General Pathology: Cell Injury, Inflammation, Neoplasia, Genetics and Immunopathology

Pathology is the bridge between basic science and the patient on your table. The general principles in this chapter (how cells adapt, die, inflame, heal, clot, mutate and turn malignant) explain every specific disease you will meet, from the swollen ankle after a sprain to the vertebral metastasis hiding behind a complaint of night pain.

Section 1Fundamentals of pathology: cell injury, adaptation and death

The language of pathology

Pathology studies the structural and functional changes in cells, tissues and organs that underlie disease. Four aspects describe any disease: its etiology (cause), its pathogenesis (the sequence of events from cause to lesion), its morphologic changes (gross and microscopic) and its clinical manifestations. A disease of unknown cause is idiopathic; one caused by treatment is iatrogenic. Cells live in a narrow range of normal function called homeostasis. When stress pushes them out of it, they first try to adapt; if the stress exceeds their ability to adapt, they suffer injury, which is reversible up to a point and then becomes cell death.

Cellular adaptations

Cardiac and skeletal muscle fibers are permanent cells that cannot divide, so they adapt by hypertrophy alone. Labile cells (epithelia, bone marrow) divide continuously, and stable (quiescent) cells such as hepatocytes, renal tubular cells and fibroblasts can re-enter the cell cycle when stimulated, so they can undergo hyperplasia. Metaplasia is reversible if the stimulus stops, but persistent metaplasia can progress to dysplasia and carcinoma; it reflects reprogramming of stem cells rather than conversion of mature cells. Mesenchymal metaplasia also occurs: myositis ossificans is bone forming in muscle after trauma, a lesion every sports practitioner should recognize on a radiograph of a thigh contusion that is not resolving.

Causes and mechanisms of cell injury

The causes of cell injury are hypoxia (the most common), physical agents, chemicals and drugs, infectious agents, immunologic reactions, genetic defects and nutritional imbalance. Hypoxia (low oxygen) must be distinguished from ischemia (low blood flow), which is more damaging because it also cuts off substrate delivery and lets metabolites accumulate.

The key biochemical mechanisms are: ATP depletion, which fails the Na+/K+ ATPase so sodium and water enter and the cell swells, and which shifts metabolism to anaerobic glycolysis, lowering pH and causing chromatin clumping; mitochondrial damage, which releases cytochrome c and triggers apoptosis; calcium influx, which activates phospholipases, proteases, endonucleases and ATPases; free radical (reactive oxygen species) damage through lipid peroxidation of membranes, protein oxidation and DNA breaks; and membrane damage. Free radicals arise from radiation, drug metabolism (acetaminophen through cytochrome P450), the Fenton reaction with free iron, inflammation and reperfusion after ischemia. They are neutralized by superoxide dismutase, catalase, glutathione peroxidase and antioxidants such as vitamins C and E.

Reversible versus irreversible injury

Reversible injury shows cellular swelling (hydropic change, the earliest light microscopic finding), fatty change in organs such as liver and heart, plasma membrane blebbing, loss of microvilli, mitochondrial swelling, ribosome detachment from the endoplasmic reticulum and chromatin clumping. These changes resolve if the stress is removed. Two events mark the point of no return: the inability to restore mitochondrial function and profound membrane damage, including lysosomal membranes. The nuclear signs of irreversible injury are pyknosis (shrinkage and condensation), karyorrhexis (fragmentation) and karyolysis (fading as DNase digests chromatin). Leakage of intracellular enzymes into the blood, such as troponin after myocardial necrosis, creatine kinase after muscle injury, or ALT after hepatocyte death, is the clinical evidence of irreversible membrane damage.

Necrosis

Necrosis is unregulated, pathologic cell death in which enzymatic digestion and protein denaturation destroy groups of cells, membranes rupture and contents leak out, provoking inflammation. The pattern depends on whether denaturation or digestion predominates and on the tissue.

Apoptosis

Apoptosis is programmed, ATP dependent cell death. The cell shrinks, its chromatin condenses (pyknosis) and fragments, the membrane forms blebs that bud off as apoptotic bodies, and macrophages engulf them after recognizing exposed phosphatidylserine. Membranes stay intact, so there is no inflammation. On microscopy the apoptotic cell is a small, intensely eosinophilic body with dense nuclear fragments (in viral hepatitis these are called Councilman bodies). DNA is cut between nucleosomes, producing a "ladder" on gel electrophoresis.

Two pathways converge on the executioner caspases (caspase-3 and caspase-7). The intrinsic (mitochondrial) pathway is triggered by DNA damage, growth factor withdrawal or misfolded proteins; it is controlled by the BCL-2 family. Anti-apoptotic BCL-2 and BCL-XL keep the mitochondrial membrane closed; pro-apoptotic BAX and BAK open it, releasing cytochrome c, which forms the apoptosome and activates caspase-9. p53 promotes the intrinsic pathway after DNA damage. The extrinsic (death receptor) pathway begins when Fas ligand binds Fas (CD95) or TNF binds its receptor, activating caspase-8; cytotoxic T cells also use perforin and granzyme. Apoptosis is physiologic in embryogenesis (removal of interdigital webs), hormone withdrawal (endometrial shedding) and elimination of self reactive lymphocytes, and pathologic in viral infection, radiation injury and organ atrophy from duct obstruction. Overexpression of BCL-2 by the t(14;18) translocation prevents apoptosis in follicular lymphoma.

Intracellular accumulations and pathologic calcification

Injured cells accumulate substances: lipids (hepatic steatosis from alcohol, obesity or diabetes), cholesterol (foam cells in atheroma), proteins (Russell bodies in plasma cells), glycogen (glycogen storage diseases) and pigments. Lipofuscin is the yellow brown "wear and tear" pigment of aging cells, derived from lipid peroxidation. Hemosiderin is aggregated ferritin seen after local hemorrhage (the color changes of a bruise) and in systemic iron overload.

Pathologic calcification takes two forms. Dystrophic calcification occurs in damaged or dead tissue with normal serum calcium: atheromas, damaged heart valves (calcific aortic stenosis), caseous tuberculosis, fat necrosis, and psammoma bodies (laminated calcifications in papillary thyroid carcinoma, serous ovarian tumors and meningioma). Metastatic calcification occurs in normal tissue because serum calcium or phosphate is high: hyperparathyroidism, chronic kidney disease with hyperphosphatemia, vitamin D toxicity, sarcoidosis and bone destroying tumors. It favors tissues that lose acid and become relatively alkaline, such as the lung interstitium, gastric mucosa, kidneys and systemic arteries.

Section 2Inflammation, repair and hemodynamic disorders

Acute inflammation

Inflammation is the vascularized tissue's response to injury or infection, designed to deliver leukocytes and plasma proteins to the site, destroy the agent and begin repair. The five cardinal signs are rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function). Acute inflammation develops within minutes to hours, lasts hours to a few days, and is dominated by edema and neutrophils.

The vascular events come first. After a brief arteriolar vasoconstriction, vasodilation (histamine, prostaglandins, nitric oxide) increases flow, causing redness and heat. Increased vascular permeability, chiefly endothelial contraction in postcapillary venules caused by histamine, bradykinin and leukotrienes, lets protein rich fluid leave the vessels. This exudate (specific gravity above 1.020, high protein, cells) differs from a transudate (low protein, low specific gravity), which results from altered hydrostatic or oncotic pressure with intact vessels. Fluid loss concentrates red cells and slows flow (stasis), which lets leukocytes move to the vessel wall.

The cellular events follow a fixed sequence of leukocyte recruitment.

1. Margination and rolling: endothelial selectins (E-selectin and P-selectin, the latter released from Weibel Palade bodies) bind sialyl Lewis X on leukocytes, slowing them.
2. Firm adhesion: leukocyte integrins (LFA-1, Mac-1), activated by chemokines, bind endothelial ICAM-1 and VCAM-1 induced by TNF and IL-1.
3. Transmigration (diapedesis): leukocytes squeeze between endothelial cells at junctions, guided by PECAM-1 (CD31), and cross the basement membrane.
4. Chemotaxis: movement up a gradient of C5a, leukotriene B4, IL-8 (CXCL8) and bacterial products.
5. Phagocytosis and killing: recognition of particles coated with opsonins (IgG Fc and C3b), engulfment, and killing by the respiratory burst, in which NADPH oxidase makes superoxide and myeloperoxidase converts hydrogen peroxide and chloride to hypochlorous acid.

Defects at each step produce recognizable diseases. Leukocyte adhesion deficiency type 1 (defective CD18 integrin) causes recurrent bacterial infections without pus and delayed separation of the umbilical cord. Chronic granulomatous disease (NADPH oxidase deficiency, usually X linked) leaves phagocytes unable to kill catalase positive organisms such as Staphylococcus aureus, Aspergillus, Serratia, Nocardia and Burkholderia; the nitroblue tetrazolium test is negative and the dihydrorhodamine flow test is abnormal. Chediak Higashi syndrome (LYST defect) causes giant granules, partial albinism and peripheral neuropathy.

Chemical mediators

Systemically, IL-1, IL-6 and TNF produce the acute phase response: fever (they raise PGE2 in the hypothalamus), leukocytosis with a left shift, and hepatic synthesis of C-reactive protein, fibrinogen, serum amyloid A and ferritin. The erythrocyte sedimentation rate rises because fibrinogen neutralizes red cell surface charge and promotes rouleaux. Aspirin and NSAIDs inhibit cyclooxygenase; corticosteroids inhibit phospholipase A2 (through lipocortin) and suppress cytokine genes, blocking both arms.

Outcomes of acute inflammation are resolution (complete restoration when injury is limited and tissue can regenerate), healing by fibrosis (when tissue is destroyed or nonregenerating), abscess formation, or progression to chronic inflammation.

Chronic and granulomatous inflammation

Chronic inflammation lasts weeks to years and features lymphocytes, plasma cells and macrophages, ongoing tissue destruction and attempts at repair by angiogenesis and fibrosis. It follows persistent infection (tuberculosis, syphilis, viruses), prolonged toxic exposure (silica) or autoimmunity (rheumatoid arthritis). Macrophages, derived from blood monocytes, are the central cell; T cells activate them with interferon gamma (classically activated, M1, microbicidal), while IL-4 and IL-13 produce alternatively activated (M2) macrophages that promote repair and fibrosis.

A granuloma is a focal collection of epithelioid macrophages (activated macrophages with pink cytoplasm), often with multinucleated giant cells (Langhans type with peripheral nuclei, or foreign body type with scattered nuclei), surrounded by lymphocytes. Th1 cells drive granuloma formation through interferon gamma, and macrophages maintain it with TNF, which is why anti-TNF drugs can reactivate latent tuberculosis. Caseating granulomas suggest tuberculosis or fungi; noncaseating granulomas suggest sarcoidosis, Crohn disease, cat scratch disease, berylliosis or a foreign body.

Repair and healing

Repair restores tissue by regeneration of the original cells (possible in labile and stable tissues with an intact framework) or by scar formation (permanent cells or destroyed framework). Scar formation proceeds through granulation tissue (new capillaries from VEGF driven angiogenesis, proliferating fibroblasts and loose matrix, appearing pink and granular at 3 to 5 days), followed by deposition of type III collagen, which is gradually replaced by stronger type I collagen as the scar remodels under metalloproteinases (zinc dependent). Myofibroblasts contract the wound. TGF-beta is the key fibrogenic growth factor; PDGF and FGF stimulate fibroblasts and vessels.

Healing by first intention occurs in a clean surgical incision with apposed edges and little tissue loss. Healing by second intention occurs in large open wounds with more inflammation, abundant granulation tissue and marked wound contraction. Wound strength reaches about 10 percent of normal at one week (when sutures are removed) and plateaus at only 70 to 80 percent of normal by about three months. Healing is impaired by infection (the most important factor), diabetes, poor perfusion, malnutrition (protein, vitamin C, zinc, copper), glucocorticoids, mechanical stress and foreign bodies. Excess collagen produces a hypertrophic scar (confined to the wound) or a keloid (extending beyond it, type III collagen rich, more common in people of African descent).

Edema, hyperemia and hemorrhage

Edema is excess fluid in the interstitium. Starling forces explain it: increased capillary hydrostatic pressure (heart failure, venous obstruction, deep vein thrombosis), decreased plasma oncotic pressure (nephrotic syndrome, cirrhosis, malnutrition, protein losing enteropathy), lymphatic obstruction (tumor, surgical node dissection, radiation, filariasis; causing nonpitting lymphedema), sodium retention (renal failure, hyperaldosteronism) and increased permeability (inflammation). Noninflammatory edema is a transudate. Hyperemia is active arteriolar dilation (exercise, inflammation, red), while congestion is passive venous engorgement (blue red, cyanotic); chronic passive congestion of the liver produces the "nutmeg liver" of right heart failure, and of the lung produces hemosiderin laden "heart failure cells."

Thrombosis

A thrombus is a blood clot formed within an intact vessel in a living person. Virchow triad lists its three predisposing factors: endothelial injury (the dominant factor in arterial and cardiac thrombi: atherosclerosis, hypertension, vasculitis, smoking), abnormal blood flow (stasis in veins and aneurysms, turbulence at bifurcations and in atrial fibrillation) and hypercoagulability. Inherited hypercoagulable states include factor V Leiden (the most common, resistance to activated protein C), prothrombin G20210A, and deficiencies of antithrombin, protein C and protein S. Acquired states include immobilization, surgery, malignancy (Trousseau migratory thrombophlebitis), pregnancy, oral contraceptives and estrogen, antiphospholipid syndrome, heparin induced thrombocytopenia, smoking and obesity.

Thrombi formed in flowing blood show lines of Zahn, alternating pale layers of platelets and fibrin and dark layers of red cells, which distinguish them from a postmortem clot (gelatinous, "chicken fat" and "currant jelly" layers, not attached). Arterial thrombi are platelet rich (white); venous thrombi are red cell rich (red). Possible fates are propagation, embolization, dissolution by fibrinolysis, and organization with recanalization.

Embolism, infarction and shock

An embolus is a detached mass carried by blood to a distant site. About 99 percent of emboli are thromboemboli. Most pulmonary emboli arise from deep veins of the leg above the knee (popliteal, femoral, iliac). A large saddle embolus at the pulmonary artery bifurcation causes sudden death or acute right heart failure; smaller ones cause infarction (more likely when bronchial circulation is already compromised) or no symptoms. Systemic (arterial) emboli arise mostly from the heart (mural thrombi after myocardial infarction, left atrial thrombi in atrial fibrillation) and lodge in the lower limbs, brain, intestines, kidneys and spleen. Paradoxical emboli cross from venous to arterial circulation through a patent foramen ovale. Other emboli include fat emboli (long bone fractures, typically 1 to 3 days later, with hypoxemia, neurologic symptoms and a petechial rash), air emboli (decompression sickness, the "bends" and caisson disease with avascular necrosis of the femoral head), amniotic fluid emboli (DIC) and septic or tumor emboli.

An infarct is an area of ischemic necrosis. White (anemic) infarcts occur in solid organs with an end arterial supply (heart, kidney, spleen) and are typically wedge shaped with the apex at the occluded vessel. Red (hemorrhagic) infarcts occur in tissues with a dual blood supply (lung, liver), loose tissue, venous occlusion (testicular or ovarian torsion) or reperfusion. Neurons undergo irreversible injury after only 3 to 5 minutes of ischemia, myocardium after 20 to 40 minutes, and skeletal muscle and fibroblasts tolerate hours.

Shock is systemic hypoperfusion from low cardiac output or low effective blood volume, causing cell hypoxia. The types are hypovolemic (hemorrhage, burns, vomiting), cardiogenic (infarction, arrhythmia, tamponade, massive pulmonary embolism), distributive (septic, anaphylactic, neurogenic) and obstructive. Hypovolemic and cardiogenic shock produce cold clammy skin with high peripheral resistance; septic shock initially produces warm flushed skin with low resistance and high output. Neurogenic shock after a cervical or high thoracic spinal cord injury causes hypotension with bradycardia from loss of sympathetic tone. Shock progresses from a nonprogressive stage (compensated by baroreflexes, catecholamines and renin angiotensin) to a progressive stage (lactic acidosis) to an irreversible stage with multiorgan failure (acute tubular necrosis, ARDS, ischemic bowel).

Section 3Neoplasia

Definitions and nomenclature

A neoplasm ("new growth") is an abnormal mass of tissue whose growth is autonomous, exceeds that of normal tissue and persists after the stimulus stops. Neoplasms are clonal: all cells descend from a single transformed cell. A tumor originally meant any swelling but is now used for neoplasm; cancer means a malignant neoplasm. Every tumor has two components: the neoplastic parenchyma, which determines its name and behavior, and the supporting stroma (connective tissue and vessels). An abundant collagenous stroma makes a tumor stony hard, called desmoplasia, as in scirrhous breast carcinoma.

Malignant tumors of epithelium are carcinomas; malignant tumors of mesenchyme are sarcomas. The misnomers are tested: lymphoma, melanoma, mesothelioma and seminoma are malignant despite the "-oma" ending. A hamartoma is a disorganized mass of tissue native to the site (pulmonary hamartoma), while a choristoma is normal tissue in an abnormal place (heterotopic pancreas in the stomach wall). Neither is a true neoplasm in the classic sense.

Benign versus malignant

Carcinoma in situ is full thickness dysplasia that has not crossed the basement membrane, so it cannot yet metastasize. Once tumor cells breach the basement membrane, the lesion is invasive.

Carcinogenesis

Cancer is a genetic disease caused by accumulated, nonlethal mutations, either inherited in the germline or acquired in somatic cells. It is multistep: the colon adenoma to carcinoma sequence classically adds APC loss, then KRAS activation, then p53 loss. The hallmarks of cancer include self sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential (telomerase), sustained angiogenesis (VEGF), invasion and metastasis, reprogrammed metabolism (aerobic glycolysis, the Warburg effect), evasion of immune destruction, genomic instability and tumor promoting inflammation.

Four classes of normal genes are the targets. Proto-oncogenes promote growth; a gain of function mutation in one allele converts them to oncogenes (dominant at the cellular level). Tumor suppressor genes restrain growth; both alleles must be lost (Knudson two hit hypothesis). In familial cancers the first hit is inherited, which explains earlier, bilateral and multifocal tumors. Genes regulating apoptosis and genes involved in DNA repair make up the other two classes; loss of DNA repair causes a "mutator phenotype."

Carcinogens fall into three groups. Chemical carcinogens act as initiators (mutagens) and promoters (which stimulate proliferation of initiated cells). Many require metabolic activation by cytochrome P450 (procarcinogens). Classic associations: aflatoxin (Aspergillus on grains and peanuts) and hepatocellular carcinoma; asbestos and mesothelioma and bronchogenic carcinoma; vinyl chloride and hepatic angiosarcoma; benzene and leukemia; aromatic amines and aniline dyes and bladder cancer; tobacco smoke (polycyclic hydrocarbons, nitrosamines) and cancers of lung, oral cavity, larynx, esophagus, pancreas, kidney and bladder; nitrosamines in smoked foods and gastric cancer; alkylating chemotherapy and leukemia. Radiation: ultraviolet B produces pyrimidine (thymine) dimers, causing basal cell and squamous cell carcinoma and melanoma, with extreme risk in xeroderma pigmentosum (defective nucleotide excision repair); ionizing radiation causes leukemia, thyroid carcinoma and sarcomas. Oncogenic microbes: HPV 16 and 18 (cervical, anal and oropharyngeal carcinoma; E6 inactivates p53, E7 inactivates RB), Epstein Barr virus (Burkitt and Hodgkin lymphoma, nasopharyngeal carcinoma), hepatitis B and C (hepatocellular carcinoma), HHV-8 (Kaposi sarcoma), HTLV-1 (adult T cell leukemia) and Helicobacter pylori (gastric adenocarcinoma and MALT lymphoma).

Invasion and metastasis

To metastasize, a carcinoma cell must loosen its attachments (loss of E-cadherin), attach to the basement membrane through laminin receptors, degrade it with matrix metalloproteinases (type IV collagenase), migrate, enter vessels, survive in the circulation, then exit and grow at a distant site. The three routes of spread are lymphatic (typical of carcinomas, first to regional nodes; the sentinel node concept), hematogenous (typical of sarcomas, and of some carcinomas such as renal cell, hepatocellular, follicular thyroid and choriocarcinoma) and seeding of body cavities (ovarian carcinoma on the peritoneum; a gastric signet ring carcinoma seeding the ovaries, the Krukenberg tumor). Venous blood carries most tumors first to the liver (portal drainage) or the lungs (caval drainage), which are the two most common sites of metastasis overall.

Tumors that metastasize to bone

Metastases are by far the most common malignant tumors of bone in adults, far outnumbering primary bone tumors. They favor red marrow sites: the vertebral bodies (the most common site, thoracic and lumbar especially), pelvis, ribs, skull and proximal femur and humerus. The valveless Batson vertebral venous plexus connects pelvic and thoracic veins directly to the spine, so a rise in intra-abdominal pressure can carry prostate or breast tumor cells straight to the vertebrae, bypassing the lungs. Metastases destroy the pedicle early, producing the "winking owl" sign on an AP lumbar radiograph, and generally spare the intervertebral disc (unlike infection, which crosses it).

Grading, staging and tumor markers

Grade describes how differentiated the tumor looks under the microscope (well, moderately or poorly differentiated, or a numeric grade I to IV) and how many mitoses it shows. Stage describes the anatomic extent of spread and is the more important predictor of prognosis. The TNM system scores the primary Tumor size and local invasion, regional lymph Node involvement and distant Metastasis. Tumor markers help monitor disease but are rarely diagnostic on their own: PSA (prostate), CEA (colorectal and others), alpha-fetoprotein (hepatocellular carcinoma, yolk sac tumors), hCG (choriocarcinoma, germ cell tumors), CA-125 (ovarian), CA 19-9 (pancreatic) and alkaline phosphatase (bone metastases, osteosarcoma).

Tumors also produce systemic effects. Cachexia results from TNF and other cytokines. Paraneoplastic syndromes include hypercalcemia from PTH related peptide (squamous cell carcinoma of the lung, renal and breast cancer), Cushing syndrome from ectopic ACTH and SIADH (small cell lung carcinoma), Lambert Eaton myasthenic syndrome (small cell carcinoma), polycythemia from erythropoietin (renal cell carcinoma, hemangioblastoma), and Trousseau migratory thrombophlebitis (pancreatic adenocarcinoma).

Section 4Genetic and congenital disorders

Mendelian inheritance

Single gene (Mendelian) disorders follow predictable patterns. Autosomal dominant disorders appear in every generation, affect both sexes equally, can pass from father to son, and give each child of an affected heterozygote a 50 percent risk. They usually involve structural proteins or receptors, often present in adulthood, and show variable expressivity (different severity among affected people) and incomplete penetrance (some carriers show no disease). Autosomal recessive disorders typically skip generations, affect both sexes, arise when two carrier parents each pass a mutant allele (a 25 percent risk per child, with two thirds of unaffected siblings being carriers), are more common with consanguinity, usually involve enzymes and present early in life. X linked recessive disorders affect mostly males, pass from carrier mothers to half their sons, and are never transmitted father to son; all daughters of an affected male are carriers. X linked dominant disorders (hypophosphatemic rickets, Rett syndrome) pass from an affected father to all daughters and no sons. Mitochondrial disorders pass only from the mother to all her children, with variable severity because of heteroplasmy (Leber hereditary optic neuropathy, MELAS, myoclonic epilepsy with ragged red fibers).

Several genetic phenomena are tested by name. Anticipation is earlier onset or greater severity in successive generations, from expanding trinucleotide repeats. Genomic imprinting means a gene's expression depends on the parent of origin: a deletion of chromosome 15q11 to q13 causes Prader Willi syndrome when the paternal copy is lost (hypotonia, hyperphagia, obesity) and Angelman syndrome when the maternal copy is lost (seizures, ataxia, inappropriate laughter). Pleiotropy is one gene affecting many organ systems, as in Marfan syndrome. Duchenne muscular dystrophy (frameshift deletion, absent dystrophin) begins in early childhood with proximal weakness, Gowers sign (climbing up the legs to stand), calf pseudohypertrophy (fat and fibrous replacement) and very high creatine kinase; Becker dystrophy (in frame mutation, reduced dystrophin) is milder and later.

Chromosomal disorders

Chromosomal abnormalities are numerical (aneuploidy, usually from meiotic nondisjunction, which rises with maternal age) or structural (deletions, translocations, inversions, isochromosomes). A Robertsonian translocation fuses the long arms of two acrocentric chromosomes and can cause familial Down syndrome.

Connective tissue disorders

Marfan syndrome is autosomal dominant, caused by mutations of fibrillin-1 (FBN1) on chromosome 15. Fibrillin forms microfibrils that scaffold elastic fibers and sequester TGF-beta; its loss weakens elastic tissue and raises TGF-beta signaling. Features include tall stature with long limbs (arm span greater than height, arachnodactyly, positive thumb and wrist signs), joint hypermobility, pectus excavatum or carinatum, scoliosis, upward and outward ectopia lentis, mitral valve prolapse, and the life threatening cystic medial degeneration of the aorta, leading to aortic root dilation, aortic regurgitation and dissection. Dural ectasia is common on lumbar imaging.

Ehlers Danlos syndromes are a group of collagen synthesis or structure defects. The common hypermobile type (genetic basis not yet defined, autosomal dominant) and classic type (type V collagen) produce joint hypermobility with frequent dislocations, hyperextensible skin, easy bruising and poor wound healing with thin "cigarette paper" scars. The vascular type (type III collagen, COL3A1) is the most dangerous, with rupture of arteries, bowel and uterus. The kyphoscoliotic type is an autosomal recessive defect of lysyl hydroxylase.

Osteogenesis imperfecta is a type I collagen defect (usually autosomal dominant) causing multiple fractures with minimal trauma, blue sclerae, hearing loss (otosclerosis) and dental imperfections; it must be distinguished from child abuse. Achondroplasia results from activating FGFR3 mutations that inhibit chondrocyte proliferation in growth plates, producing rhizomelic short limbs with a normal size trunk, a large head and lumbar spinal stenosis from short pedicles.

Congenital malformations and teratogens

Congenital anomalies are structural defects present at birth. A malformation is an intrinsic error of morphogenesis (cleft lip, congenital heart disease, neural tube defects); a disruption is secondary destruction of a normal structure (amniotic bands); a deformation results from extrinsic mechanical forces such as uterine constraint (clubfoot, congenital hip dysplasia); a sequence is a cascade from one initial anomaly (Potter sequence from oligohydramnios); an agenesis is complete absence of an organ. Causes are genetic, environmental and, most often, multifactorial or unknown.

The embryonic period (weeks 3 to 8 of gestation) is the time of organogenesis and maximal susceptibility to teratogens. Exposure in the first two weeks typically produces an all or none effect (death or normal development); after week 8, during the fetal period, effects are mainly growth retardation and functional damage.

Neural tube defects result from failure of neural tube closure in the fourth week. Anencephaly is failure of the cranial end; spina bifida of the caudal end, ranging from spina bifida occulta (vertebral arch defect, often a tuft of hair or dimple over L5 or S1, usually harmless and frequently seen on lumbar films) to meningocele (meninges protrude) and myelomeningocele (meninges and cord protrude, with paralysis, neurogenic bladder and an association with Arnold Chiari II malformation and hydrocephalus). Maternal serum and amniotic fluid alpha-fetoprotein are elevated in open defects, and periconceptional folic acid lowers the risk substantially.

Section 5Immune, environmental and nutritional disorders

Hypersensitivity reactions

Hypersensitivity is an immune response that injures the host. The Gell and Coombs classification divides it into four types by mechanism; the first three are antibody mediated and the fourth is cell mediated. The mnemonic ACID (Anaphylactic and Atopic, Cytotoxic, Immune complex, Delayed) gives the order.

Autoimmunity and immunodeficiency

Autoimmune disease results from failure of self tolerance, through genetic susceptibility (notably HLA alleles) combined with environmental triggers such as infection (molecular mimicry, as in rheumatic fever). Most are more common in women. Associations worth knowing: HLA-B27 with the seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic and enteropathic arthritis); HLA-DR4 with rheumatoid arthritis; DR3 and DR4 with type 1 diabetes; DR2 with multiple sclerosis and SLE. Key autoantibodies: ANA (sensitive screen for SLE), anti-dsDNA and anti-Smith (specific for SLE), anti-histone (drug induced lupus from hydralazine, procainamide, isoniazid), rheumatoid factor and anti-CCP (rheumatoid arthritis, anti-CCP more specific), anti-centromere (limited scleroderma, CREST), anti-Scl-70 (diffuse scleroderma), anti-Ro and anti-La (Sjogren syndrome, neonatal heart block), anti-Jo-1 (polymyositis), and c-ANCA (granulomatosis with polyangiitis).

Immunodeficiencies are primary (genetic) or secondary (acquired: HIV, malnutrition, chemotherapy, steroids, diabetes, splenectomy). The type of infection points to the defect: B cell defects cause recurrent pyogenic bacterial infections (encapsulated organisms) after maternal antibody wanes at about 6 months; T cell defects cause viral, fungal and opportunistic infections; phagocyte defects cause Staphylococcus and fungal infections; and complement defects cause recurrent Neisseria infections (C5 to C9) or angioedema (C1 esterase inhibitor). Examples: X linked (Bruton) agammaglobulinemia (BTK defect, absent B cells, males), selective IgA deficiency (the most common primary immunodeficiency, sinopulmonary infections, anaphylaxis to blood products), common variable immunodeficiency, DiGeorge syndrome (absent thymus), severe combined immunodeficiency (adenosine deaminase deficiency or IL-2 receptor gamma chain defects, "bubble boy"), Wiskott Aldrich syndrome (thrombocytopenia, eczema, infections) and ataxia telangiectasia. HIV infects CD4 T cells through CD4 and the CCR5 or CXCR4 coreceptor; AIDS is defined by a CD4 count below 200 cells per microliter or an AIDS defining illness such as Pneumocystis pneumonia or Kaposi sarcoma.

Amyloidosis

Amyloid is misfolded protein deposited extracellularly in a beta pleated sheet configuration. It stains with Congo red and shows apple green birefringence under polarized light. AL amyloid (primary) comes from immunoglobulin light chains in plasma cell disorders such as multiple myeloma. AA amyloid (secondary) comes from serum amyloid A in chronic inflammation: rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic osteomyelitis, tuberculosis and familial Mediterranean fever. Other forms: beta-2 microglobulin amyloid in long term dialysis (carpal tunnel syndrome, arthropathy), transthyretin amyloid (senile cardiac and familial neuropathy), A-beta in Alzheimer disease, and amylin in type 2 diabetic islets. Systemic amyloid damages the kidney (nephrotic syndrome, the most common serious involvement), heart (restrictive cardiomyopathy), liver, spleen, tongue (macroglossia) and nerves; abdominal fat pad or rectal biopsy confirms it.

Environmental injury, smoking and alcohol

Tobacco smoking is the leading preventable cause of death. It causes lung cancer (squamous cell and small cell carcinoma especially), cancers of the oral cavity, larynx, esophagus, pancreas, kidney, bladder and cervix, chronic obstructive pulmonary disease (centriacinar emphysema), atherosclerosis and myocardial infarction, peripheral vascular disease, thromboangiitis obliterans (Buerger disease) and peptic ulcer, and in pregnancy, low birth weight. It also impairs bone and disc healing and is a risk factor for disc degeneration and failed spinal fusion. Alcohol is metabolized by alcohol dehydrogenase and MEOS (CYP2E1) to acetaldehyde and then acetate, raising the NADH/NAD+ ratio. It causes hepatic steatosis, alcoholic hepatitis (Mallory bodies) and cirrhosis; acute and chronic pancreatitis; gastritis; cardiomyopathy; Wernicke Korsakoff syndrome; peripheral neuropathy; cerebellar degeneration; cancers of the upper aerodigestive tract, liver and breast; and fetal alcohol syndrome.

Other important exposures include carbon monoxide (binds hemoglobin with over 200 times the affinity of oxygen, cherry red skin, headache, lesions of the globus pallidus), lead (microcytic anemia with basophilic stippling, lead lines in gums and metaphyses, wrist and foot drop, encephalopathy in children; inhibits ALA dehydratase and ferrochelatase), mercury, arsenic, and the pneumoconioses: coal workers' disease, silicosis (upper lobe nodules, eggshell calcification of hilar nodes, raised tuberculosis risk) and asbestosis (lower lobe fibrosis, pleural plaques, mesothelioma and bronchogenic carcinoma; smoking multiplies the cancer risk). Ionizing radiation injures rapidly dividing cells first (bone marrow, gut, gonads), causes vascular fibrosis and later cancers.

Nutritional deficiencies and obesity

Protein energy malnutrition takes two forms. Marasmus is total calorie deficiency: severe muscle and fat wasting, an "old man" face, serum albumin near normal, no edema. Kwashiorkor is protein deficiency with relatively adequate calories: edema from low albumin, a distended abdomen from fatty liver, skin lesions ("flaky paint"), depigmented hair and apathy. Secondary malnutrition occurs in chronic illness, cancer cachexia, anorexia nervosa, malabsorption and alcoholism. The vitamin deficiencies covered in Chapter 11 (rickets and osteomalacia, scurvy, beriberi, pellagra, megaloblastic anemia) are high yield pathology as well.

Obesity is a body mass index (BMI, weight in kilograms divided by height in meters squared) of 30 or more; 25 to 29.9 is overweight. Leptin from adipose tissue signals satiety to the hypothalamus, and obese people usually have high leptin with leptin resistance; ghrelin from the stomach stimulates appetite; adiponectin falls with obesity and its loss contributes to insulin resistance. Central (visceral) obesity drives the metabolic syndrome (abdominal obesity, high triglycerides, low HDL, hypertension and high fasting glucose) and raises the risk of type 2 diabetes, hypertension, atherosclerosis, nonalcoholic fatty liver disease, gallstones, obstructive sleep apnea, osteoarthritis of weight bearing joints, and cancers of the endometrium, breast, colon, kidney and esophagus (adenocarcinoma).

Words worth knowing