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USMLE ® STEP 1 Pathology Lecture Notes USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of. Usmle Step 1 ?????????????? Step 1? - za, 30 mrt GMT Wall | VK (PDF) First Aid for the USMLE Step 1 | Mohd Sajid First Aid. PDF Drive is your search engine for PDF files. _(USMLE_Prep)_(7_Book_Set )_().pdf USMLE Step 1 Lecture Notes USMLE Step. Page 1 USMLE Step 2 CK Lecture Notes Psychiatry and Epidemiology & Ethics Page 2 USMLE.
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Best of luck on your Step 1 exam! Fundamentals of Pathology. Cellular Injury and Adaptation. Tissue Repair. Circulatory Pathology. Genetic Disorders. Principles of Neoplasia. Skin Pathology. Red Blood Cell Pathology: Vascular Pathology. Cardiac Pathology.
Respiratory Pathology. Renal Pathology. Gastrointestinal Tract Pathology. Pancreatic Pathology. Gallbladder and Biliary Tract Pathology. Liver Pathology. Central Nervous System Pathology. Female Genital Pathology. Breast Pathology. Male Pathology. Endocrine Pathology. Bone Pathology. Joint Pathology. Skeletal Muscle and Peripheral Nerve Pathology. The pathogen- esis of a disease defines the temporal sequence and the patterns of cellular injury that lead to disease.
Morphologic changes of the disease process include both gross changes and microscopic changes. The clinical significance of a disease relates to its signs and symptoms, disease course including complications, and prognosis.
Methods Used Gross examination of organs on exam questions has 2 major components: Useful gross features include consid- eration of size, shape, consistency, and color.
Prussian blue stains iron , Congo red stains amyloid , acid fast Ziehl-Neelsen, Fite stains acid-fast bacilli , periodic acid-Schiff PAS, stains high carbohydrate content mol- ecules , Gram stain stains bacteria , trichrome stains cells and connective tissue , and reticulin stains collagen type III molecules. Miyai, M. Used with permission. Figure Ancillary techniques include immunofluorescence microscopy IFM , typically used for renal and autoimmune disease, and transmission electron microscopy EM , used for renal disease, neoplasms, infections, and genetic disorders.
Molecular techniques include protein electrophoresis, Southern and Western blots, polymerase chain reaction PCR , and cytogenetic analysis karyotyping, in situ hybridization studies. Major mechanisms leading to hypoxia are ischemia, cardiopulmonary failure, and decreased oxygen- carrying capacity of the blood e.
Ischemia, due to a loss of blood supply, is the most common cause of hypoxia, and is typically related to decreased arterial flow or decreased venous outflow e. Pathogens viruses, bacteria, parasites, fungi, and prions can injure the body by direct infection of cells, production of toxins, or host inflammatory response. Immunologic dysfunction includes hypersensitivity reactions and autoimmune dis- eases. Congenital disorders are inherited genetic mutations e. Chemical injury can occur with drugs, poisons cyanide, arsenic, mercury, etc.
Angela Byrne, Radiopaedia. Homeostatic cell Metabolic changes Ischemia Toxins, etc. The critical intracellular targets that are susceptible to injury are DNA, produc- Note tion of ATP via aerobic respiration, cell membranes, and protein synthesis. Protective Factors against free radicals include: Important mechanisms of cell injury are as follows: Several key biochemical pathways are dependent on ATP.
Additionally, ATP depletion increases anaerobic glycolysis that leads to water a decrease in cellular pH. Cell Injury Note Reversible cell injury: Clinically important examples: Irreversible cell injury: It is caused by the denaturing of proteins within the called suppuration, and the resultant fluid is called pus.
Microscopic examination shows loss of the nucleus but preservation of cellular shape. Coagulative necrosis is common in most organs, including the heart, liver, and kidney, but not the brain.
Liquefaction The triglycerides are broken down by the necrosis occurs in abscesses, brain infarcts, and pancreatic necrosis. The acids may associate with calcium and form calcium soaps saponification. On gross examination fat necrosis has a chalky white Necrotic tissue within the body evokes an inflammatory response that removes the appearance. Necrotic debris may also resembles fibrin. On microscopic examination fibrinoid necrosis has an eosin- undergo dystrophic calcification.
It is often due to acute immunologic injury e. Common sites of involvement include lower limbs, gallbladder, GI tract, and testes. Dry gangrene has coagulative necrosis for the microscopic pattern, while wet gan- grene has liquefactive necrosis. Usatine, M. Next, nuclear chromatin condensation pyknosis is seen known as syndactyly.
Phagocytosis of apoptotic bodies is by adjacent menstruation; programmed cell death plays a role in endometrial gland cells or macrophages. The protein bcl-2 which inhibits apopto- sis prevents release of cytochrome c from mitochondria and binds pro-apop- totic protease activating factor Apaf The protein p53 which stimulates apoptosis is elevated by DNA injury and arrests the cell cycle.
If DNA repair is impossible, p53 stimulates apoptosis. The caspases digest nuclear and cytoskeletal proteins and also Graft-versus-host disease GVHD is activate endonucleases. The transplanted selective death of lymphocytes. Organs typically involved cilman body] , graft-versus-host disease, and cystic fibrosis duct obstruction include the skin, mucosa, liver, and GI and pancreatic atrophy. The histologic hallmark of GVHD is apoptosis. Serum enzyme markers of cell damage include aspartate aminotransferase AST liver injury , alanine aminotransferase ALT liver injury , creatine kinase CK- MB heart injury , and amylase and lipase pancreatic injury; amylase also rises with salivary gland injury.
Light microscopic examination shows small shrunken cells with lipofuscin granules. Electron microscopy shows decreased intracellular components and autophagosomes. Causes of hypertrophy include: Hypertrophy is mediated by growth factors, cytokines, and other trophic stimuli and leads to increased expression of genes and increased protein synthesis. Hypertrophy and hyperplasia often occur together.
Clinical Correlate Hyperplasia is an increase in the number of cells in a tissue or organ. Some cell Residence at high altitude, where oxygen types are unable to exhibit hyperplasia e. Hyperplasia is mediated by growth factors, cytokines, and other trophic stimuli; increased expression of growth-promoting genes proto-oncogenes ; and increased DNA synthesis and cell division.
It has been suggested that the replacement cell is of metaplasia. The esophageal epithelium better able to tolerate the environmental stresses. For example, bronchial epithelium is normally squamous, but it undergoes a undergoes squamous metaplasia in response to the chronic irritation of tobacco change to intestinal epithelium columnar smoke. The proposed mechanism is that the reserve cells or stem cells of the irritated tissue differentiate into a more protective cell type due to the influence of growth factors, cytokines, and matrix components.
It is due to indigestible material within lysosomes and is common in the liver and heart. Systemic iron overload can lead to hemosiderosis increase in total body iron stores without tissue injury or hemochromatosis increase in total body iron stores with tissue injury. Prussian blue stain can identify the iron in the hemosiderin.
The many causes include hyperparathyroidism, parathyroid adenomas, renal failure, paraneo- plastic syndrome, vitamin D intoxication, milk-alkali syndrome, sarcoidosis, Paget disease, multiple myeloma, metastatic cancer to the bone.
The calcifica- tions are located in the interstitial tissues of the stomach, kidneys, lungs, and blood vessels. The response can range from adaptation to reversible injury to irreversible injury with cell death. Irreversible cell injury often additionally involves severe damage to membranes, mitochondria, lysosomes, and nucleus. Other cellular alterations secondary to injury include pathologic accumulations lipids, proteins, pigments , hyaline change, and pathologic calcification. The important components of acute inflammation are hemodynamic changes, neu- trophils, and chemical mediators.
Neutrophil margination and adhesion. Adhesion is mediated by complementary molecules on the surface of neutrophils and endothelium. Table Adhesion and Migration Modulation of adhesion molecules in inflammation occurs as follows. Defects in adhesion can be seen in diabetes mellitus, corticosteroid use, acute alcohol intoxication, and leukocyte adhesion deficiency autosomal recessive condition with recurrent bacterial infections.
In emigration diapedesis , leukocytes emigrate from the vasculature postcapil- lary venule by extending pseudopods between the endothelial cells. They then move between the endothelial cells, migrating through the basement membrane toward the inflammatory stimulus. Chemotaxis is the attraction of cells toward a chemical mediator that is released in the area of inflammation.
Opsonins coat microbes to enhance their detec- tion and phagocytosis. Important opsonins include the Fc portion of IgG isotypes, complement system product C3b, and plasma proteins such as collectins which bind to bacterial cell walls. Engulfment occurs when the neutrophil sends out cytoplasmic processes that sur- round the bacteria. The bacteria are then internalized within a phagosome.
The phagosome fuses with lysosomes degranulation. The neutrophils have giant granules lysosomes and there is a defect in chemotaxis and degranulation. Intracellular killing. In oxygen-dependent killing, respiratory burst requires oxygen and NADPH oxidase and produces superoxide, hydroxyl radicals, and hydrogen peroxide.
Myeloperoxidase requires hydrogen peroxide and halide Cl— and produces HOCl hypochlorous acid. Oxygen-Dependent Killing Oxygen-independent killing involves lysozyme, lactoferrin, acid hydrolases, bac- tericidal permeability increasing protein BPI , and defensins. Incubate in the Deficiencies of oxygen-dependent killing include: It is characterized by a deficiency of NADPH oxidase, lack of super- oxide and hydrogen peroxide, and recurrent bacterial infections with catalase- positive organisms S.
The nitroblue tetrazolium test will be negative. In contrast to chronic granulomatous disease, the Normal Abnormal nitroblue tetrazolium test will be positive. It causes vaso- dilation and increased vascular permeability.
Triggers for release include IgE- mediated mast cell reactions, physical injury, anaphylatoxins C3a and C5a , and cytokines IL Lipoxins are antiinflammatory products which inhibit neutrophil chemotaxis. In a Nutshell Important products in the complement cascade include C5b-C9 membrane attack Mediators of Fever complex , C3a,C5a anaphylatoxins stimulate the release of histamine , C5a leuko- cyte chemotactic factor , and C3b opsonin for phagocytosis.
Tissue-based macrophages life span in connective tissue compartment is 60— days are found in connec- tive tissue histiocyte , lung pulmonary alveolar macrophages , liver Kupffer cells , bone osteoclasts , and brain microglia.
During inflammation circu- lating monocytes emigrate from the blood to the periphery and differentiate into macrophages.
The eosinophilic chemokine is eotaxin. Eosinophil granules contain major basic protein, which is toxic to parasites. Mast cells are present in high numbers in the lung and skin. Both basophils and mast cells play an important role in IgE-mediated reactions allergies and anaphylaxis and can release histamine.
Composition of a granuloma is as follows: They are enlarged cells with abundant pink cytoplasm. The PPD checks for latent thelioid cells. Types include Langhans-type giant cell peripheral arrangement tuberculosis infection, which can be of nuclei and foreign body type giant cell haphazard arrangement of nuclei.
Because of the public health risk of tuberculosis, necrotizing granulomas should be considered tuberculosis until proven otherwise. Infectious agents tend to have tropism for specific tissues and organs. There are 6 major histologic patterns: Examples include bacterial meningitis, bronchopneumonia, and abscess. Examples include necrotizing fasciitis and necrotizing pharyngitis. Granulomatous response predominates with slow-growing organisms such as mycobacteria, fungi, and parasites.
Examples include myocarditis Coxsackie virus and viral hepatitis. An inflammatory response to microbes cannot occur in severely immunosuppressed individuals due to primary immunodeficiencies or acquired immunodeficient states e. Neutrophils leave the bloodstream in a highly regulated process involving margination moving toward the vessel wall , adhesion binding to the endothelium , and emigration moving between endothelial cells to leave the postcapillary venule.
Defects in adhesion can contribute to the immunosuppression seen in diabetes mellitus and corticosteroid use. Chediak-Higashi syndrome is an example of a genetic disease with defective neutrophil degranulation.
Chronic granulomatous disease of childhood and myeloperoxidase deficiency are genetic immunodeficiencies related to defects in of oxygen-dependent killing.
A wide variety of diseases can cause chronic granulomatous inflammation, most notably TB, syphilis, leprosy, and fungal infections. Tissue repair involves 5 overlapping processes: There are 3 ECM components: Examples include surface epithelial cells skin and mucosal lining cells , hematopoietic cells, stem cells, etc.
Examples include hepatocytes, proximal tubule cells, endothelium, etc. Examples include neurons and cardiac muscle. Scar formation occurs in a series of steps when repair cannot be effected by regen- eration. Cytokines IL-1 and IL stimulate collagen production. Types of Wound Healing Primary union healing by first intention occurs when wounds are closed physi- cally with sutures, metal staples, dermal adhesive, etc.
Secondary union healing by secondary intention occurs when wounds are allowed to heal by wound contraction and is mediated by myofibroblasts at the edge of the wound. Note Repair in specific organs occurs as follows: Mild injury is repaired by regeneration of hepatocytes, sometimes with healing techniques based on clinical restoration to normal pathology.
Severe or persistent injury causes formation information and the size of the tissue of regenerative nodules that may be surrounded by fibrosis, leading to hepatic defect. It is common in burn patients.
It tends to affect the earlobes, face, neck, sternum, and forearms, and it may produce large tumor-like scars extending beyond the injury site. There is excess production of collagen that is predominantly type III. Labile cell populations that regenerate throughout life include surface epithelial cells, hematopoietic cells, and stem cells.
Stable cells that replicate at a low level through life, but can divide if stimulated, include hepatocytes, proximal tubule cells, and endothelial cells. Permanent cells that cannot replicate in adult life include neurons and cardiac muscle. Initially granulation tissue forms, which later undergoes wound contraction mediated by myofibroblasts, eventually resulting in true scar formation.
Wound healing by second intention secondary union relies on wound contraction by myofibroblasts. It has many causes. Anasarca is severe generalized edema. Effusion is fluid within the body cavities. Types of exudates include purulent pus , fibrinous, eosinophilic, and hemorrhagic. It involves interactions between the opposing forces: Transient vasoconstriction is mediated by endothelin Thrombogenic factors include a variety of processes: They form a throm- bus through a series of steps.
Platelet adhesion occurs when vWF adheres to subendothelial collagen and then platelets adhere to vWF by glycoprotein Ib. Platelet activation occurs when platelets undergo a shape change and degranulation occurs. Platelets synthesize thromboxane A2. Platelets also show membrane expression of the phospholipid complex, which is an impor- tant substrate for the coagulation cascade. Platelet aggregation occurs when additional platelets are recruited from the bloodstream. ADP and thromboxane A2 are potent mediators of aggrega- tion.
Laboratory tests for platelets include platelet count normal ,—, mm3 and platelet aggregometry. In a Nutshell Bernard-Soulier syndrome and Glanzmann thrombasthenia present as mucocutane- Bernard-Soulier Syndrome ous bleeding in childhood.
Platelet Aggregation Table The antibodies are made in the spleen, and the platelets are destroyed peripherally in the spleen by macrophages, which have Fc receptors that bind IgG-coated platelets.
Forms of ITP include: Clinically, it is characterized by petechiae, ecchymoses, menorrhagia, and nosebleeds.
Lab studies usually show decreased platelet count and prolonged bleeding time but normal prothrombin time and partial thromboplastin time.
Peripheral blood smear shows thrombocytopenia with enlarged immature platelets megathrombocytes. Bone marrow biopsy shows increased numbers of megakaryocytes with immature forms. Thrombotic thrombocytopenic purpura TTP is a rare disorder of hemostasis in which there is widespread intravascular formation of fibrin-platelet thrombi. It is sometimes associated with an acquired or inherited deficiency of the enzyme ADAMTS13, responsible for cleaving large multimers of von Willebrand factor.
Clinically, TTP most often affects adult women. The inclusion criteria are microan- giopathic hemolytic anemia and thrombocytopenia, with or without renal failure or neurologic abnormalities.
Pathology includes widespread formation of platelet thrombi with fibrin hyaline thrombi leading to intravascular hemolysis throm- botic microangiopathy. Lab studies typically show decreased platelet count and prolonged bleeding time but normal prothrombin time and partial thromboplastin time.
Peripheral blood smear shows thrombocytopenia, schistocytes, and reticulocytosis. Treatment is plasma exchange. Hemolytic uremic syndrome HUS is a form of thrombotic microangiopathy due to endothelial cell damage. It occurs mostly in children, typically after a gastroenteritis typically due to Shiga toxin-producing E. Typical HUS presents with abdominal pain, diarrhea an atypical variant is diar- rhea-negative , microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
Renal involvement is seen more commonly than in TTP. The kidney shows fibrin thrombi in the glomeruli. Renal glomerular endothelial cells are targeted by the bacterial toxin. Glomerular scarring may ensue. Treatment is supportive fluid management, dialysis, erythrocyte transfusions ; plasma exchange is only used for atypical cases. The majority of the clotting factors are produced by the liver. Note The factors are proenzymes that must be converted to the active form.
Some con- versions occur on a phospholipid surface, and some conversions require calcium. Coagulation Cascade Lab tests for coagulation include the following: A longer time means blood takes longer to clot. Clinically, hemophilia A predominately affects males. Symptoms vary depending on the degree of deficiency. Laboratory studies typically show normal platelet count and normal bleeding time, normal PT and prolonged PTT.
Treatment is factor VIII concentrate. Hemophilia B Christmas disease is an X-linked recessive condition resulting from a deficiency of factor IX that is clinically identical to hemophilia A.
Treatment is recombinant factor IX. Note Von Willebrand disease is an autosomal dominant bleeding disorder characterized Von Willebrand disease is the most by a deficiency or qualitative defect in von Willebrand factor.
Clinical features include spon- taneous bleeding from mucous membranes, prolonged bleeding from wounds, and menorrhagia in young females. Hemarthrosis is uncommon. Lab studies show normal platelet count, a prolonged bleeding time, normal PT, and often prolonged PTT. Abnormal platelet response to ristocetin adhesion defect is an important diagnostic test. Treatment for mild classic cases type I is desmo- pressin an antidiuretic hormone analog , which releases vWF from Weibel-Palade bodies of endothelial cells.
Disseminated intravascular coagulation DIC is always secondary to another dis- order. Causes are diverse. Treat the underlying disorder. Massive tissue Endothelial Sepsis destruction injury Release of tissue factor Platelet Widespread aggregation microvascular thrombosis Activation of Microangiopathic Vascular plasmin Consumption of hemolytic anemia occlusion clotting factors and platelets Fibrinolysis Proteolysis of Ischemic tissue clotting factors damage Fibrin split products Bleeding Inhibition of thrombin, platelet aggregation, and fibrin polymerization Figure Outcomes of thrombosis include vascular occlusion and infarctions; embolism; thrombolysis; and organization and recanalization.
EMBOLISM An embolism is any intravascular mass that has been carried down the bloodstream from its site of origin, resulting in the occlusion of a vessel. There are many types of emboli: Doppler ultrasound of the leg veins can be used to detect a DVT. Most cases are clinically silent and resolve. Symp- toms include shortness of breath, hemoptysis, pleuritic chest pain, and pleural effu- sion. On gross examination there is typically a hemorrhagic wedge-shaped infarct. The infarction heals by regeneration or scar formation.
Common sites of infarction include heart, brain, lungs, intestines, kidneys. Infarcts have multiple causes. On gross examination infarctions typically have a wedge shape, with the apex of the wedge tending to point to the occlusion. Microscopic pathology of infarction can show either coagulative necrosis most organs or liquifactive necrosis brain.
The general sequence of tissue changes after infarction is as follows: The cel- lular injury is initially reversible; if the hypoxia persists, the cellular injury becomes irreversible, leading to the death of cells and the patient. Stages of Shock The stages of shock are arbitrarily defined as follows.
Compensation is characterized by increased sympathetic tone, release of catecholamines, and activation of the renin-angiotensin system. The organs show various manifestations of shock: Causes include increased hydrostatic pressure, increased interstitial sodium, hypoalbuminemia and decreased colloid pressure, lymphatic obstruction, and increased endothelial permeability. Vascular wall injury triggers transient vasoconstriction, facilitation of platelet adhesion, and activation of both the extrinsic and intrinsic clotting pathways.
Formation of a platelet thrombus occurs when platelets adhere to von Willebrand factor attached to subendothelial collagen, undergo shape change and degranulation, and then aggregate with additional platelets. Causes of qualitative platelet defects include von Willebrand disease, Bernard-Soulier syndrome, Glanzmann thrombasthenia, aspirin, and uremia. In TTP, there is widespread formation of platelet thrombi with fibrin but without activation of the coagulation system. Hemolytic uremic syndrome can clinically resemble TTP and is triggered by E.
The extrinsic coagulation pathway is activated by the release of tissue factor, and is tested with the prothrombin time PT , which also tests the common coagulation pathway. Clinically, hemophilia B closely resembles hemophilia A but is due to deficiency of factor IX. Acquired coagulopathies can be due to vitamin K deficiency and liver disease.
Von Willebrand is an inherited bleeding disorder characterized by a deficiency or qualitative defect in von Willebrand factor, which facilitates formation of platelet clots.
Thrombi can lead to a spectrum of outcomes, including vascular occlusion and infarction, embolism, thrombolysis, and organization and recanalization.
Embolism is used for any intravascular mass solid, liquid, or gas that has been carried downstream from its site of origin, resulting in occlusion of a vessel.
Most emboli are thromboemboli, but many other materials have also formed emboli. Pulmonary emboli are a common form of emboli that are often clinically silent but can cause infarction or sudden death.
Most pulmonary emboli arise from deep vein thromboses. Systemic arterial emboli usually arise in the heart and may cause infarction in a variety of sites, depending upon where they lodge.
Most infarcts result from thrombotic occlusion of an artery. Anemic infarcts occur in organs with a single blood supply, whereas hemorrhagic infarcts occur in organs with a dual blood supply or secondary to venous occlusion. After infarction, ischemia leads to coagulative necrosis, which leads to inflammation, which leads to granulation tissue, which leads to fibrous scar. Major forms of shock include cardiogenic shock, hypovolemic shock, septic shock, neurogenic shock, and anaphylactic shock.
Down syndrome is the most com- Note mon of the chromosomal disorders. This results in an extremely Clinical findings can include intellectual disability; mongoloid facial features flat large chromosome and a tiny one, which face, low-bridged nose, and epicanthal folds ; Brushfield spots speckled appearance is typically lost.
Endocardial cushion defect, if present, leads to the forma- tion of an atrioventricular canal a common connection between all 4 chambers of Note the heart. Prenatal tests include maternal serum tests, ultrasonography, amniocentesis, and chorionic villus sampling. Median life expectancy is 47 years. Down Syndrome Down Syndrome Edwards syndrome trisomy 18 is caused by nondisjunction. The risk increases with maternal age. There is a very poor prognosis due to severe congenital malformations.
Prominent occiput Intellectual disability Low-set ears Micrognathia small jaw Short neck Overlapping fingers Congenital heart defects Renal malformations Limited hip abduction Rocker-bottom feet Figure The very poor prognosis is due to severe congenital malformations. Clini- cal findings include a characteristic high-pitched catlike cry; intellectual disability; congenital heart disease; and microcephaly.
Microdeletions include 13q14 retino- blastoma gene and 11p13 WAGR complex [Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability [previously known as mental retardation]. Microdeletions are too small to be detected by karyotyping and require molecular techniques for detection. The most common karyotype is 47,XXY.
Clinical findings include testic- determines male phenotype due to the ular atrophy, infertility due to azoospermia, eunuchoid body habitus, high-pitched presence of the testes-determining factor voice; female distribution of hair; and gynecomastia. Turner syndrome is a common cause of female hypogonadism.
The most common karyotype is 45,X. The second X chromosome is necessary for oogenesis and normal development of the ovary. Clinically, patients fail to develop secondary sex charac- teristics and have short stature with widely spaced nipples. Other features include gonadal dysgenesis with atrophic streak ovaries; primary amenorrhea; and infertility.
Clinical features involving other organ systems include cystic hygroma and web- bing of the neck; hypothyroidism; congenital heart disease preductal coarctation of the aorta and bicuspid aortic valve ; and hydrops fetalis. Cubitus valgus elbows turned in Rudimentary ovaries, infertility, amenorrhea Small fingernails Pigmented nevi brown spots Peripheral lymphedema swollen feet Figure Turner Syndrome Figure Individuals with ovotesticular disorder have both ovarian and testicular tissue, which is an extremely rare condition.
The most common karyotype of ovotesticular disorder is 46,XX. The gonadal sex can be either an ovary on one side and testis on the other, or ovotestes, in which there is a gonad with both testicular and ovarian tis- sue. The ductal sex is often mixed, and the phenotypic sex shows ambiguous genitalia. The 46,XX DSD category includes individuals formerly characterized as female pseudohermaphrodites with disorders of ovarian development, androgen excess, vaginal atresia, and cloacal exstrophy.
The 46,XY category includes individuals formerly characterized as male pseudohermaphrodites with disorders of testicu- lar development, disorders of androgen synthesis, severe hypospadias and cloacal exstrophy. Common types of mutations include point mutations and frameshift mutations. The form of point mutation called synonymous mutation silent mutation occurs when a base substitution results in a codon that codes for the same amino acid.
The form of point mutation called mis- sense mutation occurs when a base substitution results in a new codon and a change in amino acids.
The form of point mutation called a nonsense mutation occurs when a base substitution produces a stop codon and therefore produces a truncated protein. The location of a mutation will alter its potential effects. Mutations involving coding regions of DNA may result in abnormal amino acid sequences; decreased production of the protein; truncated or abnormally folded protein; or altered or lost function of the protein.
Mutations of promoter or enhancer regions may interfere with tran- scription factors, resulting in decreased transcription of the gene.
Patterns of inheritance for genetic diseases show wide variation, and the genetic pattern of a disease may be classified as autosomal dominant; autosomal recessive; X-linked recessive; X-linked dominant; triplet repeat mutations; genomic imprint- ing; mitochondrial; or multifactorial. It is also covered in the Physiol- ogy Lecture Notes.
Cystic fibrosis CF is the most common lethal genetic disorder in Caucasians. Due to improved therapies, some patients live into their forties, but with this increase in longevity there has been an increase in liver disease. Patients succumb to pulmonary disease. The 3 most common pulmonary infections are S. Lung transplantation is a treatment option. Patients infected with Burkholderia cepacia complex who undergo transplant have a worse prognosis. Clinically, affected children are normal at birth but, if undiagnosed and untreated, develop intellectual development disorder by age 6 months.
The lack of tyrosine causes light-colored skin and hair, since melanin is a tyrosine derivative. Affected children may have a mousy or musty odor to the sweat and urine secondary to metabolite [phenylacetate] accumulation. Treatment is dietary restriction of phenylalanine, including avoidance of the artificial sweetener aspartame. A genetic variant, benign hyperphenylalaninemia, has partial enzyme deficiency with mildly increased levels of phenylalanine which are insufficient to cause intel- lectual disability.
In a minority of cases, an abnormality of the cofactor tetrahydrobiopterin causes a variant that does not respond to dietary restriction. Transplacental accumulation of phenylalanine can cause problems with fetal devel- opment in cases of maternal PKU. Prevention requires maternal dietary restriction. Alkaptonuria ochronosis occurs when deficiency of homogentisic acid oxidase results in the accumulation of homogentisic acid.
The homogentisic acid has an affinity for connective tissues especially cartilage , resulting in a black discoloration as a consequence of oxidation of homogentisic acid. Clinical features include urine that is initially pale yellow but turns black upon standing, and black-stained cartilage, which causes discoloration of the nose and ears. Alkaptonuria also predisposes for early onset of degenerative arthritis.
Albinism is caused by a lack of the enzyme tyrosinase needed for melanin produc- tion. Affected individuals show deficiency of melanin pigmentation in the skin, hair follicles, and eyes oculocutaneous albinism , with resulting increased risk of basal cell and squamous cell carcinomas.
The glycogen storage diseases are a group of rare diseases that have in common a Note deficiency of one of the enzymes necessary for the metabolism of glycogen, which Lysosomal Storage Diseases results in the accumulation of glycogen in the liver, heart, and skeletal muscle.
Tay-Sachs is common in Ashkenazi Jews 1 in 30 carrier rate. The distribution of disease involves the retina cherry-red spot due to accentua- tion of the macula and central nervous system dilated neurons with cytoplasmic vacuoles.
Affected children are normal at birth, but by 6 months show onset of symptoms progressive mental deterioration and motor incoordination that prog- ress to death by age 2—3 years. Electron microscopy shows distended lysosomes with whorled membranes; the diagnosis can also be established with enzyme assays and DNA probes.
Although they are tissue. The distribution of disease depends on the form of disease, but can involve the retina cherry-red spot, note similarity to Tay-Sachs disease ; central nervous system dis- tended neurons with a foamy cytoplasmic vacuolization, note similarity to Tay-Sachs disease ; and reticuloendothelial system hepatosplenomegaly, lymphadenopathy, and bone marrow involvement; note difference from Tay-Sachs disease.
In Neimann-Pick types A and B, there is a mutation affecting an enzyme that metabolizes lipids; organomegaly occurs, and with type A, there is severe neuro- logic damage. In type C—the most common form—a defect in cholesterol transport causes ataxia, dysarthria, and learning difficulties. All forms are lethal, usually before adulthood.
Gaucher disease is the most common lysosomal storage disorder. Deficiency of glucocerebrosidase leads to the accumulation of glucocerebroside, predominately in the lysosomes of the reticuloendothelial system monocytes and macrophages located in reticular connective tissue. The characteristic Gaucher cells are enlarged macrophages with a fibrillary tissue paper—like cytoplasm. Diagnosis can be established with biochemical enzyme assay of glucocerebrosidase activity.
Mucopolysaccharidosis MPS is a group of lysosomal storage disorders charac- terized by deficiencies in the lysosomal enzymes required for the degradation of mucopolysaccharides glycosaminoglycans. There are 5 major classes of mutation. Marfan syndrome is due to a mutation of the fibrillin gene FBN1 on chromosome 15q Fibrillin is a glycoprotein that functions as a scaffold for the alignment of elastic fibers.
Clinical features include skeletal changes tall, thin build with long extremities, hyperextensible joints, pectus excavatum [inwardly depressed sternum], and pec- tus carinatum [pigeon breast] and abnormal eyes ectopia lentis, characterized by bilateral subluxation of the lens. Ehlers-Danlos syndrome EDS is a group of inherited connective tissue diseases that have in common a defect in collagen structure or synthesis. Clinically, the disease causes hyperextensible skin that is easily traumatized and hyperextensible joints sec- ondary to effects on the joints and adjacent ligaments.
There are a number of variants with different modes of inheritance. The condition is due to a mutation of the tumor suppressor gene NF1 located on chromosome 17 17q The normal gene product neurofibromin inhibits p21 ras oncoprotein. The plexiform variant of the neurofibromas are diagnostic. Serious complications include congenital heart disease endocardial cushion defects , duodenal atresia, Hirschsprung disease, acute lymphoblastic leukemia, and early onset of Alzheimer disease.
Cri du chat syndrome 5p- is a chromosomal deletion syndrome characterized by a high-pitched, catlike cry; intellectual disability; congenital heart disease; and microcephaly.
Microdeletions are associated with retinoblastoma and Wilms tumor. These mutations may produce autosomal dominant, autosomal recessive, or X-linked diseases. Important subtypes include von Gierke disease, Pompe disease, and McArdle syndrome. Clinical manifestations can include retinal hemangioblastoma von Hippel tumor ; hemangioblastomas of the cerebellum, brain stem, and spinal cord Lindau tumor ; cysts of the liver, pancreas, and kidneys; and multiple bilateral renal cell carcinomas.
Lesch-Nyhan syndrome results from deficiency of hypoxanthine-guanine phophori- bosyltransferase HGPRT , which impairs salvaging of the purines hypoxanthine and guanine. Clinical features include intellectual disability, hyperuricemia, and self-mutilation. Testicular feminization is an androgen insensitivity that causes failure of normal masculinization of external genitalia of XY males.
In Bruton agammaglobulinemia, defective Bruton tyrosine kinase Btk at band Xq See the Immunopathology chapter 7. Infants show failure to thrive, and death occurs in the first decade.
An example is Alport syndrome, which is a hereditary glo- intellectual developmental disorder: Alport syndrome can also be inherited in other patterns. The mutation in a coding region Huntington and occurs in the FMR-1 gene fragile X mental retardation-1 on the X chromosome spinobulbar muscular atrophy or in Xq The condition can be diagnosed with DNA probe analysis. Huntington disease is due to a triplet repeat mutation CAG of the HTT gene that produces an abnormal protein huntingtin , which is neurotoxic and causes atrophy of the caudate nucleus.
Huntington disease has an early onset age range: Figure Figure Examples include: Sensorineural hearing loss and ocular dysfunction can also develop. Patients have short stature and cardiomyopathy. On muscle biopsy, ragged red fibers are seen on Gomori trichrome staining due to the accumulation of mitochondria.
Examples include open neural tube defects and type 2 diabetes mellitus. Lipid metabolism is impaired. Most cases present in adulthood.
Bilateral acoustic neurofibromatosis neurofibromatosis type 2 is less common and caused by a defect in tumor suppressor gene NF The classic examples are Prader-Willi and Angelman syndromes. Alport disease hereditary glomerulonephritis with nerve deafness is an example. These include Leber hereditary optic neuropathy and myoclonic epilepsy with ragged red fibers. It is also covered in the Immunol- ogy Lecture Notes. Type I immediate hypersensitivity reactions anaphylactic type are character- ized by IgE-dependent release of chemical mediators from mast cells and basophils.
Cross-linking of IgE bound to antigen to IgE Fc receptors on the surface of mast cells and basophils causes degranulation. This binding triggers release of chemi- cal mediators that include histamine and heparin; eosinophil chemotactic factor; leukotriene B4 and neutrophil chemotactic factor; and prostaglandin D4, platelet- activating factor PAF , and leukotrienes C4 and D4.
Influx of eosinophils amplifies and perpetuates the reaction. Effects may be systemic anaphylaxis, as for example due to bee stings or drugs or localized food allergies, atopy, and asthma. Type II hypersensitivity reactions antibody-mediated are mediated by IgG or IgM antibodies directed against a specific target cell or tissue.
Reactions can take several forms. Antireceptor antibodies can activate or interfere with receptors; examples include Graves disease and myasthenia gravis.
Type III hypersensitivity reactions immune complex disease are characterized by the formation of in situ or circulating antibody-antigen immune complexes, which deposit in tissue resulting in inflammation and tissue injury.
Examples include serum sickness, systemic lupus erythematosus SLE , and glomerulonephritis. Females produced and are commonly directed are affected much more often than males M: Hydralazine, hemolytic anemia, thrombocytopenia, neutropenia, and lymphopenia. It tends to have a chronic, unpredictable course with remissions and relapses. Females are affected more often than males, with typical age 30— Clinical manifestations include keratoconjunctivitis sicca dry eyes and corneal ulcers; xerostomia dry mouth ; and Mikulicz syndrome enlargement of the sali- vary and lacrimal glands.
There is an increased risk of developing non-Hodgkin lymphoma. Scleroderma progressive systemic sclerosis is an autoimmune disease character- In a Nutshell ized by fibroblast stimulation and deposition of collagen in the skin and internal CREST Syndrome organs.
It affects females more than males, with typical age range of 20 to 55 years. Dermatomyositis and polymyositis. See Skeletal Muscle chapter. Mixed connective tissue disease is an overlap condition with features of systemic lupus erythematosus, systemic sclerosis, and polymyositis.
Antiribonucleoprotein antibodies are nearly always positive. Clinically, the disease affects male infants who have recurrent infections beginning at 6 months of life due to the loss of passive maternal immunity. Common infections include pharyngitis, otitis media, bronchi- tis, and pneumonia; common infecting organisms include H. Common variable immunodeficiency is a group of disorders characterized by defects in B-cell maturation that can lead to defective IgA or IgG production.
Clinically, both sexes are affected with onset in childhood of recurrent bacterial infections and with increased susceptibility to Giardia lamblia. Complications include increased frequency of developing autoimmune disease, non-Hodgkin lymphoma, and gastric cancer. Note DiGeorge syndrome is an embryologic failure to develop the 3rd and 4th pharyngeal pouches, resulting in the absence of the parathyroid glands and thymus. Clinical Adenosine inosine findings can include neonatal hypocalcemia and tetany, T-cell deficiency, and recur- Adenosine rent infections with viral and fungal organisms.
The modes Adenosine deaminase is an important of inheritance are variable and can include X-linked mutation of the common enzyme in purine metabolism; [gamma] chain of the interleukin receptors IL-2, IL-4, IL-7, IL-9, IL, and IL a deficiency of it results in accumulation and autosomal recessive deficiency of adenosine deaminase. Clinical features of deoxyadenosine within lymphoid include recurrent infections with bacteria, fungi, viruses, and protozoa; susceptibil- progenitor cells.
SCID is treated with hematopoietic stem cell transplantation since the prognosis without treatment is death of most infants within a year. The disease has a clinical triad of recurrent infections, severe thrombocytopenia, and eczema chronic spongiform dermatitis. Treatment is hematopoietic stem cell transplantation.
Complications include increased risk of non-Hodgkin lymphoma and death due to infection or hemorrhage. Complement system disorders can involve a variety of factors, with deficiencies of different factors producing different clinical patterns.
Deficiencies in complement regulatory proteins can cause C1-INH deficiency hereditary angioedema , which is characterized clinically by edema at mucosal surfaces with low C2 and C4 levels.
MHC class II deficiency can be caused by defects in positive selection of thymocytes. Mutations in genes i. Selective IgA deficiency has unknown genetic etiology. Many affected individu- als appear healthy while others have significant illness. Sinopulmonary infections, diarrhea and adverse reactions to transfusions can occur. Levels of IgA are unde- tectable whereas levels of other isotypes are normal.
There is an association with autoimmune disease. Phagocyte deficiencies See chronic granulomatous disease in Inflammation chapter. Secondary immunodeficiency is more common. Males are affected more frequently than females. Transmission of HIV can occur by many mechanisms, including sexual contact most common mode, including both homosexual transmission and an increasing rate of heterosexual transmission, with important cofactors including herpes and syphilis infection ; parenteral transmission; IV drug use; blood transfusions includ- ing those done in hemophiliacs ; accidental needle sticks in hospital workers; and vertical transmission.
If the confirmatory test is negative, testing with an HIV-1 are reservoirs for the virus. Treatment varies, and can include combination antiretro- viral treatment, reverse transcriptase inhibitors, protease inhibitors, and prophylaxis for opportunistic infections based on CD4 count. The clinical manifestations of HIV infection vary over time. The average duration of latent phase is 10 years. White plaques are present on the tongue. Kaposi sarcoma is the most common neoplasm in AIDS patients.
See Vascular Pathology chapter. Immunosuppressive agents are used to prevent and mitigate rejection. Lymphocyte cross-matching has almost eliminated this problem. The vasculature components are targeted, and the histo- pathologic changes depend on the organ involved. Examples include systemic anaphylaxis following bee stings and drugs. Localized forms of anaphylactic reaction include food allergies, atopy, and asthma. Examples include the complement-dependent cytotoxicity of autoimmune hemolytic anemia, the antibody-dependent cell-mediated cytotoxicity of pernicious anemia, and the antireceptor antibodies of Graves disease.
Examples include serum sickness, systemic lupus erythematosus, and glomerulonephritis. Examples include the delayed hypersensitivity of PPD skin tests and TB and the cytotoxic T-cell—mediated destruction of antigen-containing cells in viral infections, immune reaction to tumor-associated antigens, type 1 diabetes, and graft rejection.
Scleroderma can have anti-DNA topoisomerase I antibodies Scl- 70 , widespread skin involvement, and early involvement of the esophagus, GI tract, lung, heart, and kidney.
HIV can be spread by sexual contact, parenteral transmission, or vertical transmission. Clinical AIDS is characterized by susceptibility to a wide variety of opportunistic infections. These deposits stain red with the Congo red stain, and apple green birefringence of the amy- loid is seen on the Congo red stain under polarized light. Also present in amy- loid are serum amyloid P SAP and glycosaminoglycans heparan sulfate.
Primary amyloidosis may be seen in plasma cell disorders multiple myeloma, B-cell lymphomas, etc. Reactive systemic amyloidosis secondary amyloidosis has amyloid-associated AA protein, whose precursor is serum amyloid A SAA , an acute phase reactant produced by the liver which is elevated with ongoing chronic inflammation and neoplasia.
Reactive systemic amyloidosis can be seen with a wide variety of chronic diseases, including rheumatoid arthritis, systemic lupus erythematosus, tuberculo- sis, bronchiectasis, osteomyelitis, inflammatory bowel disease, and cancer. This autosomal recessive disease is characterized by recur- Carpal tunnel syndrome is caused when rent inflammation, fever, and neutrophil dysfunction.
Gain of function mutations of fibrosis, edema, or another pathologic pyrin are present. This form of amyloidosis may cause carpal tunnel syndrome and joint disease. It is found in Alzheimer plaques and in cerebral vessels. Endocrine type amyloidosis is seen in medullary carcinoma of the thyroid procal- citonin , adult-onset diabetes amylin , and pancreatic islet cell tumors amylin.
Cardiac involvement may cause restrictive cardiomyopathy and conduction dis- turbances. Other clinical features include hepatosplenomegaly and involvement of the gastrointestinal tract, which may produce tongue enlargement macroglossia, primarily in AL type and malabsorption.
Diagnosis in systemic forms of amyloidosis can be established with biopsy of the rectal mucosa, gingiva, or the abdominal fat pad; Congo red stain shows apple green birefringence under polarized light of amyloid deposits. The prognosis of systemic amyloidosis is poor. AL amyloidosis is diagnosed by serum and urinary protein electrophoresis and immunoelectrophoresis.
Rather, it was derived from a type of analysis called a confirmatory factor analysis that examines how the various components of MetS obesity, blood pressure, triglycerides, HDL cholesterol, and fasting blood sugar are correlated with one another. This score behaves like a z-score, in that it has a normal distribution with mean 0 and standard deviation equals 1. It was derived from a nationally representative sample of the U.
The score requires information regarding the five components of the metabolic syndrome. These are systolic blood pressure the upper number of the two numbers given in a blood pressure , triglycerides, HDL cholesterol, glucose or blood sugar , and a measure of weight status. The most common means of measuring weight status is body mass index, which is calculated from height and weight. Body weight status can also be measured from waist circumference.
Either of these measures of body weight status can be used in calculating a metabolic syndrome severity score. The measurements that are part of the metabolic syndrome are all done routinely at visits to the doctor. Your score tells you where your current metabolic syndrome status is compared to others in the US population. If your score is below zero, you have a lower degree of metabolic syndrome than the average US adult; if your score is very close to 0, then you have an average degree of metabolic syndrome.
But higher scores above 0 are associated with more risk for future disease, particularly scores above 1 which is higher than At this point we do not have detailed information on risk for CVD and diabetes based on your score, but we are working on having this.
Yes, the good news is that a major influence of metabolic syndrome is lifestyle—such as food choices and exercise—and making changes in your lifestyle can lower your metabolic syndrome score. More importantly, these decreases in score are associated with decrease in risk for future disease. Healthy diet choices such as reduced portion sizes and eating less saturated fat , getting regular exercise and weight loss are all important parts of lowering your risk.
Traditional MetS definitions are based on set cut-off values for each of the individual measurements that are part of MetS for example, blood pressure, fasting glucose. There are a few problems with the traditional MetS definitions. While these individuals would be labeled as normal by traditional MetS definitions, they would be identified as having a slightly elevated MetS severity using a continuous MetS score like this one. In particular, African American men are classified as having a low prevalence of MetS using traditional criteria despite having higher insulin resistance and risk for diabetes and cardiovascular mortality.
By following the degree of severity in MetS, the MetS score allows doctors and patients to more easily follow for improvements in MetS over time. This score has been tested among individuals with Type 2 diabetes for the ability to predict future cardiovascular disease. Higher MetS scores continued to be associated with increased risk for cardiovascular disease, even in the setting of diabetes.
The MetS score remained associated with future cardiovascular disease in diabetes any way we looked at it. Gurka, M. A confirmatory factor analysis of the metabolic syndrome in adolescents: Cardiovascular diabetology, 11 1 , Metabolism, 63 2 , MetS Calc: Metabolic Syndrome Severity Calculator.