Exam 4 Fall 2024 Adv Pathophysiology PDF

**Exam 4 Fall 2024 Adv Pathophysiology** **Opens Tuesday, December 10 at 8 am CENTRAL TIME; closes Friday, December 13 at 8 am CENTRAL TIME. *Scores will be posted by Saturday, December 14 at 5 pm.*** **NOTE: I include MOST of these concepts in the Kaltura voiceovers housed in the announcements of...

**Exam 4 Fall 2024 Adv Pathophysiology** **Opens Tuesday, December 10 at 8 am CENTRAL TIME; closes Friday, December 13 at 8 am CENTRAL TIME. *Scores will be posted by Saturday, December 14 at 5 pm.*** **NOTE: I include MOST of these concepts in the Kaltura voiceovers housed in the announcements of your canvas course but may not touch on some if fairly straight forward[.] -- *PLEASE REACH OUT TO YOUR COURSE FACULTY IF YOU HAVE ANY QUESTIONS!!!* This exam covers weeks 12, 13, 14, and 15 content. Chapters 25, 26, 27, 35, 36, 38, 39, 41, 42.** **REMINDER: Must earn an average score on all exams of 79.5% to pass the course. If a 79.5% is earned on the average exam score -- all other points from assignments and discussions will be added to calculate the final grade.** ***[Alterations in the Reproductive Systems ]*** ***Alterations in the Female Reproductive System*** ***[Hormonal and Menstrual Alterations]*** ***Primary dysmenorrhea*** ***is attributed to excessive endometrial prostaglandin production.* Painful periods produce more prostaglandin, a potent myometrial stimulant and vasoconstrictor, as asymptomatic women. *Elevated levels of prostaglandins cause uterine hypercontractility, decreased blood flow to the uterus, and increased nerve hypersensitivity, thus resulting in pain.* Secondary dysmenorrhea results from disorders in the presence of pelvic pathologic conditions such as endometriosis (the most common cause), endometritis (infection), pelvic inflammatory disease, uterine fibroids (leiomyomas), polyps, tumors, ovarian cysts, or intrauterine devices (IUDs).** **[*Endometriosis*] is the presence of functioning endometrial tissue or implants outside the uterus. Like normal endometrial tissue, the ectopic (out of place) endometrium responds to the hormonal fluctuations of the menstrual cycle. Common sites of implantation include the pelvic peritoneum, ovaries, and uterosacral ligaments. Implants can also be found outside the pelvic locations: GI tract, lungs, diaphragm, abdomen, pericardium. The exact cause of endometriosis is not known. The clinical manifestations of endometriosis can mimic other disease processes (i.e., PID, irritable bowel syndrome, ovarian cysts). Symptoms are variable in frequency and severity and most commonly include pain and infertility. Women with endometriosis report progressive dysmenorrhea, dysuria, and dyspareunia (pain on intercourse); they may also report constipation and abnormal vaginal bleeding. High risk for infertility and cancers, especially ovarian.** **[*Polycystic Ovarian Syndrome (PCOS)*.] Although the underlying cause of PCOS is unknown, a genetic basis is suspected. No single factor fully accounts for the abnormalities of PCOS and is a leading cause of infertility in the United States. Although PCOS presents in a variety of ways, it is defined as having at least two of the following three features: Irregular ovulation, elevated levels of androgens (e.g., testosterone), and the appearance of polycystic ovaries on ultrasound. Polycystic ovaries do not have to be present to diagnose PCOS, and conversely their presence alone does not establish the diagnosis. A hyperandrogenic state and ovulatory dysfunction are the cardinal features in the pathogenesis of PCOS. Excessive androgens affect follicular growth. Follicle-stimulating hormone (FSH) is decreased (note: FSH regulates the menstrual cycle and stimulates egg production in the ovaries). *G*lucose intolerance/insulin resistance (IR) often run parallel and markedly aggravate the hyperandrogenic state, thus contributing to the severity of signs and symptoms of PCOS. Obesity adds to and worsens IR.** ***[Pelvic Inflammatory Disease]* (PID)** **An acute inflammatory process caused by infection. Infection of the upper genital tract leads to inflammatory damage, including scarring, adhesions, and partial or total obstruction of the fallopian tubes. Scarring increases the risk of a later ectopic pregnancy because the mobility of an egg through the fallopian tubes is slowed by damaged cilia. Loss of the ciliated epithelial cells along the fallopian tube lining results in impaired ovum transport and increases the risk for infertility and ectopic pregnancy.** - **Scarring and adhesions also can result in chronic pelvic pain. Increased risk of uterine cancer** - **Two sexually transmitted infectious causes of PID are gonorrhea and chlamydia.** - ***[Bacterial vaginosis (BV)]* is a noninflammatory condition resulting from an overgrowth of anaerobic bacteria. The overgrowth causes a shift in the composition of the vaginal flora and produces a malodorous vaginal discharge. Pain and itching are common manifestations. *BV is present in up to 66% of PID.*** ***[Pelvic Organ Prolapse (POP)] is the descent of one or more of these structures: the vaginal wall, uterus, or apex of the vagina (after a hysterectomy). Although more than 50% of women have some version of POP on physical examination, most women have no symptoms. When prolapse becomes severe, the function of the surrounding organs can be altered. POP is thought to be caused by direct trauma (e.g., childbirth), pelvic floor surgery, obesity, constipation, pelvic organ cancers, or damage to the pelvic innervation, particularly the pudendal nerve. However, risk factors in nulliparous women include occupational activities that require heavy lifting or chronic medical conditions, such as chronic lung disease or refractory constipation (chronically increased intra-abdominal pressure). The most frequently cited risk factors are aging, obesity, and hysterectomy. Other risk factors include a strong familial tendency (from family and twin studies) and possibly a multifactorial genetic component. Prolapse of the bladder, urethra, rectum, or uterus may occur many years after an initial injury to the supporting structure.*** ***The "Cele's"*** ***[Cystocele]* is descent of a portion of the posterior bladder wall and trigone into the vaginal canal and usually is caused by the trauma of childbirth. Usually, symptoms are insignificant in mild to moderate cases. Increased bulging and descent of the anterior vaginal wall and urethra can be aggravated by vigorous activity, prolonged standing, sneezing, coughing, or straining and can be relieved by rest or assumption of a recumbent or prone position. Signs and symptoms:** - - - ***[Rectocele]* is the bulging of the rectum and posterior vaginal wall into the vaginal canal. Childbirth may increase damage. Lifelong constipation.** **[*Enterocele*] is herniation of the rectouterine pouch into the rectovaginal septum (between the rectum and posterior vaginal wall). Most large enteroceles are found in grossly obese and older adults and can be complicated by rupture or complete eversion of the vagina with trophic ulceration, edema, and fibrosis. Treatment is surgical.** **[*Spermatoceles*] (epididymal cysts) are benign cystic collections of fluid of the epididymis located between the head of the epididymis and the testis. Spermatoceles are filled with milky fluid that contains sperm. Spermatocele is differentiated from a hydrocele in that aspiration of the hydrocele recovers a clear, yellow fluid, and unlike a hydrocele, a spermatocele does not cover the entire anterior surface of the testis.** **[Malignancies]** ***[Ovarian cancer]* is commonly asymptomatic until the tumors have grown very large; and is most commonly diagnosed after metastasis has occurred. Consequently, ovarian cancer is often termed the "silent killer".** **The pathogenesis of ovarian cancer is not fully understood. In 10% to 15% of cases, a genetic predisposition is found. There is association with the breast cancer susceptibility gene 1 (BRCA1) and a smaller number with mutations of BRCA2. Difficult to classify: In the past, ovarian cancers *were thought to arise* from just epithelial cells. Ovarian cancer is not easily classified. Newer evidence suggests that tumors can arise from: the fimbriae of fallopian tubes, deposits of endometriosis, or stromal cells.** ***[Breast Cancer]*** **Inheritance factors of procancerous genes BRCA1 and BRCA2 play a role in the development of breast cancer. BRCA1 (breast cancer 1 gene) is a tumor-suppressor gene; therefore, any mutation in the gene may inhibit or alter its suppressor function, leading to uncontrolled cell proliferation. BRCA2 (breast cancer 2 gene) helps repair damaged DNA and maintain the stability of a cell\'s genetic information. Males who develop breast cancer are more likely to have a BRCA2 mutation than a BRCA1 mutation. Risk factors and possible causes of breast cancer can be divided into the following categories: age, gender, personal and family history of breast cancer, histologic, genetic, and reproductive risk factors, exogenous hormone use, and environmental factors. Environmental factors: smoking, increased alcohol consumption, obesity. Adipose tissue secretes leptin that promotes breast cancer cell proliferation by inhibiting cell death signaling pathways. Sedentary lifestyle decreases immune function, increases insulin resistance, and increases inflammation.** **Alterations of the Male Reproductive System** **[Lower Urinary Tract Obstructions in Males:] Bladder outflow obstruction (BOO) resulting in urinary hesitancy, intermittency, nocturia and dribbling. Symptoms affect quality of life. Associated with urethral stricture, benign prostatic hyperplasia, and prostate cancer.** ***[1) Urethral strictures]:* Most urethral strictures result from injury to the urethral mucosa and surrounding tissues.** ***[2) Benign Prostatic Hyperplasia] (BPH)* The prostate enlarges as nodules form and grow known as nodular hyperplasia (increased production of cells), and glandular cells enlarge. The development of BPH occurs over a prolonged period, and changes within the urinary tract are slow and insidious. As nodular hyperplasia progresses, tissues that surround the prostatic urethra compress it, usually causing bladder outflow obstruction (BOO).** ***[3) Prostate Cancer]* Most are classified as adenocarcinomas and usually develop in androgen-dependent epithelium.** **More than 95% of prostatic neoplasms are adenocarcinomas, and most occur in the periphery of the prostate. Prostatic adenocarcinoma is a heterogeneous group of tumors with a diverse spectrum of molecular and pathologic characteristics and, therefore, diverse clinical behaviors and challenges. The cells of origin of a prostatic adenocarcinoma are thought to originate from the basal or luminal prostate epithelial cells, and genetic mutation**. **BRCA2 mutation has the highest risk for developing prostate cancer. Interactions of environmental factors and genetic factors contribute to risk of prostate cancer. The first manifestations of disease are those of BOO: slow urinary stream, hesitancy, incomplete emptying, frequency, nocturia, and dysuria. Unlike the symptoms of obstruction caused by BPH, the symptoms of obstruction caused by prostatic cancer are progressive and do not remit.** **Screening for prostatic cancer includes prostate-specific antigen (PSA) blood test and digital rectal exam (DRE). The issue of prostate cancer screening is controversial. NOTE: Evidence is lacking on whether PSA screening or DRE reduces the mortality from prostate cancer or that the benefits outweigh the harms of screening. Nonetheless, the PSA test is commonly used in the diagnosis and management of prostate cancer. PSA screening may reduce the prostate cancer mortality risk but is associated with false positive results, biopsy complications, and overdiagnosis. DRE may detect early prostatic carcinomas, but it has low sensitivity and specificity. *Cancer diagnosis is confirmed through tissue biopsy and microscopic examination of tissue.*** ***[Erectile Dysfunction]* Persons with ED have more endothelial damage, and ED may be the first symptom of endothelial injury. Penile erection requires a series of coordinated and complex events involving neuronal pathways, vascular response, and psychosomatic stimulation. Endocrine regulation is critical for successful sexual development (SD) and for normal sexual function. Failure of the pituitary gland to maintain relative ratio of endogenous levels likely disrupt processes in sexual function. Testosterone is the most important androgen for libido and spermatogenesis. Androgen deficiency can lead to ED, loss of libido, and a decline in reproductive capacity. Emotional and psychological response (e.g., anxiety, depression, and loss of self-esteem) can affect sexual functioning. The pathophysiologic mechanisms responsible for such changes are not known.** ***[Infertility]* affects approximately 15% of all couples and is defined as the inability to conceive over 1 year of unprotected intercourse. The rate of infertility may be increasing because of increased rates of STIs, environmental exposures, delayed childbearing, or lack of previous reporting. Causes of infertility include ovulatory disorder, abnormal semen, blockage of the fallopian tubes, and endometriosis. Ovulatory factors account for approximately 40% of infertility. Regular ovulation occurs as a result of a functioning hypothalamic/pituitary axis. Ovulation can be disrupted by hormonal imbalances (e.g., TSH, estrogen, progesterone), chronic conditions, and stress. Advancing age is a major factor for infertility because the regularity of ovulation and the quality of ova decrease with age. Approximately 20% of cases are because of abnormalities of the reproductive tract, such as tubal pathologies. Endometriosis, adhesions, and scarring from PID are major contributors to blockages within the reproductive tract of persons with a uterus and ovaries.** **Sexually Transmitted Infections** **Sexually transmitted infection (STI) In the past an infection transmitted through sexual intercourse was called a venereal disease. Because of its limited scope, the term venereal disease has been replaced with sexually transmitted infection (STI). Many infected individuals do not seek treatment because symptoms are absent, minor, or transient or because health services are inaccessible, unaffordable, or culturally insensitive.** **[*Gonorrhea*] is caused by Neisseria gonorrhoeae, aerobic, non--spore-forming, oxidase-positive, gram-negative diplococci. Transmission of gonococcal infection generally requires direct contact of epithelial (mucosal) surfaces. CDC reported a total of 616,392 new cases, with as many as 1,000,000 cases undiagnosed. Continues to rise!!** **As many as 5% to 10% of infected men never have signs or symptoms of gonorrhea.** **More than half of gonorrhea infections in women are initially asymptomatic.** **If a pregnant person has gonorrhea at the time of delivery, gonorrhea can infect the infant. Most states require that all infants receive prophylactic ophthalmic antibiotics to prevent gonococcal eye infection (ophthalmia neonatorum). Topical antibiotics may not be effective in eliminating neonatal infection, and systemic treatment is indicated for all newborns with known exposure. Untreated infection causes bilateral corneal ulceration, with a profuse yellow or gray purulent exudate, and is followed by necrosis, scarring, and blindness.** ***[Chlamydia]* is the common name for infections caused by C. trachomatis. C. trachomatis is responsible for a variety of syndromes, including acute urethral syndrome, nongonococcal urethritis (NGU), mucopurulent cervicitis, and *PID*. Chlamydia is a leading cause of preventable infertility and ectopic pregnancy. Because chlamydia is often asymptomatic, it is estimated that just over a million unreported infections occur annually.** **Risk groups for chlamydia include age younger than 26, recent new sexual partner, and drug use or other risky behaviors. Like gonorrhea, Chlamydia infection can be transmitted to the infant during birth and can cause eye infections and pneumonia in affected newborns.** ***[Human papillomavirus (HPV)]* is the most common sexually transmitted virus in the United States particularly. HPV infection is the most common symptomatic viral STI in the United States** **in teens and young adults! Although more than 5.5 million cases are diagnosed yearly, the prevalence of 24 million cases is considered underestimated because HPV infection is often subclinical. The virus is easily transmissible through direct contact with lesions or infected secretions.** **Prevention of HPV acquisition in young adults is important! In young females, the cervix is more vulnerable to HPV. It is unknown why some people are able to clear HPV infection and others cannot. Fortunately, most cases of HPV are transient, and 70% of healthy individuals will spontaneously eliminate the virus. The persistence of the virus and the immune response play a role in the development of cancer following HPV exposure. Behaviors and conditions that affect overall health status affect the body\'s ability to clear HPV infection. Alcohol use, smoking, and HIV infection are strongly correlated with persistent HPV infection.** ***[Alterations of the Pulmonary System]*** **[Obstructive Pulmonary diseases:] These disorders are characterized by infiltration of the lung by inflammatory cells with the release of numerous cytokines (Interleukins are a group of cytokines that are usually pro-inflammatory) that contribute to airway damage and mucus production. Airway obstruction is worse with expiration. More force (i.e., use of accessory muscles of expiration) or more time is required to expire a given volume of air, and emptying of the lungs is slowed causing AIR-TRAPPING thus increased residual volume. Individuals have an increased work of breathing with subsequent dyspnea, hypoxia, and hypercapnia. The most common obstructive diseases are asthma and chronic obstructive pulmonary disease (COPD) (chronic bronchitis and emphysema).** ***[Asthma]*. Most common is allergic asthma.** ***Early asthmatic response*: Antigen exposure to the bronchial mucosa -- Initiates airway hyperresponsiveness** **Immune activation: Antigen presented to T-helper cells -- Interleukins (cytokines) and IgE production.** **IgE causes mast cell degradation and inflammatory mediators are released including histamine, prostaglandins, and leukotrienes: these mediators cause increased capillary permeability, mucosal edema, bronchial smooth muscle contraction (bronchospasm), and tenacious mucus secretion from mucosal goblet cells with narrowing of and obstruction to airway.** ***Late asthmatic response* begins a few hours after the early response. Release of toxic neuropeptides contribute to increased bronchial hyperresponsiveness. Impaired expiration causes air trapping, hyperinflation distal to obstructions and increased work-of-breathing (WOB). Hypoxemia further increases hyperventilation through stimulation of the respiratory center, causing Paco~2~ to decrease and pH to increase (respiratory alkalosis).** ***Status Asthmaticus: Bronchospasms are becoming more and more severe! With progressive obstruction of expiratory airflow, air trapping becomes more severe and the lungs and thorax become hyperexpanded, putting the respiratory muscles at a mechanical disadvantage. This leads to a fall in tidal volume with increasing CO~2~ retention and respiratory acidosis.* Respiratory acidosis signals respiratory failure. Ventilation is severely impaired, little air exchange is taking place "silent chest".** **[Chronic Obstructive Pulmonary Disease (COPD). Two common types:]** ***[Chronic Bronchitis]* *is defined as hypersecretion of mucus and chronic productive cough that continues for at least 3 months of the year (usually the winter months) for at least 2 consecutive years.* Continual bronchial inflammation causes bronchial edema and increases the size and number of mucous glands and goblet cells in the airway epithelium. Thick, tenacious mucus is produced and cannot be cleared because of impaired ciliary function. The lung's defense mechanisms are, therefore, compromised, increasing susceptibility to pulmonary infection, which contributes to airway injury. Hypercapnia (increase in P~a~CO~2~) related to chronic hypoventilation is common.** ***[Emphysema]* is characterized by destruction of alveoli walls through the breakdown of elastin within the septa. This destruction of alveoli walls causes abnormal permanent enlargement of the air spaces in the lungs, also known as gas-exchange acini. Expiration becomes difficult because loss of elastic recoil reduces the volume of air that can be expired passively, and air is trapped in the lungs. Air trapping causes hyperexpansion of the chest (barrel chest), which puts the muscles of respiration at a mechanical disadvantage. Smoking is a common cause of emphysema; however, α~1~-Antitrypsin deficiency is suggested in nonsmokers and individuals who develop emphysema before age 40 years.** ***[Cor pulmonale]*: It is associated with pulmonary disorders. Cor pulmonale is caused by hypoxemia and hypercapnia that leads to pulmonary vasoconstriction and increased pressures in the pulmonary system. As increased pulmonary arterial pressure causes increased workload on the right ventricle Cor pulmonale develops -- as it progresses further hypertrophy and dilation of the right ventricle eventually leads to right-sided heart failure.** **[Restrictive Lung Diseases:] Decreased compliance (stiffness) meaning it takes more effort to expand the lungs during *inspiration*. Examples are aspiration, pulmonary edema, acute respiratory distress syndrome (ARDS), and pneumoconiosis. *[Example of a Restrictive Lung Disease: Pneumoconiosis]* represents any change in the lung caused by inhalation of inorganic dust particles, which usually occurs in the workplace. The dusts of silica (silicosis), asbestos (asbestosis), and coal (black lung) are the most common causes of pneumoconiosis. *It is NOT reversible, and treatment is usually palliative and focuses on preventing further exposure.*** ***[Pulmonary Vascular Disease - Pulmonary Emboli (PE)]: The first symptom in 25% of people with PE is death. Most common cause: Deep Vein Thrombosis (DVT) develops, embolus breaks off and travels through the circulation to a pulmonary vessel. Risk factors, referred to as the triad of Virchow, are venous stasis (immobility), injury to epithelial cells that line the vessels (trauma, infection such as COVID-19), and hypercoagulability (malignancy).*** **[Malignancies of the Respiratory Tract]** **Lung Cancer -- Two main categories: *Non--Small Cell Lung Cancer (NSCLC) Three major types:*** ***1) Squamous cell carcinoma accounts for about 30% of bronchogenic carcinomas:* Tumors are typically located centrally near the hila and project into bronchi. Because of this central location, nonproductive cough or hemoptysis is common. Chest pain is a late symptom associated with large tumors. *These tumors can remain fairly well localized and tend not to metastasize until late in the course of the disease.*** ***2) Adenocarcinoma (tumor arising from glands) of the lung constitutes 35% to 40% of all bronchogenic carcinomas. Environmental tobacco smoke, occupational carcinogens, viruses, hormones, and positive family history are associated with this tumor type. Pulmonary adenocarcinoma develops in a stepwise fashion through atypical adenomatous hyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma to invasive carcinoma. These tumors, which are usually smaller than 4 cm, more commonly arise in the peripheral regions of the pulmonary parenchyma. Individuals may be asymptomatic, and the tumors may be discovered by routine chest imaging in the early stages, or the individual may present with pleuritic chest pain and shortness of breath from pleural involvement by the tumor.*** ***3) Large cell carcinomas constitute approximately 10% of bronchogenic carcinomas. These transformed epithelial cells have lost clear evidence of maturation and are considered an undifferentiated non--small cell carcinoma. Rapid growth and early metastasis that is usually widespread.*** ***Small cell lung carcinomas (SCLCs)* are the most common type of neuroendocrine lung tumors. Most tumors arise from the central part of the lung. Because these tumors *show a rapid rate of growth and tend to metastasize early* and widely, this type of carcinoma has the worst prognosis of all lung cancers. Staging for small cell carcinoma is divided into only two categories: limited disease and extensive disease.** **Tobacco smoke contains more than 7000 chemicals, 69 of which are classified as carcinogens. Air pollution and other inhaled toxins also contain numerous carcinogens. These chemicals, along with an inherited genetic predisposition to cancers, result in tumor development. Once lung cancer is initiated by these carcinogen-induced mutations, tumor development is promoted by additional mutations that alter the production and response to growth factors that alter cell growth and differentiation and by the production of inflammatory mediators. The bronchial mucosa suffers multiple carcinogenic "hits" because of repetitive exposure to tobacco smoke, and, eventually, epithelial cell changes begin progressing from metaplasia to carcinoma in situ and finally to invasive carcinoma. Further tumor progression includes invasion of surrounding tissues and finally metastasis to distant sites, including the brain, bone marrow, and liver.** **Alterations of the Pulmonary System in Children** ***[Pediatric obstructive apnea syndrome (OSAS)]* Results from partial or complete upper airway obstruction during sleep. The incidence is higher among obese children. Airway narrowing is caused from craniofacial abnormalities (low mandibular plane angle), obesity (increases airway collapsibility), asthma, allergies, adeno-tonsillar hypertrophy. Sleep patterns are affected and include snoring, labored breathing, oxygen desaturation with hypercapnia waking the child up, and the pattern repeats. Associated with cognitive and neurobehavioral impairment.** ***[Surfactant Deficiency Disorder (SDD]):* SDD, also known as respiratory distress syndrome, almost occurs exclusively in premature infants born before 28 weeks gestation. What does surfactant do? It produces a detergent-like effect that separates the liquid molecules in the alveoli to decrease alveolar surface tension. This expands the alveoli to facilitate gas exchange. Also, lungs in the premature infant are underdeveloped and have small alveoli adding to the difficulty of proper alveoli inflation.** ***[Cystic Fibrosis]*: Autosomal recessive disease with multiorgan involvement. It affects the lungs, digestive tract, and reproductive organs. Mutations of a gene, known as the cystic fibrosis transmembrane conduction regulator (CFTR), cause abnormal expression of the CFTR protein. SO WHAT -- Without adequate CFTR function, chloride and water are not transported appropriately across epithelial membranes. This causes thick, dehydrated mucus. Mucous plugs, chronic inflammation and infection. (Respiratory failure is almost always the cause of death).** ***[Bronchiolitis]* -- most common viral respiratory tract infection of the small airways in children younger than 2 years of age. The most common pathogen is the respiratory syncytial virus (RSV). Premature infants are more susceptible to a severe or even a deadly course. Viral infections can cause necrosis of the bronchial epithelium and destruction of ciliated epithelial cells. Mucosa becomes edematous along with accumulation of mucus, and bronchospasms with narrowing of peripheral airways.** **[*Sudden infant death syndrome* (SIDS)] -- is the most common cause of sudden unexpected infant death. The etiology of SIDS remains unknown. Highest risk is from 2-4 months of age. However, risk factors associated with SIDS: low-birth weight, large family size, lower socioeconomic status, sleeping on soft bedding, parental smoking (see page 1207 for complete list). Education is key to prevention.** ***[Alterations of Digestive Function]*** ***[Gastroesophageal reflux disease (GERD)]* is the reflux of acid and pepsin from the stomach to the esophagus that causes esophagitis.** **Abnormalities in lower esophageal sphincter (LES) function, esophageal motility, and gastric motility or emptying can cause GERD. Spontaneous relaxation of the LES may be triggered by gastric distention after meals and trigger acid reflux. Acid reflux may be triggered by diet and lifestyle factors such as food intake that causes delayed gastric emptying, acidic foods, and obesity. Vomiting, coughing, lifting, bending, and pregnancy also increase abdominal pressure, contributing to the development of reflux esophagitis.** **Gastric contents are *highly acidic* *(low pH=2)* or contain bile salts and pancreatic or intestinal enzymes, reflux esophagitis can be severe. In individuals with weak esophageal peristalsis, refluxed chyme remains in the esophagus longer than usual. The refluxate causes mucosal injury and inflammation, with hyperemia, increased capillary permeability, edema, tissue fragility, and erosion. Precancerous lesions can be a long-term consequence. Precancerous lesions can progress *to adenocarcinoma*.** **Peptic Ulcer Disease** ***[Duodenal ulcers]* occur with greater frequency than other types of peptic ulcers and *are generally caused by Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) use*. Independently or in combination, cause acid and pepsin concentrations in the duodenum to increase and penetrate the mucosal barrier, causing ulceration. The increased duodenal acid promotes metaplasia in the duodenum and *favors H. pylori colonization*. Both H. pylori and the increased acid result in decreased duodenal bicarbonate production. In addition, H. pylori infection activates immune cells (T and B lymphocytes with the infiltration of neutrophils) and the release of inflammatory cytokines which damage the mucosa. H. pylori also produces a toxin that causes loss of protective mucosal cells, resulting in ulceration. H. pylori mucosal infection can promote gastric cancer, but the incidence is lower for duodenal ulcer than for gastric ulcer, and the mechanism is unknown*.*** ***[Gastric ulcers]* are ulcers of the stomach.** ***The primary defect is an abnormality that increases the mucosal barrier\'s permeability to hydrogen ions.* Gastric secretion may be normal or less than normal, and there may be a decreased mass of parietal cells. Commonly developing in the *antral area of the stomach*, Chronic gastritis is often associated with the development of gastric ulcers and may precipitate ulcer formation by limiting the mucosa\'s ability to secrete a protective layer of mucus. Other factors include:** **  Decreased mucosal synthesis of prostaglandins** **  Damage to the mucosal membrane from duodenal reflux of bile and pancreatic enzymes** **  Use of NSAIDs (decreases prostaglandin synthesis)** **  H. pylori infection** **Characteristic** **Gastric Ulcer** **Duodenal Ulcer** ----------------------------------- ---------------------------- ---------------------------- **Age of Onset** **50-70 years of age** **20-50 years of age** **Family history** **Usually negative** **Positive** **Cancer risk** **Increased** **Not increased** **Helicobacter pylori infection** **Often present** **Often present** **Pain** **Immediate after eating** **2-3 hours after eating** **Inflammatory Bowel Disease** ***[Ulcerative colitis]*** **The disease begins in the rectum (proctitis) and may extend proximally to the entire colon (pancolitis). The lesions are limited to mucosal epithelium, are not transmural, and do not involve "skip" lesions. There is decreased secretion of mucin, which is antimicrobial and provides a protective layer against pathogens. Loss of this protection leads to increased permeability of the mucosa, increased passage of pathogens and other antigens, and stimulation of the gut immune system with an inflammatory response. There is activation of T cells and dendritic cells, triggering the production of proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-12 and IL-23, toxic oxygen free radicals, and interferon-gamma (IFN-γ), producing damage to the intestinal epithelium. Some of these molecules have become important targets for treatment. The mucosa is inflamed and is involved in a continuous fashion. With milder inflammation, the mucosa is hyperemic and edematous and may appear dark red. In more severe inflammation, the mucosa becomes hemorrhagic, and small erosions form and coalesce into ulcers. Abscess formation, necrosis, and ragged ulceration of the mucosa ensue. Edema and thickening of the muscularis mucosae may narrow the lumen of the involved colon. Mucosal destruction and inflammation cause bleeding, cramping pain, and an urge to defecate. Frequent diarrhea, with passage of small amounts of blood and purulent mucus, is common. Loss of the absorptive mucosal surface and rapid colonic transit time cause large volumes of watery diarrhea.** **[*Crohn's disease* (CD)] Inflammation begins in the intestinal submucosa and spreads with discontinuous *transmural involvement or "skip lesions" that can involve any part of the GI tract from the mouth to the perianal area.* Skip lesions are distinguished by inflamed areas mixed with uninflamed areas, noncaseating granulomas, fistulas, and deep penetrating ulcers. The typical lesion associated with CD is a granuloma or a mass of inflammatory tissue with a cobblestone appearance of inflamed tissue surrounded by ulceration. Fistula may form in the perianal area between loops of intestine and may extend into the bladder, rectum, or vagina and form intra-abdominal abscesses. Strictures may develop, promoting obstruction. *Small intestinal malabsorption is common*.** **FEATURE** **ULCERATIVE COLITIS** **CROHN'S DISEASE** ----------------------------------------- -------------------------------------------------------- ----------------------------------------------------------- **Incidence** **Age at onset** **Any age; 10-40 years most common** **Any age; 10-30 years most common** **Family history** **Less common** **More common** **Pathophysiology** **Location of lesions** **Colon and rectum, continuous and no "skip" lesions** **All of GI tract: mouth to anus, "skip" lesions common** **Inflammation and ulceration** **Mucosal layer involved** **Entire intestinal wall involved** **Strictures and possible obstruction** **Rare** **Common** **Clinical Manifestations** **Abdominal pain** **Occasional** **Common** **Diarrhea** **Common** **Common** **Bloody stools** **Common** **Less common** **Small intestinal malabsorption** **Rare** **Common** ***[Diverticular disease]*** - **Diverticula can occur anywhere in the GI tract, particularly at weak points in the colon wall. *The most common sites are the left sigmoid colon (located in the large intestines). Associated with muscle thickening*. This contributes to increased intraluminal pressure and herniation. Pressure within the narrow lumen can increase enough to rupture the diverticula, causing inflammation and diverticulitis. Bacteria and local ischemia also may be contributing factors. Complicated diverticulitis includes abscess, fistula, obstruction, bleeding, or perforation.** **Disorders of the Accessory Organs: Liver** **Cirrhosis involves the replacement of normal healthy liver tissue with scar tissue. Cirrhosis is an irreversible inflammatory, fibrotic liver disease. Chaotic fibrosis alters or obstructs biliary channels and blood flow. New vascular channels form shunts, and blood from the portal vein bypasses the liver, contributing to portal hypertension, metabolic alterations, and toxin accumulation.** ***[Alcoholic cirrhosis]* is caused by the toxic effects of alcohol metabolism in the liver, immunologic alterations, inflammatory cytokines, oxidative stress from lipid peroxidation, malnutrition, and an ongoing cycle of liver injury and regeneration. Alcohol is transformed into acetaldehyde; excessive amounts are toxic and significantly alter hepatocyte function and activate hepatic stellate cells, a primary cell involved in liver fibrosis. Enzyme and protein synthesis may be depressed or altered, and hormone and ammonia degradation is diminished. Acetaldehyde inhibits protein synthesis and export of proteins from the liver, alters metabolism of vitamins and minerals, and induces malnutrition. Fibrosis and scarring interspersed with regenerating nodules alter the structure of the liver and obstruct biliary and vascular channels. Eventually hepatocytes lose their ability to regenerate with progression to liver failure.** ***[Nonalcoholic fatty liver disease (NAFLD)]* is the infiltration of hepatocytes with fat, primarily in the form of triglycerides, that occurs in the absence of alcohol intake and inflammation. It is associated with obesity (including obese children), insulin resistance, high levels of cholesterol and triglycerides that exceed metabolic capacity, metabolic syndrome, and type 2 diabetes mellitus. NAFLD is the most common chronic liver disease in the United States.** ***[Portal hypertension]* is caused by disorders that cause resistance to flow in the portal venous system. Intrahepatic causes result from *vascular remodeling with shunts*, and the most common cause is cirrhosis of the liver. Post hepatic causes is usually associated with cardiac disorders that impair the pumping ability of the right side of the heart. This causes blood to collect and increases pressure in the veins of the portal system. Complications of portal hypertension:** **1) *Esophageal varices:* Varices are distended, tortuous collateral veins. Prolonged elevation of pressure in the portal vein causes collateral veins to open between the portal vein and systemic veins. The prolonged pressure is distributed throughout the GI tract and results in transformation into varices, particularly in the lower esophagus and stomach.** **2*) Ascites* is the accumulation of fluid in the peritoneal cavity. Ascites traps body fluid in the peritoneal space, from which it cannot escape. Ascites reduces the amount of body fluid available for normal physiological functions. Portal hypertension causes capillary hydrostatic pressure to exceed capillary oncotic pressure (see Chapter 3), pushing water into the peritoneal cavity. Reduced serum albumin levels reduce capillary oncotic pressure adding to the fluid shift.** **3) *Hepatic encephalopathy* results from a combination of biochemical alterations that affect neurotransmission and brain function. Liver dysfunction and the development of collateral vessels that shunt blood around the liver to the systemic circulation permit toxins absorbed from the GI tract and normally removed by the liver, to accumulate and circulate freely to the brain. The accumulated toxins alter cerebral energy metabolism, interfere with neurotransmission, and cause edema. The most hazardous substances are end products of intestinal protein digestion, particularly ammonia, which cannot be converted to urea by the diseased liver.** **Disorders of the Gallbladder and Pancreas** ***[Cholelithiasis]* is the presence of gallstones. Gallstones form in the biliary tract as a result of impaired metabolism of cholesterol, bilirubin, and bile acid (BA) and *hypomotility* of the gallbladder.** **Supersaturation sets the stage for cholesterol crystal formation (cholesterol nucleation), or the formation of "microstones." More crystals aggregate on the microstones, which grow to form "macrostones." This process more commonly occurs in the gallbladder. Prolonged exposure to supersaturated bile can decrease gallbladder motility, with incomplete postprandial emptying.** **Jaundice indicates that the stone is located in the common bile duct.** ***[Acute Pancreatitis]*** **- Reflux of bile acid (BA) into the pancreatic duct from gallstone obstruction of the common bile duct and ethanol metabolites within the pancreas promote intracellular pancreatic injury, including calcium overload.** **Gallstones can slip out of the gallbladder and block the bile duct, preventing pancreatic enzymes (for example trypsin) from reaching the small intestine. This forces the enzymes back into the pancreas, where they irritate the cells and cause inflammation. Cellular injury leads to recruitment of neutrophils with release of inflammatory mediators*. Bile duct obstruction increases* with recruitment of neutrophils. *Both a pancreatic and systemic inflammatory response is promoted*.** **Sustained hypercalcemia increases the content of calcium in the pancreatic secretions, resulting in an accelerated transformation of trypsinogen to trypsin with cell injury, inflammation, and necrosis.** **Trypsin activation causes autodigestion.** ***Alterations of Digestive Function in Children*** ***[Cleft lip (CL) and cleft palate (CP)]* are the most common craniofacial malformation of the newborn.** **Cleft lip is caused by *the incomplete fusion of the nasomedial or intermaxillary process* beginning the fourth week of embryonic development, a period of rapid development. The cleft causes structures of the face and mouth to develop without the normal restraints of encircling lip muscles. *The facial cleft may affect not only the lip but also the external nose, nasal cartilages, nasal septum, and alveolar processes*. The cleft is usually just beneath the center of one nostril. The defect may occur bilaterally and may be symmetrical or asymmetrical. The more complete the CL, the greater the chance that teeth in the line of the cleft will be missing or malformed.** **Cleft palate is often associated with CL but may occur without it. *The fissure may affect only the uvula and soft palate or may extend forward to the nostril and involve the hard palate and the maxillary alveolar ridge*. It may be unilateral or bilateral, with the cleft occupying the midline posteriorly and as far forward as the alveolar process (the ridge of bone that holds the teeth), where it deviates to the involved side. Clefts involving the palate only are usually, but not necessarily, in the midline. In some cases, the vomer (the small, thin bone separating the left and right nasal cavities) and nasal septum are partly or completely undeveloped. When these facial bones are involved, the nasal cavity may freely communicate with the oral cavity.** **Cleft lip and/or palate** - ***Family history*. Parents with a family history of cleft lip or cleft palate face a higher risk of having a baby with a cleft.** - ***Exposure to certain substances during pregnancy*. Cleft lip and cleft palate may be more likely to occur in persons who smoke cigarettes, drink alcohol or take certain medications.** - ***Obesity and/or diabetes.* There is some evidence that obesity as well as diabetes may be linked to the increased risk of cleft lip and palate.** ***[Infantile hypertrophic pyloric stenosis (IHPS)]* is an acquired narrowing and distal obstruction of the pylorus and a common cause of postprandial (after a meal) vomiting.** **It is the most common cause of intestinal obstruction in infancy. The etiology of IHPS is unknown, but genetic and environmental factors, bottle feeding, younger maternal age, maternal smoking, and erythromycin administration in the first two weeks of life have shown associations with the disease. Individual muscle fibers of the longitudinal and circular muscles thicken, so the entire *pyloric sphincter* *becomes enlarged and inflexible*. Muscle fibers thicken, the opening of the pyloric sphincter becomes narrow. *The mucosal lining of the pyloric opening is folded and narrowed by the encroaching muscle.* Because of the extra peristaltic effort necessary to force the gastric contents through the narrow opening, the muscle layers of the stomach may become hypertrophied as well.** ***[Hirschsprung disease]*** - **The congenital malformation results from failure of neural crest cells to migrate into the GI tract. There is an absence of parasympathetic plexuses (Meissner and Auerbach plexuses) along variable lengths of the *colon (located in the large intestines)*. *Lacking neural stimulation in muscle layers of the colon* causes failure to propel feces through the colon, leading to functional obstruction. This causes the proximal colon to become distended, hence the term megacolon is often used. Abdominal distention and poor feeding are common.** ***[Intussusception]*** - **The ileum commonly telescopes into the cecum and part of the ascending colon by collapsing through the ileocecal valve, although intussusception can occur anywhere from the duodenum to the rectum. The proximal portion of the intestine (the intussusceptum) telescopes into the distal portion (the intussuscipiens) in the direction of peristaltic flow. Compression leads to venous stasis, engorgement, edema, exudation, and further vascular compression within hours. Edema and compression obstruct the flow of chyme through the intestine. *Unless the intussusception is treated, serious complications can occur - bleeding, necrosis, and bowel perforation ensue.*** ***[Alterations of the Renal and Urinary Tract Systems]*** ***[Cystitis: ]*** **[*1) Urinary tract infection* (UTI]): Common clinical manifestations of a urinary tract infection in an older adult are confusion and poorly localized abdominal discomfort. Can be very difficult to diagnose due to vague symptoms. Two common factors account for UTI: virulence of the pathogen and the efficiency of the immune response. The most common causative organism is** **Escherichia coli (finger like projections that cling to /bind to the uroepithelium and resist flushing by flow of urine) particularly in females due to the anatomical structure.** **[*2) Painful bladder syndrome/interstitial cystitis* (PBS/IC)] Considered a chronic bladder pain disorder. Can be difficult to diagnose -- rule out other causes. *PBS is often associated with other systemic chronic disorders such as fibromyalgia, irritable bowel disease, and chronic fatigue syndrome* The exact cause of PBS/IC is unknown, *but an autoimmune reaction may be responsible for the inflammatory response, which includes mast cell activation, altered epithelial permeability, neuroinflammation, and increased sensory nerve sensitivity. Chronic inflammation leads to fibrosis of the bladder. Inflammation and fibrosis of the bladder wall are accompanied by pain. Bladder volume may decrease as a result of fibrosis that is due to chronic inflammation.*** ***Painful bladder syndrome (BPS), also known as interstitial cystitis (IC), is a chronic condition that causes bladder pain and pressure, and a frequent or urgent need to urinate. Symptoms: Pain and pressure in the bladder, pelvic pain, and a frequent or urgent need to urinate. Symptoms can range from mild to severe, and may come and go or persist. PBS can significantly impact quality of life, and can sometimes lead to other health problems such as depression.*** ***[Nephrolithiasis (Kidney Stones):] They can be located in the kidneys, ureters, and bladder. Stones are classified according to the primary minerals that make up the stone. However,* the most common type of kidney stone is calcium oxalate. Pathophysiology: a) supersaturation of the mineral in the urine, b) grow through crystallization or agglomeration (aggregation), and c) lack of stone inhibitors (uromodulin).Microorganisms usually associated with acute pyelonephritis include E. coli, Proteus, or Pseudomonas. These microorganisms split urea into ammonia, making alkaline urine that increases the risk of stone formation.** **[*Acute glomerulonephritis (AG)*] Common causes: infection, ischemia, free radicals, drugs, toxins, and vascular disorders. Includes renal diseases in which glomerular inflammation is caused by immune mechanisms. *The most common type of immune injury is related to antigen-antibody complexes in the glomerulus.* The complexes damage the glomerular capillary filtration membrane including the endothelium, basement membrane, and epithelium. *The severe AG symptoms include sudden onset of hematuria, red blood cell casts and proteinuria (much milder than nephrotic syndrome), and can also be accompanied by edema, hypertension, and impaired renal function.*** **[*Acute Kidney Injury* (AKI)] may be acute and rapidly progressive (within hours), and the process may be reversible. Renal insufficiency refers to a decline in renal function to about 25% of normal or an eGFR of 25 to 30 ml/minute. (eGFR is extremely useful in determining improvement or decline in kidney function). Levels of serum creatinine and urea are mildly elevated. However, changes in serum creatinine level occur only if more than 50% of glomerular filtration is lost. *Table 38.11 in textbook (modified:)*** **[Prerenal AKI:] Inadequate kidney perfusion is the most common reason for AKI.** - **Hypovolemia -- such as blood loss** - **Reduced cardiac output: heart failure with reduced ejection fraction** - **Systemic hypotension or hypoperfusion** - **Acute Myocardial Infarction** **[Intrarenal AKI: ]** - **Renal vein thrombosis** - **Renal artery stenosis** - **Acute tubular necrosis (postischemic or nephrotoxic)** - **Glomerular: immune-complex diseases such as lupus nephritis** **[Postrenal AKI:]** **disorders associated with urinary tract obstruction** - **Bladder outlet: Benign prostatic hypertrophy** - **Ureteral obstruction destruction (tumors, stones, clots)** - **Neurogenic bladder** ***[Chronic Kidney Failure]* The factors that contribute to the pathogenesis of CKD are complex and involve the interaction of many cells, cytokines, and structural alterations. CKD is the progressive and irreversible loss of renal function indicated by a decline in GFR. CKD is associated with systemic diseases, such as diabetes mellitus (most significant risk factor), hypertension, and systemic lupus erythematosus. CKD also is associated with intrinsic kidney diseases, such as AKI, chronic glomerulonephritis, or vascular disorders. The progression phase of the disease is characterized by a persistent state of inflammation and hypoxia and oxidative stress that contribute to the development of renal fibrosis. The kidneys have a remarkable ability to adapt to the loss of nephron mass. Symptomatic changes result from increased plasma levels of creatinine, urea, and potassium. Alterations in salt and water balance usually do not become apparent until renal function declines to less than 25% of normal when adaptive renal reserves have been exhausted.** **Two factors that have consistently been recognized to advance renal disease are proteinuria and angiotensin II activity. Glomerular hyperfiltration, increased glomerular capillary permeability, and loss of negative charge may lead to proteinuria. Proteinuria contributes to tubulointerstitial injury by accumulating in the interstitial space of the nephron tubules. There is activation of complement proteins and other mediators and cells, such as macrophages, that promote inflammation and progressive fibrosis. Angiotensin II (from activation of the renin-angiotensin-aldosterone system \[RAAS\]) causes efferent arteriolar vasoconstriction that promotes glomerular hypertension, systemic hypertension, and hyperfiltration.** **Renal regulatory mechanisms, such as tubular glomerular feedback and the RAAS, are also affected, making it impossible for the kidney to compensate for water--electrolyte and acid-base disturbances.** **Systematic effects of CKD -- see table 38.16 (pg. 1261). You will see that no organ system is spared from progressive declining kidney function. Here are a few to focus on:** ***Hematologic*: The kidneys are the primary site of production for erythropoietin (EPO), a hormone that stimulates the bone marrow to produce red blood cells. Reduced erythropoietin secretion associated with CKD reduces red blood cell (RBC) production. NOTE: also, the uremic environment shortens the life span of the RBC.** ***Skeletal:* Hypocalcemia is accelerated by impaired renal synthesis of 1,25-dihydroxy-vitamin D. Renal phosphate excretion also diminished. Phosphate binds to calcium -- contributing further to hypocalcemia. (Hypocalcemia/hyperphosphatemia. Calcium-phosphate have a reciprocal relationship -- one goes up the other goes down.). Decreased calcium levels TRIGGERS: parathyroid to secrete PTH. COMBINED EFFECTS: secondary hyperparathyroidism and vitamin D deficiency cause renal osteodystrophy and increased risk of skeletal fractures.** ***Acid-base balance*: End-Stage Renal Failure (ESRF) Metabolic acidosis (Chapter 3) develops when GFR decreases to less than 20% to 25% of normal. The causes of acidosis are primarily related to decreased hydrogen ion elimination and decreased bicarbonate reabsorption*.* With ESRF, metabolic acidosis may be severe enough to require alkali therapy and dialysis. Bicarbonate levels should be maintained at about 22 mEq/L. Electrolyte Imbalance: With progression of ESRF total body potassium levels may become life threatening (Hyperkalemia).** **Alterations of Renal and Urinary Tract Function in Children** ***[Hypospadias]* is the condition when the urethral meatus is located on the ventral portion or undersurface of the penis. Epispadias is characterized by the dorsal urethra that has not fused and has failed to form a tube.** ***[Vesicoureteral Reflux (VUR)] An estimated 30-40% of children younger than 5 years old who develop a UTI have VUR. In Primary VUR, urine sweeps up into the ureter and flows back into the bladder and an abnormally short submucosal tunnel and ureter that permits reflux by the rising pressure of the filling bladder. The combination of reflux lower UTI is an important cause of pyelonephritis. Renal parenchymal injury, scarring, hypertension and CKD can occur many years later making early diagnosis and treatment important. Secondary VUR develops in association with acquired conditions such neurogenic bladder dysfunction or ureteral obstructions.*** **[*[Nephrotic syndrome]*](https://jigsaw.vitalsource.com/books/9780323088541/content/id/B9780323088541170018_g3020) is more common in children than adults. It is characterized by the excretion of 3.0 g or more of protein (massive proteinuria) in the urine per day, hypoalbuminemia (less than 3.0 g/dl), hyperlipidemia, and peripheral edema. Nephrotic syndrome is characteristic of glomerular injury and occurs when the basement membrane in the kidney\'s glomerulus becomes abnormally permeable.** - **Hypoalbuminemia (low protein in blood) because of proteinuria (high levels of protein escaping in the urine) - the basement membrane in the kidney\'s glomerulus becomes abnormally permeable, causing too much protein to be released into the urine** - **Hyperlipidemia - Decreased catabolism of lipids (causes excess lipids in blood) due to reduced concentration of lipoprotein lipase in the blood, which is a primary enzyme involved in this process.** - **Edema -- decreased serum protein leads to edema. Decreased oncotic pressure.** ***Primary causes of nephrotic syndrome* include membranous glomerulonephritis and minimal change disease. *Secondary forms of nephrotic syndrome* occur in systemic diseases including diabetes mellitus, amyloidosis, and systemic lupus erythematosus. Nephrotic syndrome also is seen with certain drugs, infections, malignancies, and vascular disorders.**