend to have bleedings and thromboses. Lungs: Only a few patients get pulmonary lesions directly attributable to lupus. 4
Rheumatoid arthritis - RA Most patients with arthritis do not know which type they have.yet joint problems are the #1 recognized cause of occupational disability. RA is a common, usually chronic, systemic, dread inflammatory disease. Its outstanding feature is progressive, symmetrical synovitis, with pain and morning stiffness, and which may lead to deformity and destruction of the joints. An acute and chronic inflammatory synovitis leads to proliferation of a vascular connective tissue in the synovium("pannus"). You won't see pus. On arthroscopy, pannus looks like a sea anemone. Pannus spreads over and erodes the articular cartilage and even bone leading to fibrosis of the joint. RA RHEUMATOID FACTOR, present in most RA patients, is polyclonal antibody against the Fc portion of IgG. When present, the patient is said to be "seropositive"; otherwise, "seronegative." Its presence means the disease is more likely to be familial, there is more likely to be vasculitis, there are more likely to be rheumatoid nodules, and there is more likely to be eye involvement. 5
RHEUMATOID NODULES occur in maybe 20% of patients with rheumatoid arthritis. These consist of an acellular center of eosinophilic material ("fibrinoid", as before a mix of plasma proteins) surrounded by palisaded histiocytes and other cells. They may occur nearly anywhere; most often about extensor surfaces, sometimes the pericardium, aortic valve (thankfully rare), lung parenchyma. fibrinoid histiocytes RA Small joints are most often affected, especially the proximal interphalangeal joints, metacarpophalangeal joints (ulnar deviation), wrists, knees, ankles. Tendons may rupture, especially those that extend the last two fingers. Whatever the cause, central to today's thinking about rheumatoid arthritis is the understanding that the irreversible destruction of the joints begins with the first symptoms, and is cumulative and progressive. Hence the emphasis on diseasemodifying medications (methotrexate, many others from various classes) early-on, rather than just antiinflammatories. 6
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TRANSPLANT REJECTION HYPERACUTE REJECTION happens when the patient gets a allograft and already has (or almost immediately makes) antibodies against it. There is a visible pattern of typeiii immune injury; typeii has also occurred. At removal of the organ, the pathologist will see a vasculitis, lots of neutrophils, complement deposition, and probably little thrombi wherever the endothelial cells got killed. ACUTE CELLULAR REJECTION, which may happen months or years after surgery, is mediated by T-cells. In the kidney (where this is best known) we look for "tubulitis" (lymphocytes in-between tubule cells), and "endotheliitis" (lymphocytes under the endothelium). ACUTE HUMORAL REJECTION, which also can begin months or years after transplantation, is caused by antibodies, with both typeii and typeiii injury. Of course the blood vessel intima take the most severe injury, and we see edema, fibroblast proliferation. We also look for C4d in the capillaries. Making the distinction from acute cellular rejection is very important, of course, because they're treated differently. CHRONIC REJECTION is still rather mysterious, and is usual in old allografts. Mostly you will see fibrosis of the organ and dense fibrous narrowing of the arterial lumens mostly by concentric proliferation of the intima. GRAFT VS. HOST DISEASE ("GVH") Whenbonemarrow(ormuchless often, some other organ containing T- cells) is transplanted into an immunedisabled patient, T-cells in the graft attack the"foreign" histo-compatibility antigens of the recipient. Acutegraftvs. hostdiseasemayoccur 20-100 days following a transplant, even if HLA antigens appear identical. It involves primarily the skin(exfoliative dermatitis), gut(diarrhea, malabsorption, bloodydiarrhea), and liver(biliaryepithelium jaundice). 8