Week 2 Flashcards

Question

Identify clinical features Primarily due to alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease, biliary disease and iron overload

Answer 1

CHRONIC LIVER FAILURE AND CIRRHOSIS Clinical a. May be clinically silent to symptomatic (anorexia, weight loss, weakness) b. Jaundice and subsequent pruritus, sometimes severe c. Impaired estrogen metabolism, hyperestrogenemia (1) Palmar erythema (vasodilation) (2) Spider angiomata (3) In men: hypergonadism and gynecomastia d. Advanced disease leads to death via: (1) Same causes as acute liver failure (2) Hepatocellular carcinoma (HCC) (3) GI hemorrhage (4) Bacterial infection

Answer 2

PORTAL HYPERTENSION Due to ⭡ portal venous blood flow secondary to a hyperdynamic circulation a. Due to arterial vasodilation in splanchnic circulation via nitrous oxide b. Leads to increased splanchnic arterial blood flow → increased venous efflux into the portal venous system → ⭡ portal venous pressure

Answer 3

PORTAL HYPERTENSION *3 causes A. Pre-hepatic causes 1. Portal vein thrombosis 2. Massive splenomegaly B. Post-hepatic causes 1. Severe right sided heart failure 2. Constructive pericarditis 3. Hepatic vein outflow obstruction (Budd-Chiari syndrome) C. Intrahepatic cause - CIRRHOSIS (most common cause)

Answer 4

ASCITES; excess serous fluid in the peritoneal cavity a. Increased neutrophils suggests secondary infection b. Bloody fluid suggests disseminated intra-abdominal cancer c. Pathogenesis (1) Sinusoidal hypertension drives fluid into the space of Disse which is removed by hepatic lymphatics (2) Movement of protein-rich hepatic lymph into the peritoneal cavity (3) Splanchnic vasodilation and hyperdynamic circulation (decreased bp - release of vasoconstrictors, activation of renin-angiotensin, secretion of ADH - increased perfusion pressure of interstitial capillaries - extravasation of fluid into abdominal cavity)

Answer 5

PORTOSYSTEMIC SHUNTS; increased pressure causes reverse of flow from portal to systemic circulation via collateral and new vessels a. Rectum - causing HEMORRHOIDS (dilated veins) b. Falciform ligament of the liver involving the periumbilical and abdominal wall collaterals - causing CAPUT MEDUSAE c. Esophagogastric junction - causing ESOPHAGEAL VARICES (40% of pts with advanced cirrhosis)

Answer 6

SPLENOMEGALY - SPLEEM can be up to 1000gm (normal - 150gm) - may cause thrombocytopenia or pancytopenia

Answer 7

HEPATOPULMONARY SYNDROME | **Another life threatening consequence of liver disease

Answer 8

Acute on chronic liver failure

Answer 9

ABCDEF causes of liver failure A - Acetaminophen, hepatitis A, autoimmune hepatitis, alcoholic liver disease B - Hepatitis B C - Hepatitis C, cryptogenic D - Drugs/toxins, hepatitis D E - Hepatitis E, esoteric causes (Wilson disease, Budd-Chiari) F - Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)

Answer 10

1. Albumin 2. Bilirubin 3. Alkaline phosphates 4. GGT (gamma glutamyltransferase) 5. Transaminases (AST and ALT) 6. Ammonia 7. Prothrombin time (PT) and activated partial thrombophlebitis time (aPTT) 8. Serum globulin 9. Urine urobilinogen levels 10. CBC (complete blood count

Answer 11

1. Albumin Chronic liver disease • Degree of hypoalbuminemia correlates with severity of chronic liver disease • NOT a good indicator of acute hepatic dysfunction 2. Bilirubin * *from heme degradation

Answer 12

Increased direct (conjugated) bilirubin a. Hepatitis (viral or ischemic causes) or cirrhosis b. Drug-induced and pregnancy-induced cholestasis c. Sepsis d. Inherited disorders (Dubin-Johnson, Rotor) e. Biliary cirrhosis and sclerosing cholangitis f. Obstruction (tumor, stone, etc.) Increased indirect (unconjugated) bilirubin a. Hemolysis or ineffective erythropoiesis b. Prolonged fasting c. Inherited disorders (Crigler-Najjar syndromes, Gilbert syndrome) d. Sepsis e. Hepatitis or cirrhosis f. Drugs

Answer 13

A. GGT (gamma glutamyltransferase) B. Ammonia C. Alkaline phosphatase

Answer 14

TRANSAMINASES A. AST (formerly SGOT) and ALT (formerly SGPT) B. ALT (8-20); more specific for LIVER INJURY than AST C. AST (8-20); elevated more than twice as much as ALT in ALCOHOL INJURY (memory device: Another Scotch & Tonic) ALT - liver injury AST - alcohol injury

Answer 15

A. Prothrombin time (PT) and activated Partial thromboplastin time (aPTT) 1. Prolonged interval due to various clotting factor deficiencies or inactivity 2. Involves fibrinogen, prothrombin and factors V, VII, IX and X 3. Prolongation due to severe widespread liver necrosis (hepatitis, cirrhosis) B. SERUM GLOBULIN C. Urine Urobilinogen levels D. CBC • Viral hepatitis may cause a relative or absolute lymphocytosis • Increased MCV with liver disease

Answer 16

Balanced diet 1. Energy; Carbohydrate + protein + Fat 2. Essential and non-essential amino acids 3. Fatty acids 4. Vitamins and minerals

Answer 17

1. Primary malnutrition | 2. Secondary or conditional malnutrition

Answer 18

1. Ignorance - Infants on artificial milk need iron supplement - Iodine deficiency common in areas remote from ocean; risk of goiter 2. Poverty 3. Infections 4. Chronic alcoholism - Dietary deficiency, defective GI absorption, abnormal nutrient use and storage - Common deficiencies: Thiamine, pyridoxine, folate and Vitamin A 5. Acute + Chronic illnesses - BMR in many illnesses resulting in increased daily requirements for all nutrients 6. Self imposed dietary restriction

Answer 19

1. Chronic alcoholic - deficiency; Folate, Pyridoxine, thiamine, Vit A 2. IRON (baby on artificial milk) 3. IODINE

Answer 20

PROTEIN-ENERGY MALNUTRITION (PEM) ** Malnutrition in children: defined as a child whose weight falls to less than 80% of normal weight. Ways of evaluation mild or moderate PEM: 1. Body weight. Measured by body mass index (BMI). A BMI less than 16kg/m2 is considered malnutrition (normal range 18.5 to 25 kg/m2). 2. Fat stores  skin folds. 3. Muscle mass  circumference of the arm. 4. Serum protein  adequacy of the visceral protein (albumin and transferrin) reflect visceral protein compartment

Answer 21

1. 16kg/m2 2. A. Marasmus B. Kwashiorkor ``` 3. A. Somatic compartment - skeletal muscles - affected in MARASMUS** B. Visceral compartment (organs) - affected in KWASHIORKOR** ``` 4. A. Somatic - MARASMUS B. Visceral - KWASHIORKOR

Answer 22

MARASMUS 1. Global starvation 2. Somatic compartment is affected more severely 3. Diminished subcutaneous fat: Decreased body weight (<60% for expected age) 4. Growth retardation - muscle wasting, wrinkled face. 5. Extremities are emaciated head looks larger than body (shrunken old person) 6. Increased risk of infections 7. Deficiencies of other required nutrients such as iodine and vitamins. 8. Hypoplasia of bone marrow: Anemia 9. Serum electrolytes and protein normal 10. No edema**

Answer 23

1. Anemia, increased risk of infection, loss of subcutaneous fat - MARASMUS **NO EDEMA

Answer 24

KWASHIORKOR Characteristic skin lesions; “FLAKEY POINT” - alternating zones of hyper/hypo pigmentations - desquamations ``` Hair changes – Overall loss of color or – Alternating bands of pale and darker hair (“flag sign”) – Fine texture. – Loss of firm attachment to the scalp. ``` * *Edema, ascities, skin changes - Pitting edema/ascites characteristic of kwashiorkor; ↓plasma oncotic pressure - Caused by hypoalbuminemia leading to a loss of plasma oncotic pressure Micro - Loss of villi & microvilli Small intestinal Enzyme e.g Disaccharidase

Answer 25

1. * * Protein deprivation is relatively greater than reduction in calories (kwashiorkor) 2. Kwashiokor * *FATTY CHANGES; lipid vacuoles are holes in the cell cytoplasm 3. HYPOALBUMINEMIA 4. The edema and ascites adds to the weight. ``` 5. 4 features of kwashiokor A. Ascites B. Edema C. “Flaky paint” skin D. Alternating hair color (flag skin) ```

Answer 26

SECONDARY PEM Signs of secondary PEM 1. Depletion of subcutaneous fat in the arms, chest wall, shoulders or metacarpal regions 2. Wasting of the quadriceps femoris and deltoid muscles 3. Ankle or sacral edema 4. Bedridden or hospitalized malnourished patients have an increased risk of infection, sepsis, impaired wound healing and death after surgery CACHEXIA Secondary PEM in patients with AIDS or advanced cancers, and in these settings it is known as cachexia: It is controlled by; - production of metabolic cytokines by the tumor, like TNF, IL-1, IL-6

Answer 27

1. CACHEXIA | 2. HYPOCELLULAR

Answer 28

1. Anorexia Nervosa • Clinical findings are similar to those seen in severe PEM. • Amenorrhea: related to DECREASED secretion of gonadotropin-releasing hormone (GnRH) - DECREASED LH and FSH. • Anemia, lymphopenia, and hypoalbuminemia. • Increased susceptibility to cardiac arrhythmia and sudden death (hypokalemia related). • Finding related to decrease thyroid hormone levels: – Cold intolerance. – Bradycardia. – Constipation. – Changes in the skin and hair; Fine pale hair (lanugo). • Bone density is decreased - LOW low estrogen levels & low Ca+ intake. 2. Bulimia ** Occur in previously healthy young women with an obsession of being thin!! Huge amount of food (mainly carb) is ingested followed by induced vomiting. 1. Amenorrhea occur in 50% of patients. 2. Major medical complications relate to vomiting: i. Electrolyte imbalances (hypokalemia) - cardiac arrhythmias. ii. Pulmonary aspiration of gastric contents. iii. Esophageal and gastric rupture.

Answer 29

1. ANOREXIA - low thyroid - Amenorrhea, constipation, dry skin, hypoalbuminemia, hypokalemia, osteopenia 2. HYPOKALEMIA 3. Amenorrhea - Low levels of GnRH 4. Pulmonary aspiration (Pt has BULIMIA)

Answer 30

Vitamins ⮚ Total thirteen vitamins are necessary for health ⮚ Necessary in trace amounts for metabolic functions ⮚ Endogenously synthesized vitamins (e.g. vitamin D and vitamin K and biotin, niacin from tryptophan) ⮚ Vitamin C , can’t be synthesized endogenously  need to be provided in diet. ``` 2 absorption mechanisms ⮚ Vitamins A, D, E, and K: fat soluble ⮚ Vitamins C and B: water soluble ** Fat-soluble vitamins are more readily stored in the body, but they may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions ``` 3. Fat soluble vitamins ; A,D,E,K

Answer 31

VITAMIN A DEFICIENCY • In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants. • Adult patients with malaborption syndromes, such as celiac disease, Crohn’s disease, and colitis, may develop vitamin A deficiency, in conjunction with depletion of other fat-soluble vitamins.

Answer 32

``` 1. A. Celiac disease B. Chronic use of mineral oil D. Gastric bypass surgery E. Inflammatory bowel disease ``` 2. LIVER

Answer 33

Forms of Vitamin A 1. Retinol (transport from of vit. A) 2. Retinol ester (storage form of vit.A 90% stored in liver in perisinusoidal stellate (Ito) cells) 3. Retinol ester oxidized in vivo to retinal (form used in visual pigment) 4. Retinoic acid -(affects growth regulation and differentiation)

Answer 34

1. Chylomicrons 2. Retinol binding protein 3. Apolipoprotein E receptor 4. Beta-carotene

Answer 35

1. Maintenance of normal vision. 2. Maintenance of specialized epithelia: Vitamin A and retinoids play an important role in the orderly differentiation of mucus-secreting epithelium; when a deficiency state exists, the epithelium undergoes squamous metaplasia, differentiating into a keratinizing epithelium 3. Antioxidant 4. Enhancement of immunity to infections: Vitamin A supplementation can reduce morbidity and mortality from some forms of diarrhea, and in preschool children with measles 5. Plays role in Fatty acid metabolism: including fatty acid oxidation in fat tissue and muscle, adipogenesis, and lipoprotein metabolism 6. Retinoids are used clinically for the treatment of skin disorders such as severe acne and certain forms of psoriasis, and also in the treatment of acute promyelocytic leukemia.

Answer 36

``` 1. B.Epithelial growth and differentiation C. Fatty acid metabolism D.Maintenance of immune system E. Maintenance of normal vision ```

Answer 37

Night blindness (earliest manifestation) - rhodopsin reduced in rods - reduced ability to see in dim light Early eye lesions I. Conjunctival xerosis ; conjunctiva becomes dry, thickened, wrinkled, pigmented, loses shiny luster II. Bitot’s spot (build of keratin debris) - bilateral, triangular, raised whitish plaques - plaques appear as fine foam with bubbles Late Eye lesions I. Corneal xerosis - begins with drying; hazy granular surface - softening of cornea - ulceration and necrosis II. Corneal ulcers - circular punched out - leads to perforation and prolapse of iris - keratoma alacia; loss of the eye - child usually seriously ill with fever (~50% mortality)

Answer 38

1. Bitot’s spot (build of keratin debris) - bilateral, triangular, raised whitish plaques - plaques appear as fine foam with bubbles ``` 2. A. Bitot spots B. Corneal ulcer D. Keratomalacia F. Night blindness G. Xerophthalmia H. Xerosis conjunctivae ``` 3. Vit A deficiency - SQUAMOUS METAPLASIA **decreased rhodopsin regeneration - night blindness A. Conjunctiva - xeropthalmia B. Cornea - keratomalacia BLINDNESS C. Bronchitis - bronchopneumonia D. Pancreatic ducts E. Urinary tract - kidney stones F. Follicular hyperkeratosis of skin 4. Genitourinary tract A. Hematuria (secondary to nephrolithiasis) B. Hydronephrosis (secondary to nephrolithiasis) D. Nephrolithiasis **VIT A DEF consequences I. Night blindness II. Xeropthalmia (dry eye) III. Bitot spot

Answer 39

Vit A Toxicity 1. Acute toxicity; Headache, dizziness, stupor, blurred vision 2. Chronic toxicity a. Weight loss b. Anorexia c. Nausea and vomiting d. Bone and joint pain e. Increased risk of fractures 3. Teratogenic in pregnancy

Answer 40

All water soluble – widely availableVitamin B12 (animal origin): only exception ▪ Vegan diet needs to supplemented with Vitamin B12

Answer 41

THIAMINE (Vit B1) - thiamin pyrophosphate (TPP) Causes of thiamine deficiency • Chronic alcoholism (in the United States) is the most common cause. • Diet of unenriched rice is the most common cause of deficiency in developing countries. ** Wet beriberi; Dilated cardiomyopathy with biventricular heart failure and dependent pitting edema; cardiac muscle lacks ATP; IV thiamine reverses cardiomyopathy in some cases

Answer 42

Vitamin B2; RIBOFLAVIN

Answer 43

NIACIN Function - Essential component of NAD & NADP - Used in the treatment of hypercholesterolemia (lowers plasma LDL level by reducing hepatic synthesis of VLDL) Complication of niacin deficiency - Patients who have corn-based diets commonly develop niacin deficiency(pellagra) because the niacin in corn is in a bound form that cannot be reabsorbed, and corn is deficient in tryptophan.

Answer 44

1. Vitamin A supplementation can be TERATOGENIC | 2. Vitamin C - fragile vessels

Answer 45

``` Vitamin C functions - Antioxidant: may retard atherosclerosis (by reducing oxidation of LDL) - Collagen formation: - Aids in the absorption of iron ``` Consequences of Vit C deficiency 1. Impaired wound healing 2. Hemorrhages from fragile vessels due to weak collagen: for example gingival mucosa 3. Characterized by bone disease in children; defective formation of osteoid matrix (due to impaired synthesis of hydroxyproline and hydroxylysine) 4. Swelling of the large joints with inflammation and subperiostal hemorrhages: May results in “pseudo paralysis” with characteristics frog-legged positioning * * Skin lesions: perifollicular, hyperkeratotic papular rash - purpura and ecchymoses on the skin * * Note the marked hematomas due to capillary hemorrhages in the legs of the patient with scurvy.

Answer 46

VITAMIN D 90% of the vitamin D requirement is endogenously derived from photochemical conversion of 7- dehydrocholesterol present in the skin. 2 forms 1) Vitamin D3 (cholecalciferol, derived from 7-dehydrocholesterol present in skin) 2) Vitamin D2 (ergocalciferol derived from plant ergosterol). **Vitamin D3 is also known as CHOLECALCIFEROL

Answer 47

1. Photochemical synthesis of vitamin D from Vitamin D precursors in the skin and absorption of vitamin D from foods and supplements in the gut 2. Binding of vitamin D from both of these sources to plasma α1-globulin (D-binding protein or DBP) and transport into the liver 3. Conversion of vitamin D into 25-hydroxycholecalciferol ( 25-OH-D) in the liver, through the effect of 25-Ohases 4. Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, in the kidney, the most active form of vitamin D, through the activity of α1-hydroxylase (1-OHase) 1-OHas * Activity increased in; - hypophosphatemia - increases in PTH hormone level * Changes in calcium affect activity through PTH

Answer 48

1. C. Convert D3 to 25(OH)D 2. SKIN to LIVER to KIDNEY 3. D3 4. A. 1-OHas

Answer 49

1. Major Function of 1,25-dihydroxyvitamin D ( Vitamin D active form) - Maintenance of normal plasma level of calcium/phosphate 2. Effects of Vitamin D on Calcium and Phosphorus Homeostasis 1. Stimulation of intestinal calcium absorption. 2. Stimulation of calcium reabsorption in the kidney. 3. Interact with parathyroid hormone (PTH) in the regulation of blood calcium. i. Together, they enhance the expression of RANKL (receptor activator of NF-κB ligand) on osteoblasts. ii. RANKL binds to its receptor (RANK) located in preosteoclasts , inducing the differentiation of these cells into mature osteoclasts 4. Mineralization of bone i. It contributes to the mineralization of osteoid matrix and epiphyseal cartilage in the formation of both flat and long bones in the skeleton ii. It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, involved in the deposition of calcium during bone development.

Answer 50

Vit D deficiency states 1. Insufficient vitamin D in diet 2. Insufficient production of vitamin D in skin due to limited exposure of sunlight (heavily veiled women) 3. Inadequate absorption (fat malabsorption syndromes) 4. Abnormal conversion of Vitamin D to its active form (Liver disease and chronic renal failure) 5. Renal disorders causing decreased synthesis of 1,25-dihydroxyvitamin D Vit D deficiency in HYPOCALCEMIA (4) 1. Increase PTH secretion 2. Increase osteoclast activity 3. Increase renal phosphate excretion 4. Decrease renal calcium excretion

Answer 51

1. An excess of unmineralized matrix. A. Rickets- Children B. Osteomalacia- Adult 2. Milder forms of vitamin D deficiency leading to an increase risk of bone loss and hip fractures are quite common in the elderly in the United States and Europe

Answer 52

RICKETS ** When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and tibia, causing lumbar lordosis and bowing of the legs short stature **BOWING OF LEGS, RACHITIC ROSARY

Answer 53

In a child with rickets, what chest deformity can occur? PIGEON BREAST DEFORMITY What can occur to the spine in rickets? LORDOSIS In adults, vitamin D deficiency leads to which bone disease? OSTEOMALACIA

Answer 54

OSTEOMALACIA - Adult

Answer 55

1. Vitamin D regulate B. Calcium homeostasis F. Phosphate homeostasis 2. What increase 1-OHase activity D. Hypophosphatemia E. Increases in PTH hormone level 3. A. The main effect of 1,25 (OH)2D on the kidney is: INCREASED CALCIUM REABSORBTION B. The main effect of 1,25 (OH)2D on the intestines is: INCREASED CALCIUM ABSORPTION 4. Main effect of 1,25 (OH) 2D in combination with PTH on bone metabolism C. INCREASE RANKL EXPRESSION ON OSTEOBLASTS 5. OSTEOCALCIN

Answer 56

A. HYPOCALCEMIA and Vitamin D deficiency 1. PTH: Increase 2. Osteoclast activity: Increase 3. Renal phosphate excretion: Increase 4. Renal calcium excretion: Decrease B. Osteomalacia patients ***PERSISTENT OSTEOID (NON-CALCIFIED BONE)

Answer 57

Vitamin D toxicity (Megadoses) **Cannot get toxic from prolonged sun exposure ** hypervitaminosis D is from the deposit of what material in the soft tissue? Calcium

Answer 58

1. Histology of adipose tissue - Each clear space corresponds to the fat vacuole in a single adipocyte. When making slides of fat, the tissue is placed through alcohol which dissolves the fat leaving a clear space. ``` 2. Definition of obesity; BMI >30 kg/m2 – Other methods to measure: • Triceps skinfold thickness • Mid-arm circumference • Ratio of waist and hip circumferences – Central (visceral) obesity: Fat accumulates in trunk, mesentery and around viscera ``` 3. Adipocyte numbers – Total number established by adolescence – In adults, numbers remain constant 4. Central obesity (or visceral obesity) - in addition to fat in subcutaneous tissue, fat is also around the ORGANS - fat accumulate around trunk and in abdominal cavity

Answer 59

``` 1. LEPTIN from fat cells – Effects: • Increase energy expenditure and heat generation • Stimulates physical activity • Decreases food intake – If no ob gene, cannot make leptin • Leads to early onset severe obesity – Leptin receptor (OB-R) is from db (diabetes) gene • If no db gene, also see severe obesity ``` ``` 2. ADIPONECTIN from fat cells – Concentration inverse to fat stores (high fat stores have low concentration; lean have high concentration) – Fatty acid metabolism • Directs fatty acids to muscle for use • Decreases fatty acid uptake in liver • Decreases glucose production by liver – Increases insulin sensitivity ``` 3. GHRELIN 4. PYY

Answer 60

1. Db - LEPTIN receptor gene ob - LEPTIN gene 2. LEPTIN - synthesized by fat cells 3. BMI of 30 has higher LEPTIN levels than BMI 18 4. Increased LEPTIN A. INCREASE energy expenditure B. INCREASE heat production C. DECREASE food intake 5. OBESE

Answer 61

1. B. It is lower in concentration in an obese person as compared to a lean person E. It stimulates fatty oxidation in muscle 2. GHRELIN DECREASES after meal 3. PYY INCREASES after meal

Answer 62

• Type 2 diabetes with insulin resistance and hyperinsulinemia • Metabolic syndrome: – Includes visceral adiposity, Type 2 diabetes, hypertension, dyslipidemia • Increased risk of atherosclerosis • Non-alcoholic fatty liver disease • Cholelithiasis with high concentration of cholesterol in stones • Hypersomnolence and Hypoventilation Syndrome (Pickwickian Syndrome) – Associated with sleep apnea and polycythemia * Osteoarthritis * Increased cancer risk for multiple locations * Steroid metabolism: Changes in androgen and estrogen balance • Dyslipidemia: Increase triglycerides with decrease HDL * Hypertension

Answer 63

1. Osteoarthritis 2. Type 2 DM (insulin resistant) 3. NONALCOHOLIC FATTY LIVER DISEASE 4. CHOLELITHIASIS (gallstones) 5. HDL decreases in obesity 6. Polycythemia in severely obese person * *HYPOVENTILATION SYNDROME Obesity associated with; increased risk of cancer, hypersomnolence, high conc cholesterol (obesity associated gall stones)

Answer 64

Common polyps 1. Hyperplastic 2. Colonic adenomas --- > Sporadic Colonic adenocarcinoma 3. Inflammatory Polyps 4. Hamartomatous polyps: Sporadic and Syndromic Colorectal Neoplasia 1. Sporadic 2. Familial: (FAP, MYH-associated, Lynch syndrome) 3. Colitis (Ulcerative Colitis and Crohn Disease); Associated Neoplasia

Answer 65

HYPERPLASTIC POLYPS (Non-neoplastic) Micro Serrated surface architecture (morphologic hallmark); typically restricted to the upper third, or less, of the crypt Gross: Smooth, nodular protrusions of the mucosa, often on the crests of mucosal folds A) Polyp surface with irregular tufting of epithelial cells B) Tufting results from epithelial overcrowding C) Epithelial crowding produces a serrated architecture when crypts are cut in cross- section

Answer 66

COLONIC ADENOMA • Majority of adenomas do not progress to become adenocarcinomas • S/S: Most adenomas are clinically silent with - large polyps that produce occult bleeding and anemia - rare villous adenomas that cause hypoproteinemic hypokalemia by secreting large amounts of protein and potassium • Four types: Tubular adenoma, Tubulo-villous adenoma, Villous adenoma and Serrated adenoma

Answer 67

A. Tubular adenoma B. Villus adenoma C. Dysplastic epithelial cells D. Sessile serrated adenoma COLONIC ADENOMA • Size: 0.3 to 10 cm in diameter • Pedunculated or sessile • Having a texture resembling velvety or smooth • Histologically: **• Nuclear hyperchromasia (hallmark of epithelial dysplasia) and elongation, and stratification , changes easily appreciated at the surface of the adenoma - Cytologically: prominent nucleoli, eosinophilic cytoplasm, and a reduction in the number of goblet cells - Pedunculated adenomas have slender fibromuscular stalks containing prominent blood vessels derived from the submucosa : usually covered by nonneoplastic epithelium, but dysplastic epithelium sometimes present

Answer 68

``` INFLAMMATORY POLYPS (Non-neoplastic) • Mixture of epithelial and stromal components admixed with inflammatory cells • Often related: - Inflammatory bowel disease (Crohn's disease or ulcerative colitis) - Anastomosis - Ischemic colitis - Infection ```

Answer 69

1. Hamartomatous polyps | 2. Colonic Hamartomatous polyps

Answer 70

1. Juvenile polyposis ** 2. Peutz-Jeghers syndrome ** 3. Cowden syndrome, Bannayan-Ruvalcaba-Riley syndrome 4. Cronkhite- Canada syndrome 5. Tuberous sclerosis 6. Familial adenomatous polyposis (FAP) * *classic FAP, attenuated FAP, Gardner syndrome , Turcot syndorme, MYH-associated polyposis

Answer 71

JUVENILE POLYPS A. Sporadic juvenile polyps (retention polyp): Usually solitary lesions B. Juvenile polyposis syndrome (Autosomal Dominant): - (3 -100) hamartomatous polyps - Require colectomy to limit the chronic and sometimes severe hemorrhage associated with polyp ulceration

Answer 72

JUVENILE POLYPS - Dysplasia is extremely rare in sporadic juvenile polyps** - Dysplasia associated with Juvenile polyposis syndrome, both within the juvenile polyps and in separate adenomas - 30% to 50% of pts with juvenile polyposis develop colonic adenocarcinoma by age 45 AUTOSOMAL DOMINANT • A minority cases: polyps in stomach and small bowel that undergo malignant transformation • Pulmonary arteriovenous malformations and other congenital malformations • Mutation identified: <50% cases - Most common: SMAD4, which encodes a cytoplasmic intermediate in the TGF-β signaling pathway - Others: BMPR1A, a kinase that is a member of the TGF-β superfamily, may be mutated in other cases - Other responsible genes: remain to be discovered!!!!!! (MAY BE YOU ARE ONE OF THEM TO DISCOVER☺ )

Answer 73

Peutz-Jeghers polyps **differentiate from juvenile polyps Pathogenesis • Germline heterozygous loss-of-function mutations in the gene STK11: ~50% familial Peutz-Jeghers syndrome and a subset of sporadic Peutz-Jeghers syndrome • STK11 is a tumor suppressor gene that encodes a kinase that regulates cell polarization and acts as a brake on growth and anabolic metabolism • Loss of fu

Answer 74

Peutz-Jeghers Syndrome: Clinical Features • Most common in SMALL INTESTINE> stomach and colon >bladder and lungs • Morphology of Peutz-Jeghers polyps overlap with that of sporadic hamartomatous polyps • Diagnosis: - Multiple polyps in the small intestine + mucocutaneous hyperpigmentation + a positive family history • Detection of STK11 mutations can be helpful, particularly diagnostically in patients with polyps who lack mucocutaneous hyperpigmentation. • Absence of STK11 mutations does not exclude the diagnosis

Answer 75

1. Familial Adenomatous Polyposis (FAP) 2. MYH-associated Polyposis Syndrome 3. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Lynch syndrome )

Answer 76

Familial adenomatous polyposis (FAP) • At least 100 polyps are necessary for a diagnosis of classic FAP, but as many as several thousand may be present • Morphologically indistinguishable from sporadic adenomas; flat or depressed adenomas are also prevalent in FAP • Microscopic adenomas, consisting of only one or two dysplastic crypts, are frequently observed in otherwise normal-appearing mucosa • Colectomy prevents colorectal cancer, but patient remain at risk for neoplasia at other sites: - Adenomas elsewhere in GI tract, particularly adjacent to the ampulla of Vater and in the stomach • Associated with a variety of extraintestinal manifestations : - Congenital hypertrophy of the retinal pigment epithelium, which can generally be detected at birth

Answer 77

Familial adenomatous polyposis (FAP) Pathogenesis - Mutations of the adenomatous polyposis coli, or APC, gene, a key negative regulator of the Wnt signaling pathway - Approximately 75% of cases are inherited, remaining appear to be caused by de novo mutations - Specific APC mutations associated with the development of other extraintestinal manifestations of FAP and partly explain variants such as Gardner syndrome and Turcot syndrome

Answer 78

MYH-associated Polyposis Syndrome • Bi-allelic mutations of the base-excision repair gene MYH ( MUTYH) • Serrated polyps, often with KRAS mutations, are frequently present in MUTYH-associated polyposis

Answer 79

(HNPCC)= Lynch syndrome • Account for 2% to 4% of all colorectal cancers, most common hereditary colorectal carcinoma syndrome • Colon cancers in HNPCC patients occur at younger ages than sporadic colon cancers • Often located in the right colon • Inherited mutations in mismatch repair (MMR ) genes (encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication, particulary seen in microsatellite regions) - At least five mismatch repair genes: Majority of patients: mutations in MSH2 or MLH1; less commonly MSH6 or PMS2; others: PMS1, EPCAM

Answer 80

COLONIC ADENOCARCINOMA • Per rectal bleeding • Screening: at age 50 years (colonoscopy and occult blood testing) • Presentation: - Proximal colon: Polypoid and exophytic; rarely obstruct lumen; Iron deficiency anemia (fatigue and weakness) - Distal colon: Annular lesions that produce “napkin ring” constructions and luminal narrowing - obstruction; * Presentation; occult bleeding, changes in bowel habits, or cramping and left lower quadrant discomfort * *Associated with STREPTOCOCCUS BOVIS ENDOCARDITIS * *Serum tumor marker; CEA for treatment response and follow up; NOT FOR SCREENING

Answer 81

COLONIC ADENOCARCINOMA • Dietary factors: most closely associated with colorectal cancer; - Low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat - Theorized: a. Reduced fiber content leads to decreased stool bulk and altered composition of the intestinal microbiota - increase synthesis of potentially toxic oxidative by products of bacterial metabolism, remain in contact with the colonic mucosa for longer periods b. High fat intake also enhances hepatic synthesis of cholesterol and bile acids, which can be converted into carcinogens by intestinal bacteria

Answer 82

COLONIC ADENOCARCINOMA ** Pharmacologic chemoprevention: a) Some NSAIDs cause polyp regression in FAP patients in whom the rectum was left in place after colectomy. It is suspected that this effect is mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2) b) COX-2 is necessary for production of prostaglandin E2, which promotes epithelial proliferation, particularly after injury c) COX-2 expression is regulated by TLR4, which recognizes lipopolysaccharide and is also overexpressed in adenomas and carcinomas

Answer 83

* Molecular events: heterogeneous and includes genetic and epigenetic abnormalities * Involved at least two genetic pathways: 1) APC/β-catenin pathway, which is activated in the classic adenoma-carcinoma sequence (80% of sporadic ) and 2) Microsatellite instability pathway, which is associated with defects in DNA mismatch repair and accumulation of mutations in microsatellite repeat regions of the genome - Both pathways involve the stepwise accumulation of multiple mutations, but differ in the genes involved and the mechanisms by which mutations accumulate - EPIGENETIC EVENTS (methylation-induced gene silencing) -- > enhance progression along either pathway

Answer 84

1. CLASSIC ADENOMA - CARCINOMA Sequence 2. DNA mismatch repair deficiency, mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability 3. A subset of MICROSATELLITE UNSTABLE colon cancers without mutations in DNA mismatch repair enzymes demonstrate the CpG island hypermethylation phenotype (CIMP): - MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function - BRAF mutation - No KRAS and TP53 mutation 4. A small group of colon cancers display increased CpG island methylation in ABSENCE OF MICROSATELLITE instability.

Answer 85

COLORECTAL CARCINOMA - PATHOGENESIS 1. CLASSIC ADENOMA - CARCINOMA SEQUENCE • Typically includes mutation of APC early in the neoplastic process • Normally APC protein binds to and promotes --- > degradatio

Answer 86

Colorectal carcinoma A. Well-differentiated adenocarcinoma B. Poorly differentiated adenocarcinoma C. Mucinous adenocarcinoma Metastatic colorectal carcinoma. A, Lymph node metastasis. Note the glandular structures within the subcapsular sinus. B, Solitary subpleural nodule of colorectal carcinoma metastatic to the lung. C, Liver containing two large and many smaller metastases.

Answer 87

COLITIS ASSOCIATED DYSPLASIA Colitis associated Neoplasia • Incidence of CRC in patients with IBD: Six times higher >general population RISK OF DYSPLASIA related to several factors; 1. Duration of the disease; risk increases sharply 8-10yrs after disease onset 2. Extent of the disease; pancolitis are at greater risk than those with only left-sided disease 3. Nature of the inflammatory response; Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) confers increased risk

Answer 88

• Typically enrolled in surveillance programs : - screening starts ~8-10 years after diagnosis of IBD and surveillance colonoscopy recommended every 1 to 2 years thereafter • IBD and primary sclerosing cholangitis: - generally enrolled for surveillance at the time of diagnosis. • Surveillance requires regular and extensive mucosal biopsies: - Low-grade dysplasia - High-grade dysplasia

Answer 89

Gastroenteritis (stomach flu) is caused by a number of bacteria and viruses. Viral gastroenteritis is especially widespread worldwide in infants and children with the most severe disease seen in underdeveloped countries where nutritional deprivation is a primary factor. The spectrum and severity of disease depends of the virus itself as well as the underlying health of the individual. Most virus- caused gastroenteritis (GE) have symptoms of diarrhea, nausea, vomiting, fever and abdominal pain and resolves without clinical intervention after several days. Recovery requires bed rest and supportive therapy, especially administration of fluids. In more severe cases of GE, especially those caused by rotavirus infection of infants, aggressive rehydration therapy may be required. The viruses are spread by the fecal-oral route via contaminated water and food and by personal contact. The incubation period for GE is usually 2-4 days. Recall discussions about Enteroviruses within Picornaviridae. In order to produce disease symptoms, the virus merely infects the cells lining the lumen of the GI tract. Lysis of these cells leads to disruption of the salt and ion flow and an electrolyte imbalance ensues. This process leads to diarrhea, which in severe cases, can lead to dehydration, especially in children who are malnourished. See Jan. 11 lecture for the specifics of Adenoviruses.

Answer 90

1. Rotavirus ; reoviridae ; double stranded RNA genome, segmented genome 2. Calicivirus ; caliciviridae ; + polarity RNA 3. Norovirus (genotypes 1,2) ; caliciviridae; + polarity RNA 4. Coronavirus ; cornaviridae; + polarity RNA 5. Astrovirus ; astroviridae ; + polarity RNA 6. Adenovirus types 40,41 ; adenoviridae ; double stranded DNA genome 7. Picornaviruses (enteroviruses - Coxsackie A) ; picornaviridae ; + polarity

Answer 91

REOVIRIDAE (reo =respiratory enteric orphan) Characteristics of reovirus particles a. 60-80 nm b. Usually naked virion (for our purposes it is non-enveloped) c. stable to acid and in the environment d. Structural features of the virus particle: Two concentric icosahedral capsids – * External capsid + internal capsid, the latter is commonly designated "core" * Tubular structures originates from the vertices of the core (internal capsid) and extend through the vertices of the external capsid e. RNA dependent RNA polymerase + capping enzymes are located inside of core (internal capsid) f. Double stranded RNA genome in 10-12 segments (depending on the reovirus), genome segments classified based on length of genome segment: L = large, M = medium, S = small g. mRNA and (+) strand of DS RNA are capped at 5' end

Answer 92

Replication in CYTOPLASM Viral replication and transcription of the genome to form viral mRNAs are unusual. Both of these events occur WITHIN THE CORE STRUCTURE of the virus. First step of the reovirus infection of target cells is the attachment of virus to specific receptors on the surface of the cell. After entry of the virus particle into the cell, the outermost capsid is removed (partial uncoating). Unlike the case of most other viruses the genome of the virus is not released from the inner capsid (core). The core associated viral enzymes are activated in the sense that the viral RNA polymerase becomes active inside the core and RNA synthesis ensues. Two types of RNA are synthesized inside the core: 1) new genomic RNA segments and 2) viral mRNAs. The tubular projections that originate at the vertices of the core structure serve as transport channels for viral mRNAs out of the core and into the cytoplasm. Remember each of the 10 segments of genome RNA are transcribed and the transcription products exit the core via the tubular projections Following translation of the viral mRNAs in the cytoplasm of the cell, new structural (capsid) proteins are synthesized, newly synthesized viral genome segments are encapsidated and the progeny virus is produced.

Answer 93

Genus: OrthoReovirus

Answer 94

1. Genus: Orbovirus, Arbovirus 2. Genus: Coltivirus, Arbovirus * *saddle back or diphasic fever (similar to poxvirus and yellow fever)

Answer 95

Genus: Rotavirus, Two primary human serotypes Symptoms: - Diarrhea, fever, abdominal pain, vomiting, dehydration --> fatal unless treated, death Treatment: - AGGRESSIVE use of oral rehydration therapy Diagnosis: Elisa (Rotazyme), virus seen in stools by electron microscopy, PCR (RT-PCR) methods for viral RNA

Answer 96

1. First Generation Of Rotavirus vaccine (RotaShield) -Rise and fall of the Rotavirus vaccine, intussusceptions linked to the vaccine, In-folding of the intestine led to bowel obstruction 2. New Generation Vaccines: Rotarix – Oral, live-attenuated vaccine containing ONE strain of rotovirus, two doses- first dose after 6 weeks of age and second dose at least 4 weeks later “RotaTeq” Vaccine (Merck), oral, live attenuated vaccine - A pentavelent vaccine; Vaccine consists of 5 rotavirus types that were created by molecular biology techniques - Each of the five types were produced by genome reassortment (recall Influenza virus lecture) - The five types correspond to 5 different antigenic forms of rotavirus Minimum age of vaccination = 6 weeks Start vaccination series prior to 12 weeks - 3 doses of RotaTeq, administered at 2,4, and 6 months of age ** Vaccines are not FDA approved for older children and adults.

Answer 97

Caliciviridae: Members of Caliciviridae are not well characterized because of their inability to grow well in tissue culture (Monkey calicivirus grows to limited extent in culture, model system)

Answer 98

Norovirus genus - Also designated Norwalk virus - Noroviruses are divided into 6 genotypes, Members of 3 genotypes G1, G2, and G4 infect humans Norovirus infection - Specificity of Infection: Some individuals appear to be resistant to infection by certain strains of norovirus Blood group (ABO) Glycolipids/ Glycoproteins act as cell surface receptors for norovirus. Certain individuals having a specific blood group (types B and AB) will bind norovirus poorly or not at all thereby preventing the initial stages of the infection and imparting resistance. Infects individuals of all ages Disease symptoms: - Nausea, abdominal pain, vomiting, diarrhea, chills, headache, myalgia, and fever

Answer 99

NOROVIRUS GENUS; aka NORWALK VIRUS - A major cause of nonbacterial/non-parasitic gastroenteritis in U.S and world-wide - Spread by fecal oral route- contaminated food and water, person to person spread and aerosols (created as a result of violent vomiting) - Peak incidence of disease during winter months, referred to as “winter vomiting disease” 1. Cause gastroenteritis in both adults and children where people work and live in closed quarters or communities 2. Long-term care facilities, dormitories, cruise ships, hospitals, military encampment and prisons ** Diagnostic methods: ELISA, electron microscopy, and RT-PCR (state of the art)

Answer 100

CORONAVIRIDAE In the discussion of respiratory viruses it was indicated that a type of coronavirus causes severe acute respiratory syndrome (SARS). In addition to respiratory infections, coronaviruses can cause infections of the gastrointestinal tract. SARS, for example, can cause both a respiratory infection and a GI tract infection, which suggests that the receptor for the virus is on the surface of several cell types. The prevalence of Coronavirus has not been determined. REPLICATION A. Cytoplasmic, replication cycle has been characterized, but it will not be discussed in any detail. B. Replicative intermediate formed (+ RNA) C. Nucleocapsids "bud" at plasma membrane and cytoplasmic vesicles including those of the endoplasmic reticulum (ER) D. Limited or no CPE in tissue culture

Answer 101

Genus: Coronavirus

Answer 102

Astroviridae Family of viruses that infect birds and mammals that is separated into two genera; 1) Mamastroviruses and 2) Avastroviruses World wide Astroviruses (certain types within the Mamastrovirus genus) cause high levels of gastroenteritis is both children and adults. No antiviral drugs or vaccines are available to treat or prevent infections Infectious process: - Spread by the fecal oral route and person to person contact - Based on the presence of anti-astrovirus antibodies in young children, the virus infection is very common in young children. Most infections are asymptomatic. Overt infections are usually mild and symptoms include nausea, vomiting, fever, diarrhea and abdominal pain. Dehydration is rare as is hospitalization.

Answer 103

I. Government Regulation A. Herbal products are not classified as drugs B. Herbal products considered dietary supplements C. Do not have to prove safe or effective ``` II. FDA Supplemental Facts A. Similar to Nutrition Facts on Foods B. Contain common name C. Botanical name and plant part D. Serving size E. Recommended daily amount F. Total wt of proprietary blend ``` III. Marketing claims for herbs A. Herbal products cannot be marketed for prevention or treatment of a disease B. Labelling 1. Standardized, certain concentration is consistent between batches 2. NF (national formulary) meets standards for level of marker compound and labeling C. Herbs are natural 1. Not uniform in active ingredients; multiple active ingredients may act in synergy 2. Active ingredient varies with climate, soil and fertilization 3. Herbs contain a multiple active ingredients 4. Herb product activity dependent on family of compounds

Answer 104

GARLIC Marketed Uses 1. Lower cholesterol 2. “Heart health” Reduce risk myocardial infarct or thrombotic stroke Differences between garlic preps 1. Allin converted to allicin (garlic odor) by allinase in plant and GI tract 2. Heat evaporates diallyl sulfides Action on platelets 1. Inhibit platelet aggregation 2. Ajoene (Allicin metabolite) and Diallyl trisulfide inhibit platelet thromboxane generation Drug Interaction and Cautions 1. Caution use of high doses 4 cloves/day with antiplatelet drugs 2. Chopped Garlic in oil, need to store in refrigerator - Clostridium infection has been reported if stored at room temperature

Answer 105

HORSE CHESTNUT Marketed Claims 1. Improve vasculature 2. Reduce problems associated with varicose veins 3. Product Venostat CONTRAINDICATIONS 1. ANTICOAGULANTS, ASPIRIN OR NSAIDS 3. CATEGORY X FOR PREGNANCY AND BREAST FEEDING

Answer 106

GINKO BILOBA Adverse Effects and Cautions 1. Major adverse effect is bleeding 2. Ingestion of ginko seeds (contain ginkotoxin) toxic, cause seizures Drug Interactions 1. Antiplatelet drugs (aspirin, NSAIDs) 2. Enhanced bleeding with heparin and warfarin 3. Enhanced bleeding with IIb/IIa receptor antagonists (clopidogrel)

Answer 107

``` ST. JOHN’S WORT MARKETED USES 1. Improve MOOD 2. Improve sleep quality 3. Reduce anxiety ``` ANTI-ANXIETY ACTION 1. GABA mediated effect - Affinity for GABA receptors - Action inhibited by flumazenil Effect on MAO to Enhance Mood 1. MAO inhibition is mediated by Hypericin Effect on Serotonin Re-Uptake to Enhance Mood 1. Directly Inhibits 5-HT uptake in selected regions of brain 2. Occurs at levels attained with dosing of St John’s Wort extract

Answer 108

ST. JOHN’S WORT SIDE EFFECTS 1. Generally well tolerated 2. Minor effects of - Headache - Loss of appetite DRUG INTERACTIONS 1. Should not be taken with – MAO inhibitors – Selective serotonin re-uptake inhibitors 2. Induces P450 isozyme Cyp 3A4 – May need to increase dose of oral contraceptives, theophylline, warfarin

Answer 109

VALERIAN **active ingredient; valerenic acid, valtrate, glutamine Adverse effects 1. Drowsiness 2. Increased sedation when mixed with alcohol 3. Caution use with benzodiazepines, barbiturates or MAO inhibitors

Answer 110

ECHINACEA Stimulate immune system; arabinogalactan promotes release of TNF and IL-1 from macrophages*** ``` Effect on Colds 1. ORAL TREATMENT WITH AN ORAL EXTRACT FOR 12 WEEKS 302 INDIVIDUALS 2. Not effective in preventing colds 3. Less severe symptoms for a cold **Not effective in kids <12yrs ``` Side effects 1. ALLERGIC REACTIONS** 2. Avoid chronic use due to potential to suppress immune system (< 8 weeks)

Answer 111

SAW PALMETTO ACTIONS OF SAW PALMETTO 1. May block the translocation of the cytosol androgen receptor to the nucleus 2. Inhibitor of 5α-reductase enyzme converts testosterone to dihydrotestosterone 3. Some studies show Comparable or less effective than Finasteride (5α-reductase inhibitor) if taken for 6 Months. Other studies show saw palmetto combined with stinging nettle are Comparable to finasteride. All studies show better tolerated than finasteride. Saw palmetto reduces urination difficulty.

Answer 112

GINSENG ACTIVE INGREDIENTS 1. Ginsenosides, most studies conducted on this chemical group 2. Over 20 different ginsenosides in ginseng 3. Amount different between species Action 1. Memory and stress - decrease levels of neurotransmitters elevated during stress 2. CV effects • Red ginseng may increase HDLs • Panax ginseng inhibits platelet aggregation 3. Effect on immune system - Stimulate chemotaxis more than placebo of polymorphonuclear cells -Antiviral activity may be mediated by stimulation of interferon production 4. ENDOCRINE EFFECTS -Increases glycogen storage -Helps reduce fasting blood glucose Adverse effects - Nervouseness - Avoid taking with caffeine - Ginseng abuse syndrome; Hypertension, excitability, sleeplessness, nervousness and morning diarrhea

Answer 113

KAVA Adverse effects - sedation, impairment of motor skills - yellow skin and nails - HEPATIC TOXICITY FDA warning issued in 2002 regarding hepatic damage

Answer 114

FEVERFEW Adverse effects 1. drowsiness, dizziness 2. postfeverfew syndrome of insomnia, joint pain, muscle aches when stopping feverfew 3. Women, reports of menstrual irregularities, heavier menstrual flow*** 4. Mouth ulceration, lips swell 5. Potential interaction to increase bleeding with aspirin and anticoagulants

Answer 115

``` 1. Herbs to avoid prior to surgery A. Pharmacodynamic (5); - Feverfew, - Garlic, - Ginko Biloba, - Ginseng, - Horse Chestnut (AESCULIN - risk of bleeding) B. pharmacokinetic (1) - ST JOHN’s WORT ``` 2. Herbs to avoid mixing with alcohol (2) - Valerian - Kava 3. Herbs to avoid mixing with MAOI or SSRI (2) - ST JOHN’s WORT - Valerian

Answer 116

1. D. St. John 2. C. ESCIN induce leg pain ***  A. Ajoene (antiplatelet agent in garlic)  B. Aesculin (coumarin like agent in horse chestnut)  C. Escin  D. Heteroxylan (stimulates phagocytosis-echinacea)  E. Parthenolide (feverfew inhibitor of platelet serotonin release)

Answer 117

GERD - trial of PPI This patient has classic symptoms of gastroesophageal reflux disease (GERD). • Symptoms of heartburn and regurgitation are strong predictors for the clinical diagnosis of GERD. • GERD is due to inappropriate relaxation of the Lower Esophageal Sphincter (LES). • The most appropriate next step in a patient without alarm symptoms (dysphagia, unintentional weight loss, hematemesis, or melena) is an empiric trial of a PPI.

Answer 118

BARIUM SWALLOW show BIRD BEAK - ACHALASIA; loss of peristalsis and incomplete lower esophageal sphincter relaxation - Inflammatory destruction of inhibitory neurons in the esophageal myenteric (Auerbach) plexus results in loss of peristalsis and incomplete lower esophageal sphincter relaxation. - Barium radiography shows a dilated esophagus with narrowing at the lower esophageal sphincter, described as a “bird's beak.” * **MANOMETRY is required to confirm the diagnosis of achalasia. - Treatment includes pharmacologic, endoscopic, and surgical modalities.

Answer 119

Check first for HEMODYNAMIC STABILITY **Stabilize the patient first - give him fluids Next differential to tackle - MALLORY WEISS TEAR; sudden rise in abdominal pressure or transmural pressure gradient across the gastroesophageal junction **EGD for diagnosis - The pathogenesis of MWT is not completely understood. - Most cases seem to occur as a result of a sudden rise in abdominal pressure or transmural pressure gradient across the gastroesophageal junction. - When these forces are high enough to cause distention in this poorly distended area, an acute gastroesophageal tear or laceration may occur. * * Surgery should be reserved for situations where endoscopic hemostasis of bleeding has failed or transmural esophageal perforation is a problem.

Answer 120

1. UPPER ENDOSCOPY shows Esophageal Adenocarcinoma - arise in mucosa of the esophagus; can invade submucosa and muscular layer Pathophys Mechanism - alcohol - tobacco - GERD and Barrett esophagus Critical to treatment decisions are the stage of the disease and the patient's overall physiologic status.

Answer 121

1. H.pylori testing; check for infection A. Serologic testing; limitation - doesnt test for active H pylori infection and has poor predictive value B. FECAL ANTIGEN test and UREA BREATH test offer a more accurate means of noninvasive testing for H. pylori, as both of these test modalities assess for the presence of active infection. Fecal antigen and urea breath tests are equivalent in terms of their accuracy. The choice of fecal antigen testing versus urea breath testing will typically depend on test availability and patient preference.

Answer 122

1. UPPER ENDOSCOPY (EGD) - shows PEPTIC ULCER DISEASE (PUD) * *Cardinal symptom in uncomplicated PUD is epigastric pain or discomfort - accompanying symptoms; nocturnal pain, relief of pain with eating, early satiety, nausea, bloating or abdominal fullness * *A complication is ACTIVE BLEEDING Peptic ulcers are diagnosed not by symptoms but instead by the presence of a mucosal break 5 mm or larger in the stomach or duodenum. Upper endoscopy is considered the gold standard in the diagnosis of PUD. The goal of therapy is to treat complications (e.g., active bleeding), eliminate the underlying cause whenever possible, relieve symptoms, and heal ulcers.

Answer 123

1. MULTIDISCIPLINARY STAGING OF CANCER; staging based on imaging is required Cancer that develops in any portion of the stomach and may spread to other organs. Presents with weight loss and abdominal pain, although patients with proximal or gastroesophageal junction tumors may present with dysphagia. Upper GI endoscopy with biopsy demonstrating carcinoma is required to confirm the diagnosis. Staging based on imaging is required. Early-stage disease is treated with surgery alone. Locally advanced disease should undergo surgery followed by postoperative chemoradiation, or chemotherapy before and after surgery. Metastatic disease is treated with chemotherapy or chemoradiation and supportive care measures.

Answer 124

Abdominal xray - Dilated bowels - SMALL BOWEL OBSTRUCTION * *Nonoperative treatment; fluid resuscitation, bowel decompression, analgesia * *Operative treatment; EXPLORATORY LAPAROTOMY performed in patients with; Complete SBO, all cases with documented peritonitis, evidence of strangulation, patients who don/t respond to nonoperatve tx Common causes of SBO in adults include: •Previous surgery with the formation of intra-abdominal adhesions, including colorectal/gynecologic surgery, resection of intra-abdominal tumors, laparotomy for trauma •Inguinal hernia with incarceration; ventral, incisional, umbilical, and parastomal hernias •Crohn disease •Intestinal malignancy •Appendicitis

Answer 125

1. Serology testing for IgA-tTG (immunoglobulin A -tissue transglutaminase) * ****CELIAC DISEASE - another sensitive and specific serologic marker is Endomysial antibodies (EMA) Celiac disease is a systemic autoimmune disorder triggered by gluten peptides from grains including wheat, rye, and barley. These peptides are resistant to human proteases, allowing them to persist intact in the small intestinal lumen. The diagnosis of celiac disease requires positive serologic markers and a compatible small- bowel biopsy. IgA tissue transglutaminase (tTG) antibodies and endomysial antibodies (EMA) are sensitive and specific serologic markers; testing for these should be done while the patient is consuming gluten.

Answer 126

1. APPENDICITIS; acute inflammation of the vermiform appendix * *Laparoscopic intervention - take it out ( surgical appendectomy) Acute inflammation of the vermiform appendix. Typically presents as acute abdominal pain starting in the midabdomen and later localizing to the right lower quadrant. Associated with fever, anorexia, nausea, vomiting, and elevation of the neutrophil count. Diagnosis is usually made clinically. If investigation is required, CT scan and ultrasonography may show dilatation of the appendix outer diameter to more than 6 mm. Definitive treatment is surgical appendectomy.

Answer 127

1. (IBS - Irritable bowel syndrome) - The pain or discomfort MAY be relieved by defecation Irritable bowel syndrome is a chronic condition characterized by abdominal pain associated with bowel dysfunction. The pain or discomfort may be relieved by defecation. It is important to determine whether there are any dietary associations such as lactose- containing foods or fructose-containing foods. Exam of the abdomen is usually unremarkable. There may be mild and poorly localized tenderness in the RLQ and/or LLQ. The diagnosis is based on the patient's history, and there are no specific diagnostic tests. If the patient has worrying symptoms or findings such as anemia, weight loss, or fever, then these require more thorough investigation. Treatment should be individualized and is dependent on the patient's predominant symptoms.

Answer 128

1. COLONOSCOPY **IBD (Inflammatory Bowel Disease) ; Crohn’s disease (SIGNIFICANT WEIGHT LOSS AND DIARRHEA) Diagnosis confirmed by colonoscopy with ileoscopy and tissue biopsy. The overall treatment goals are to induce and maintain remission plus prevent relapse or recurrence. Complications include extraintestinal involvement, intestinal obstruction, abscess formation, sinuses, and fistulae. vs ulcerative colitis - TOXIC MEGACOLON can occur with associated risk of perforation - BOWEL ADENOCARCINOMA is a complication in 3-5% of pts • Form of inflammatory bowel disease that affects the rectum and extends proximally. • Patients commonly experience bloody diarrhea, chronic diarrhea (or both) • Diagnosis requires endoscopy with biopsy and negative stool culture. • Relapses are often associated with pathogens; therefore, stool should be obtained for culture in all cases of disease flare-up. • Treatment aims to induce and maintain remission. Drug choice and formulation depends on the severity and extent of disease.

Answer 129

1. COLONOSCOPY; determine stage of cancer and do biopsy * *COLON CANCER; third leading cause of death Third leading cause of cancer deaths in the US in men and women. Rare below 40 years of age. Symptoms are not specific and occur frequently in benign colorectal conditions. Surgical resection is the main curative treatment. Combined modality treatment (chemotherapy, radiation therapy, resection of metastases) has increased survival in selected cases. Overall 5-year survival is 59% in the US.

Answer 130

**Patient has DIVERTICULAR DISEASE 1. Discharge home with ABX therapy and close follow up **Patient is stable, no fever so can send them home - patient with acute diverticulitis present with fever, leukocytosis and left lower quadrant pain Tx: bowel rest, antibiotics, surgical intervention Usually asymptomatic; may have constipation or nonspecific abdominal symptoms. Symptomatic acute diverticulitis presents with fever, leukocytosis, and left lower quadrant pain. CT scan is the imaging modality of choice for acute diverticulitis. Treatment includes bowel rest, antibiotics, and surgical intervention. Complications include bleeding, segmental colitis, perforation, abscess, fistulas, and obstruction.

Answer 131

1. Weight loss, diet and exercise * *NON ALCOHOLIC FATTY LIVER (STEATOSIS) Nonalcoholic hepatic steatosis, or nonalcoholic fatty liver disease, is the most common cause of chronic liver disease in the Western world. It is projected to become a leading indication for liver transplantation, superseding hepatitis C. The diagnosis of hepatic steatosis is based on exclusion of other etiologies, such as alcohol use, along with histology. Associated with obesity and features of the metabolic syndrome in most cases. May progress to steatohepatitis and end-stage liver disease. There are no currently recommended drug treatments. Lifestyle modification remains the first-line therapy.

Answer 132

* *HEPATIC CIRRHOSIS 1. Treatment for Hep C infection * *Patient has active Hepatitis infection; treatment of underlying causative condition to slow or halt the progression of cirrhosis Cirrhosis is the pathologic end-stage of any chronic liver disease It is essential to treat the underlying causative condition such as:  Hepatitis B and C  Alcoholic liver disease  Hemochromatosis  Wilson disease  Alpha-1 antitrypsin deficiency  Primary biliary cholangitis  Primary sclerosing cholangitis  Autoimmune hepatitis  Budd-Chiari syndrome

Answer 133

* *CHOLELITHIASIS 1. Cholecystectomy prior to hospital discharge ; **definitive treatment for symptomatic patients - Common risk factors include older age, female gender and pregnancy, obesity, rapid weight loss, and a family history. - Abdominal ultrasound provides effective diagnostic imaging. - Laparoscopic cholecystectomy represents definitive treatment for symptomatic patients. - Complications such as cholecystitis, cholangitis, and pancreatitis develop commonly.

Answer 134

1. Direct toxic insult * *PANCREATITIS; steady, sudden onset abdominal pain radiating to the back Cardinal symptom is usually steady, sudden-onset abdominal pain radiating to the back. Associated with nausea and vomiting. A history of cholelithiasis or alcohol intake is often present. Typical signs include epigastric tenderness, fever, and tachycardia. Elevated serum amylase and lipase concentration supports but is not pathognomonic for the diagnosis of acute pancreatitis. Initial treatment includes resuscitation with intravenous fluids and correction of electrolyte abnormalities, analgesia, and tight glucose control. Treatment of severe acute pancreatitis includes support of end organ failure, most commonly of respiratory, renal, and circulatory systems.

Answer 135

PANCREATIC CANCER Fourth most common cause of cancer-related death in the US. Most common presentation is at 65 to 75 years of age with painless obstructive jaundice and weight loss. Generally presents late with advanced disease. Surgical resection offers the only hope for cure. Chemotherapy and radiation therapy, as primary treatment modalities, produce a small but statistically significant benefit. Adjuvant chemotherapy prolongs survival. Only a minority (5% to 10%) of patients can undergo potentially curative surgery: these patients have a 5-year survival of up to 22%, which decreases to <2% in the presence of distant metastasis. Patients with metastatic disease (50% to 55%) have a limited survival of only 3 to 6 months.

Answer 136

1. Upper GI series * *TYPE I (SLIDING) HIATAL HERNIA, with about one third of the upper stomach in the chest * *Patient will benefit from - NISSEN FUNDOPLICATION

Answer 137

1. Variant: general term for any change regardless of frequency 2. Single nucleotide variants/polymorphisms (SNV/SNP), one base is changed 3. Insertions and deletions (grouped together under the term “indel”) 4. Structural variants (e.g. translocations, rearrangements) 5. Simple tandem repeats (STR) - Dinucleotide, trinucleotide repeats ** Common Disease Common Variant Hypothesis: Role of common variants in disease: The common disease-common variant (CDCV) hypothesis predicts that common variants in human populations will confer risk to a given disease. Examples: APOE ε4 in Alzheimer's disease, IL23R in Crohn's disease.

Answer 138

1. POLYMORPHISM - Some individuals incorrectly use the term polymorphism to connote a benign mutation.) - A locus which has many (>100) alleles is said to be highly polymorphic.

Answer 139

MONOGENIC INHERITANCE - Because the trait/disease phenotype in these cases is dictated by one gene, this is known as single gene (or monogenic) inheritance. - In terms of molecular basis, treatment and risk of recurrence to family members, we know the most about single gene disorders. - The simplest case of inheritance involves a single gene having two different alleles in a population. The presence of one allele gives a particular phenotype, while the other allele results in a second phenotype which may be very similar or strikingly different. Some genes have alleles that are deleterious such as deletion mutations in the DMD gene. Other genes have alleles that are relatively innocuous or beneficial. - For example, the HLA antigens and blood group antigens represent genes where many different alleles may be present in a population, although an individual can have only two different alleles at a given locus.

Answer 140

Allelic constitution refers to the configuration of alleles at a given locus. - A genetic locus that has two different alleles is said to be heterozygous. - Heterozygosity can mean either the presence of a wild type and a mutant allele, or the presence of two different mutant alleles. - The term heteroallelic is used if two defective alleles are present.

Answer 141

1. For monogenic traits/diseases, variations in phenotype can result from the presence of differing defective alleles at a given locus or from the presence of differing alleles at different loci. 2. Allelic heterogeneity describes different alleles at the same locus which gives rise to the same or similar disease. Example: in the case of cystic fibrosis, - we have noted that there are several different alleles that give rise to CF. - Individuals who are homoallelic for the delta F508 allele have the PI (pancreatic insufficiency) form of CF, while those who have a “milder” allele (e.g 455 Ala - Glu) and the delta F508 allele will have the less severe PS form of teh disease - Disease severity and clinical management is dependent on the types of mutant alleles present. **ALLELIC HETEROGENEITY EXAMPLE 1: CYSTIC FIBROSIS I. F508/+ (heterozygous) - normal carrier II. F508/F508 (homoallelic) - severe PI form II. F508/455 (heteroallelic) - less severe PS form

Answer 142

LOCUS HETEROGENEITY E,g PKU - results from failure to convert phenylalanine to tyrosine - 97% of all PKU have defects in phenylalanine hydroxylase (see pathways). 3% have defects in other loci. Type I Gene; phenylalanine hydroxylase Location; chromosome 12 Phenotype; restrict phenylalanine + provide tyrosine Type II Gene; BH4 reductase Location; chromosome 4 Phenotype; restrict phe+ L-DOPA + 5HT Type III Gene; biopterin synthesis Location; several loci Phenotype; restrict phe+ L-DOPA + 5HT

Answer 143

* *All kids will be heterozygous | - 100% offspring will be phenotypically normal

Answer 144

Mitochondrial inheritance  Mt genome= 37 genes involved in ox-phosphorylation, rRNAs and tRNAs  Disruption of energy production is pleiotropic (many sequellae)  >100 known point mutations + >100 known rearrangements  Mitochondrial = maternal only inheritance - Mom to all offspring - Dad to no offspring

Answer 145

1. Allelic Heterogeneity: one gene with multiple alleles that give rise to same/similar disease 2. Locus Heterogeneity: one of several genes (with or without multiple alleles) that give rise to the same/similar disease. 3. Mendelian = monogenic inheritance Mitochondrial: passed from mom to all offspring (rare exceptions) 4. Complex mode of inheritance A. Polygenic B. Multifactorial

Answer 146

1. Multifactorial inheritance 2. Polygenic inheritance - Genetic background refers to all other genes that influence the action of the gene in question. Genetic phenomena like sex influence, incomplete penetrance and variable expressivity are often explained by invoking genetic interactions. However, for most cases of polygenic inheritance, the identity of the interacting genes is not known. * * Polygenic inheritance includes forms of penetrance and variable expressivity. Although some traits/disorders are most probably the consequence of the interaction of two or more genes, in most cases the actual participating genes have not been identified. ** In a few cases, allelic heterogeneity (caused by genomic instability), not genetic interactions or gene-environment, provides a better explanation for observed variation (example: Fragile X syndrome).

Answer 147

1. Penetrance 2. A modifier gene - Incomplete penetrance is a characteristic of dominant inheritance; no cases of incomplete penetrance are known for recessive traits. - The generalized pedigree to the right illustrates incomplete penetrance. It looks like the disease has “skipped a generation".

Answer 148

1. Complete penetrance; CF 2. Complete penetrance with variable age of onset; HD 3. Incomplete penetrance; polydactyl (AD) - also in brachydactyly and in fragile X syndrome * *Formular of penetrance = # cases with phenotype / # cases with genotype 4. Retinitis Pigmentosa (RP): An example of true polygenic inheritance (GIM text pp 299-301) - Two unlinked genes (peripherin and ROM1) encode photoreceptor proteins. - In a few families, patients heterozygous for either (but not both) loci do not develop retinal degeneration. Patients heterozygous at both peripherin and ROM1 develop the disease. Polygenic summary and exception - For polygenic modes (like incomplete penetrance), two or more genes determine the phenotypic outcome. In a few cases, monogenic allelic heterogeneity (caused by genomic instability) provides a better explanation for observed variations in phenotype.

Answer 149

FRAGILE X SYNDROME and UNSTABLE REPEATS * * Fragile X syndrome is the second most common cause of mental retardation (Trisomy 21 is the most common) and most common hereditary form of intellectual disability. - Cytology: Cells cultured from Fragile X patients have a novel secondary constriction on the X chromosome, called a fragile site, which is the site of frequent breakage. This site fails to condense during metaphase like other chromosomes. - Phenotypes: Frequency of affected males is 1 in 3600. Affected males are moderately retarded, have large testes (macroorchidism), large heads, large protruding ears, prominent jaw and stubby hands. Speech development is delayed. As adults, they are usually nonassertive, but friendly. Some males have symptoms of autism.

Answer 150

FRAGILE X SYNDROME Fragile X syndrome segregates as an X- linked dominant trait with incomplete penetrance. It is considered to be X-linked dominant because a single defective allele in the X-linked FMR1 gene causes some mental deficiency in females. Fragile X exhibits incomplete penetrance because not all carriers of a "defective" allele are affected; % penetrance is sex dependent. Incomplete penetrance of Fragile X syndrome is not a consequence of polygenic interactions; it is best explained by allelic heterogeneity. In a standard fragile X pedigree, a phenotypically normal man who passes the disease allele to his daughters and his grandsons is called a nonpenetrant transmitting male (NTM; square with a bullet). While the brothers of this NTM have a 9% risk of being affected, the grandsons and greatgrandsons have a higher chance of being affected (37% and 50% respectively). The risk of the granddaughters and great-granddaughters being affected also increases from 5% (sister affected) to 17% and 20% respectively (see pedigrees). Therefore, position in the pedigree in part determines the risk of developing the syndrome. This is known as the SHERMAN PARADOX.

Answer 151

SHERMAN PARADOX - The paradox has been partly resolved by the discovery of the nature of the Fragile X mutation. Multiple CGG trinucleotide repeats are present in the 5' noncoding region of fragile X gene (FMR1). Phenotypically normal males and females have less than 50 repeats. - NTMs and carrier females have variant alleles with between 50 and 200 repeats called premutation alleles. - Normal and premutation alleles allow for normal levels of functional FMR1 gene product and normal mental development ensues. - However, during female meiosis, the premutation allele can expand to 200-3000 CGG repeats, so that a fraction of gametes carry the fully expanded (and defective) FMR1 allele. - Normal alleles can also expand to full mutations, but at a much lower frequency than premutation alleles; therefore, normal females only rarely make gametes with full mutations. - The highest range of repeats correlates well with the absence of the FMR1 mRNA and the presence of clinical disease. ** NTMs are said to be nonpenetrant because they have a "defective" allele but do not express the phenotype. This is a slight twist on accepted meaning of penetrance, because premutation allele is not truly defective since it allows for normal levels of FMR1; but it does confer increased risk of expansion to the "full" mutation.

Answer 152

Diagnosis of fragile X syndrome is based on molecular genetic analysis which has replaced karyotype visualization of the fragile X chromosomes following cell culture in folate deficient media. Most labs now use either (1) Southern blot analysis to measure methylation and the size of expansions in large pre-mutation or full mutation alleles or (2) PCR to identify normal alleles and discriminate small differences in the intermediate and premutation sizes.

Answer 153

Expanding triplets have also been implicated in myotonic dystrophy, Kennedy syndrome (androgen receptor gene) and Huntington's disease. 1. Fragile X CGG 2. Huntington CAG 3. Myotonic dystrophy GCT 4. X linked spinal and bulbar muscular atrophy CAG 5. Spinocerebellar ataxia type I CAG 6. Fragile site FRAXE GCC

Answer 154

ANTICIPATION - Anticipation may also stem from ascertainment bias, that is, mildly affected individuals may escape detection in prior generations perhaps because of archaic detection methods. This would erroneously reduce penetrance in that generation and give the appearance of increasing penetrance over generations. E.g 1. Huntington disease is a variable age of onset autosomal dominant disorder characterized by personality changes, motor abnormalities (choreiform movements), gradual loss of cognition and premature death. Variable age of onset. Disease stems from expansion of CAG repeat in the huntingtin gene; extent of repeat correlates inversely with age of onset. 2. Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia, ptosis, cataracts, hypogonadism, frontal balding, ECG changes. Defect in one form of this disorder is an amplified trinucleotide repeat in the 3' untranslated region of a protein kinase gene on chromosome 19. Repeat expansion accounts for the phenotypic worsening over generations. Diagnostic probes for measuring repeats and predicting disease status are available.

Answer 155

 Monogenic traits: Allelic and Locus heterogeneity  Penetrance, sex influence, some RP can be explained by polygenic inheritance  ANTICIPATION in Fragile X and others is based on ALLELIC INSTABILITY (TRIPLET EXPANSION), not gene- gene interactions.

Answer 156

VARIABLE EXPRESSIVITY ** While penetrance refers to the presence or absence of any effect of a gene, expressivity refers to the type or degree of manifestation of a gene that is a penetrant. Examples: - Neurofibromatosis (NF1) is an autosomal dominant neurocutaneous disorder. - Mild cases involve presence of café au lait spots (light brown in color) and benign skin tumors, neurofibromas. In more severe cases, thousands of disfiguring neurofibromas and malignant tumors (eye, brain, and spinal cord), mental retardation and/or speech impediment can be present. A wide variety of NF1 mutations have been found in NF patients. - ***Most studies have not found an obvious relation between particular NF1 mutations and the resulting clinical manifestations. The variability of the NF1 phenotype, even in individuals with the same NF1 gene mutation, suggests that other factors are involved in determining the clinical manifestations, but the nature of these factors has not yet been determined. * *CASE FOR POLYGENIC INHERITANCE IN EXPRESSIVITY - VARIABLE PHENOTYPE EVEN IN THOSE WITH SAME NF1 MUTATION

Answer 157

1. Osteogenesis imperfecta. Principal features: blue sclerae, very fragile bones and deafness, skeletal deformities. Overall incidence 1/10,000. Autosomal dominant with nearly 100% penetrance. Expressivity varies greatly from patient to patient within same family. 2. Muscular dystrophies: Duchenne, Becker forms both involve the mutations in the same gene. These do not fit the definition of expressivity, because the variations in phenotype are not based on the interaction of a single gene with other genetic loci, but rather on the presence of the several defective alleles at one genetic locus. Allelic heterogeneity is more applicable term in this case. III. Uniparental Disomy/Genomic Imprinting

Answer 158

In rare cases, a gamete disomic for a given chromosome will fertilize one which is nullisomic for the same chromosome. The resulting zygote will have a euploid chromosome number but (at least) two chromosomes (e.g. two maternal chromosome 15s) were inherited from the same parent (UNIPARENTAL DISOMY). Some genes are activated or inactivated in a sex-specific manner, a phenomenon called GENOMIC IMPRINTING. It follows that uniparental disomy could lead to a gene being present in either two active or inactive doses. Several human diseases result from this functional imbalance and the phenotype depends on the "parent of origin". ** Prader-Willi (PWS) and Angelman Syndromes (AS) are parent of origin diseases and stem from genomic imprinting of several genes in critical region on chromosome 15. Genomic imprinting can inactivate expression of some genes in a sex-specific manner.

Answer 159

PW and AS can stem from several mechanisms: (1) Physical deletion of the active PWS gene(s) in a sperm + fertilization of an egg where the genes are not expressed results in a zygote where no critical region genes are expressed. Conversely, physical deletion of the active AS genes in an egg + fertilization by a sperm where the AS genes are not expressed results in a zygote where no critical region genes are expressed. Deletion explains 70% of PWS and AS cases. (2) Uniparental disomy can form zygotes where both c15’s are maternal OR paternal in origin. If both C15s are maternal in origin, no active paternal genes are present and PWS follows. There is no consensus on the number of genes in the PWS and AS critical regions. PWS can result from inheritance of pair of maternal chromosome 15’s and no paternal 15’s (30% of all cases). AS results from the inheritance of pair of paternal chromosome 15s and no maternal 15s (5% of cases).

Answer 160

MULTIFACTROIAL TRAITS (sometimes called complex traits) are those that have both a genetic and an environmental basis. Note that for many physical and behavioral traits, there is a continuous spectrum of phenotypes (measured in meters, grams, test scores, etc.). These are referred to as quantitative traits because measuring methods (biometry) are used to describe the trait and the measurements vary across individuals in a population. Many quantitative traits can be explained by multifactorial inheritance. Consider height as an example of a trait with continuous distribution. Four models can be proposed to explain the population frequencies: one gene, two genes, three genes, three or more genes + environment. Note that as more features are added to the model, the number of possible genotypes increases and the appearance of the bell curve approaches the actual distribution. Examples of normal human traits affected by a number of genes and environmental factors: skin and hair color, height, weight, blood pressure, intelligence.

Answer 161

Threshold (Dichotomous) vs Quantitative traits: A number of complex human diseases do not occur in a bell-shaped distribution, instead they are either fully present or absent in an individual. One explanation is that the liability (genes + environment) for a given disorder follows the bell curve and that only when a certain threshold is reached will the disease phenotype manifest itself. * *Examples of threshold human diseases: 1. Pyloric stenosis is 5X more common in males than females (threshold is higher in women) 2. Neural tube defects 3. Cleft Lip/Palate 4. Cardiovascular disease: Genotype of individual (family history of heart attack) + environmental factors (cigarette smoking, stress, and diet) 5. lung disease in patients with α1-antitrypsin deficiency is determined by mutations in the alpha1anti-trypsin gene and environment factors (smoking).

Answer 162

Alzheimer’s disease (Examples of Monogenic and Multifactorial Disease) Description: Slow progression that results in memory loss and alteration of intellectual function and cognitive abilities (e.g. loss of executive function). AD is the most common form of dementia occurring after age 40. Incidence: 1 in 9 age 65 or older; 1 in 3 age 85 or older. Early onset forms occur before age 60 and are likely to be inherited as autosomal dominant traits. Late onset forms are more common than early onset and in some cases appear to be multifactorial. Pathology: Neurofibrillary tangles are found in neurons of cerebral cortex and hippocampus. Amyloid deposits within senile plaques are caused by the accumulation of amyloid precursor protein (APP). Presenilin 1 and presenilin 2 are required for processing of APP. Mutations in these genes and APP itself lead to early onset forms of the disease. Abnormal APP cleavage leads to amyloid deposits (see figures)

Answer 163

Locus heterogeneity in Alzheimer disease: Early onset forms are caused by mutations in either APP, PSEN1 or PSEN2. But these three genes only explain a small percentage of all affected persons. See table. ApoE, an Alzheimer’s disease susceptibility gene. The apoE gene has a number of missense polymorphisms. Two common sets of linked polymorphisms result in amino acid substitutions at 112 and 158 as shown below. - chromosome 1; presenilin II - early - chromosome 14; presenilin I - early - chromosome 19; APOE - BOTH (MOST COMON) - chromosome 21; APP - early * *unknown for late ApoE alleles were found to confer risk in a dose dependent fashion. ApoEe4 allele results in increased risk of development and decrease in age of onset. ApoE4 homozygotes have a 90% chance of developing by age 75, while apoEe4/apoEeX have a 45% chance and apoEeX/apoEeX have only a 20% chance (where EX is any allele except E4). ApoEe4 binds to APP more rapidly and may affect its processing. 3. Clinical Utility of ApoEe4 testing (See p492 in Genetics in Medicine. 7th edition) Population screening vs Diagnostic testing Population PPV for e4/e4 = 23% vs Diagnostic PPV for e4/e4 = 98% So, ApoE testing may be helpful in confirming a diagnosis of dementia in a patient with dementia. However even in this case, testing has limited practical value because of the absence of suitable treatments.

Answer 164

A. SLOW PROGRESSIVE LOSS OF MEMORY AND COGNITIVE FUNCTION B. 0.1% AGE 60-69; 2.2% ABOVE AGE 80 C. PATHOLOGY: NEUROFIBRILLARY TANGLES, APP in AMYLOID DEPOSITS, ROLE OF PRESENILINS D. EARLY ONSET (AGE 40-50) ONLY ACCOUNT FOR A FEW % OF TOTAL CASES - LARGELY AUTOSOMAL DOMINANT - LOCUS HETEROGENEITY - PRESENILIN AND APP GENES E. LATE ONSET (AGE 60 AND UP) 50% OF ALL CASES - MULTIFACTORIAL (?) - GENES UNKNOWN F. APOE VARIANTS LEAD TO BOTH EARLY AND LATE FORMS - E4/E4; 90% by age 75 - E4/EX; 45% by age 75 - EX/EX; 20% by age 75 G. MULTIFACTORIAL: ONE COPY E4 + (Age, head trauma, ???)

Answer 165

OBESITY - Unlike the other chronic diseases, however, it is not a silent killer, but one whose external manifestations are evident to afflicted individuals from its outset as weight gain and increased girth. **WEST VIRGINIA now leads the nation in obesity

Answer 166

1. A. Cortisol excess (Cushing syndrome) B. Hypothyroidism C. Growth hormone deficiency 2. Obesity physiopathology A. Afferent signals; GHRELIN, PYY, Insulin, amylin, IL6, LEPTIN, ADIPONECTIN, others B. Efferent signals; sympathetic, parasympathetic, thyroid hormones

Answer 167

1. Anticonvulsant/mood stabilizers; carbamazepine, gabapentin, pregabalin, valproic acid, lithium 2. Antidepressants A. MAOI; Phenelzine B. SSRI; Citalopram, escitalopram, fluvoxamine C. Presynaptic alpha 2 antagonist; mirtazapine D. SNRI; duloxetine E. Tricyclics; amitryptyline, imipramine 3. Antidiabetics; insulin, meglintinides, sulfonylureas 4. Antipsychotics; atypical and conventional 5. Others; antihistamines, corticosteroids, hormonal contraceptives - depolarizing injections

Answer 168

➢ Overweight: BMI 25–29.9 kg/m2 ➢ Class 1 obesity: BMI 30–34.9 kg/m2 ➢ Class 2 obesity: BMI 35–39.9 kg/m2 ➢ Class 3 obesity: BMI ≥

Answer 169

❑ Assess (assess weight and risk factors) ❑ Advise (advise weight loss, personalize the recommendation to the patient) ❑ Agree (agree on a target for behavior change) ❑ Assist (assist with a referral) ❑ Arrange (arrange follow-up) Dietary strategies 1. Calorie restriction 2. Physical activity 3. Any calorie reduction diet leads to weight loss 4. Calorie deficit diet following federal dietary guidelines Behaviors associated with weight loss maintenance ❑ Participation in structured weight management program ❑ Physical activity >60 mins/day most days of the week

Answer 170

``` 1. FDA approved indications A. Patient with obesity (BMI >30) B. Patient overweight (BMI >27) with presence of increased adiposity complications - Type 2 DM - Hypertension - Dyslipidemia ``` 2. Other principles - Anti obesity medications promote variable weight loss over variable duration in patient whom are overweight or obese - Some patients have an average of 5-10% weight loss with variations

Answer 171

Phentermine (Adipex-P) - mean weight loss; 3.6kg (7.9lbs) Common side effects • Headache • Elevated blood pressure • Palpitations • Insomnia • Dry mouth • Constipation • Anxiety Contraindications • Anxiety disorders (agitated states) • History of heart disease • Uncontrolled hypertension • MAO inhibitors • Pregnancy and breastfeeding • History of drug abuse

Answer 172

Orlistat (Alli, Xenical) Common side effects • Decreased absorption of fat-soluble vitamins • Oily spotting • Flatulence with discharge • Fecal urgency • Increased defecation Contraindications • Chronic malabsorption syndrome • Pregnancy and breast feeding (Category X) • Cholestasis • Warfarin • Antiepileptic drugs Orlistat Drug Interactions A. Amiodarone: decrease serum concentration B. Cyclosporine: decrease serum concentration • Administer orlistat at least 3 hours before or after cyclosporine C. Levothyroxine: decrease serum concentration • Separate administration by at least 4 hours • Monitor for signs and symptoms of hypothyroidism D. Anticonvulsants: decrease serum concentration E. Warfarin: enhance the anticoagulant effect of vitamin K antagonist

Answer 173

Locaserin (Belviq) Common side effects • Headache • Nausea • Dry mouth • Dizziness • Fatigue • Constipation Contraindications/use with caution • Pregnancy and breastfeeding • SSRI • SNRI/MAOI • St

Answer 174

Phentermine/Topiramate (Qsymia) ``` Common side effects • Insomnia • Dry mouth • Constipation • Paresthesia • Dizziness • Dysgeusia • Increased heart rate ``` contraindications • Pregnancy and breastfeeding • Hyperthyroidism • Glaucoma • MAO inhibitor • Sympathomimetic amines Qsymia REMS program A. To inform prescribers and females of reproductive age the potential of: • Increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to Qsymia during the first trimester of pregnancy • Important of pregnancy prevention for females of reproductive potential receiving Qsymia • Need to discontinue Qsymia if pregnancy occurs B. Pregnancy test should be taken BEFORE starting treatment and every mouth after while on treatment

Answer 175

Naltrexone/Buproprion (Contrave) ``` Common side effects • Nausea • Constipation • Headache • Vomiting • Dizziness • Increased thirst • Insomnia ``` Contraindications • Uncontrolled hypertension • Seizure disorders • Anorexia nervosa or bulimia • Drug or alcohol withdrawal • MAO inhibitors

Answer 176

Liraglutide (Saxenda) Common side effects • Headache • Diarrhea • Constipation • Vomiting • Abdominal pain • Gastroenteritis Contraindications • History of or family history of medullary thyroid cancer history • Patients with multiple endocrine neoplasia syndrome type 2 • Pregnancy

Answer 177

1. Screening and prevention ❖ Screen for obesity ❖ Refer for intensive treatment interventions ❖ Review medication lists: could changes reduce weight gain? ❖ Encourage behaviors that can prevent weight gain 2. Diagnosis ❖ Use BMI to diagnose obesity Diagnose obesity ❖ Combine with other patient characteristics to assess risk ❖ Measure waist circumference if BMI 25-34.9 kg/m^2 A. Abdominal obesity increases health risk B. Focus history and physical exam on ▪ Weight-related conditions ▪ Weight trajectory ▪ Previous weight loss attempts C. Screen for diabetes, nonalcoholic fatty liver disease, thyroid dysfunction, dyslipidemia

Answer 178

The Hardy-Weinberg equation allows one to determine the frequency of a given genotype from the frequencies of the alleles of locus in question. Allele frequencies are determined by counting the number of alleles of one type and dividing by the total number of all the different alleles. P+q = 1 ``` (p+q)^2 = p^2 + 2pq + q^2 = 1. Where; P^2 = the frequency of BB genotype 2pq = the frequency of Bb genotype Q^2 = the frequency of bb genotype ```

Answer 179

Allele frequencies have clinical and forensic significance. Because these values can vary from population to population, the risk of carrier status varies (sometimes dramatically) and influences the risk of having an affected offspring. These population-specific allele frequencies allow us to calculate the probability of carrier status (examples will follow). In forensic science, the probability of a match between two DNA samples is dependent on the frequencies of the alleles in a given population; in modern applications, allele frequencies have been determined for many population subgroups (race, ethnicity, etc.).

Answer 180

The Hardy-Weinberg law states that genotypes will be distributed in a population BASED ON the ALLELE FREQUENCIES and the GENOTYPE FREQUENCIES will REMAIN CONSTANT from generation to generation. This law only holds as long as all of the following conditions are met: 1. The population exhibits random mating with little stratification, assortative mating or inbreeding. 2. The trait is present in a LARGE POPULATION. 3. There is a NEGLIGIBLE NET MUTATION RATE between the B and b alleles. 4. There is a NEGLIGIBLE AMOUNT OF MIGRATION into or out of the population. 5. There is a NEGLIGIBLE AMOUNT OF SELECTION, that is, all genotypes are equally viable and equally fertile.

Answer 181

1. The population exhibits random mating with little stratification, assortative mating or inbreeding. For example, if one genotype (bb) rarely mates, then the b allele frequency will decline over time. There are three classes of nonrandom matings: (A) Consanguineous matings result in an increase in homozygous genotypes and a decrease in heterozygotes. (B) A stratified population is one having subgroups that do not intermarry. Basis can be culture, economic status, race, religion etc. C) Assortative mating is the choice of mate based on phenotype (intelligence, stature, skin color, musical talent etc.); as in consanguineous matings, heterozygous types are also underrepresented in assortative matings or stratified populations. Here's why: In random mating population where; p = 0.5 and q = 0.5 AA = p^2 = 0.25, Aa = 2pq = 0.50 aa = q^2 = 0.25 In population where nonrandom matings predominate, i.e. mostly BB X BB and bb X bb, the frequency of heterozygotes will decline so that AA = 0.50, Aa = 0, aa = 0.50

Answer 182

- The trait is present in a large population. In a small population one genotype may be transmitted exclusively to a subsequent generation by chance. - ***The net effect would be a reduction in the frequency of one or more alleles not present in this genotype. - This exclusive transmission can happen in any population, but is much less likely to happen in large populations. - GENETIC DRIFT applies to the establishment of new alleles or allele frequencies in a population and to the formation of subpopulations isolated from larger population.

Answer 183

There is a negligible net mutation rate between the B and b alleles. For example, two alleles may differ by a single site (point mutation). Their frequencies can change under the following conditions. (A) A high mutation rate in favor of forming the b allele will tend to raise its frequency. (B) Alleles are lost when individuals have no offspring. This can be significant if the trait reduces the fitness of the carrier. For autosomal dominant disorders, the mutation rate at a given locus must account for the proportion of alleles lost by selection. Genetic fitness is the probability of transmitting one's genes to the next generation. For example, fitness (f) for achondroplasia is 20%. This means that 80% of the defective alleles are lost every generation. For X-linked recessive disorders that have zero fitness, one third of all recessive alleles are lost every generation. If this population is in HW equilibrium, then the proportion of mutant alleles that result from spontaneous mutations is one third. Mutation rates can be relatively high for some genetic loci and may depend on the size and DNA sequence of the gene. New mutations may account for many of the clinical cases of a given disorder.

Answer 184

There is a negligible amount of migration into or out of the population. Founder effect occurs when a group of colonists do not have the same allele frequencies as their original population or the population they move into. For example, Lake Maracaibo Venezuelans have high frequency of Huntington’s disease because one or a few individuals (possibly European colonists) had many offspring there and thereby introduced the disease. So the allele frequency in Venezuela is higher than in Europe. Other examples: Ellis van Creveld syndrome in the Amish, tyrosinemia in French Canadians.

Answer 185

There is a negligible amount of selection, that is, all genotypes are equally viable and equally fertile. If there is complete selection against aa individuals, only AA and Aa will contribute to the gene pool of the next generation. This will reduce q (freq (a)) over time, but will not completely eliminate it.

Answer 186

Application A. MN blood groups. Determine the frequency of M and N alleles from the information on the genotypes. Use equations (1) and (2) below. Genotype frequencies: MM = 36; MN = 48; NN = 16. Total sample = 100 B. Albinism, autosomal recessive disorder: Given the frequency of albinos = 1/20,000 in the general population, please determine the frequency of AA and Aa in the population. 1/20,000 is the genotype frequency. C. Tay Sachs Disease Given the frequency of affected individual with Tay Sachs disease determine the carrier frequency in each of these populations D. Hardy-Weinberg statement for X - linked genes: For female populations: p2 + 2pq + q2 = 1 (the standard form of HW) For male populations, there are only two possible genotypes: H/(Y) whose genotype frequency = p, and h/(Y) whose genotype frequency is q Example: The frequency of males with Factor VIII hemophilia is 1 in 10,000. What is the frequency of carrier females in this population? freq q = 1/10,000 2 pq = 2 (9999/10,000) (1/10,000) = 0.000199 = 0.0002 = 0.02%

Answer 187

Determination of risk to an individual is an essential part of genetic counseling. For single gene disorders, assessing the probability of recurrence of a given disorder can be fairly straightforward. For example, if the parents are known to be carriers of an autosomal recessive disorder, the probability of having an affected child is 1/4. Carrier status for some disorders is readily determined by (1) direct detection of the wild type and mutant alleles (by PCR, for example) or (2) detection of closely linked genetic markers, such as RFLPs or HLA markers. However, for the majority of diseases the carrier status cannot be directly determined.

Answer 188

A) if carrier status is known, Punnett square is sufficient. B) if carrier status is not known, use the population-based frequency (and/or Bayes' theorem) + Punnett square calculation. VB. Risk calculation for Complex traits Empiric (observed) risk is used as the probability of recurrence. Empiric risk is based on the observed numbers of affected individuals divided by the number of offspring.

Answer 189

1. Build a pedigree based on family data 2. Determine the genotype and probability of genotype for the prospective couple 3. Determine the probability of having an affected offspring given genotype (probable) of the parents. 4. Combine the three probabilities (for autosomal). P(carrier or affected) x P (carrier or affected) x Punnett probability = P (having an affected) 5. Always round p to 1 for this course.

Answer 190

i. Gastric acid secretion - a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint - the secretion of H+ by parietal cells. ii. Neuronal (acetylcholine), paracrine (histamine) and endocrine (gastrin) factors all regulate acid secretion by acting on their specific receptors (M3, H2 and CCK2, respectively) present on the basolateral membrane of parietal cells in the body and fundus of the stomach. iii. Ach and gastrin signal through GPCRs that couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells. Ach also indirectly affects by increasing the release of histamine from the enterochromaffin-like (ECL) cells in the fundus of the stomach and gastrin from the G cells of the gastric antrum. iv. Gastrin stimulates acid secretion indirectly by inducing the release of histamine by ECL cells v. Histamine acts as a paracrine mediator, diffusing from its site of release to nearby parietal cells, where it activates H2 receptors. The H2 receptor is a GPCR that activates Gs-adenylyl cyclase-cAMP-PKA pathway. vi. In parietal cells, the cAMP and the Ca2+-dependent pathways activate H+,K+ ATPase (the proton pump), which exchanges hydrogen and potassium ion across the parietal cell membrane. vii. Somatostatin (SST) is a small peptide, produced by antral D cells. SST inhibits gastric acid secretion (NEGATIVE FEEDBACK LOOP - activated by acidification of grastic luminal pH <3)

Answer 191

GASTRIC DEFENSE * *PGE2 and PGI2 i. The primary esophageal defense is the LOWER ESOPHAGEAL SPHINCTER, which prevents reflux of acidic gastric contents into the esophagus. ii. The stomach protects itself from acid damage by a number of mechanisms that require ADEQUATE MUCOSAL BLOOD FLOW. iii. First key defense is the SECRETION OF A MUCUS LAYER that protects gastric epithelial cells. MUCUS PRODUCTION is stimulated by PGE2 and PGI2, which also DIRECTLY INHIBIT GASTRIC ACID SECRETION by parietal cells. iv. Second important defense is the secretion of bicarbonate ions by superficial gastric epithelial cells.

Answer 192

A. General Comments i. Disease can result from an increase in gastric acid secretion, pepsin activity, NSAIDs, H. pylori and/or a decrease in mucus, HCO3- or PGs. ii. Therapy is aimed at decreasing acid or promoting mucosal protection. B. Antacids 1. *Two general antacid categories a. Systemic antacids – NaHCO3 (baking soda, Alka Seltzer) b. Non-systemic antacids – CaCO3 (Tums), Al(OH)3, Mg(OH)2 (milk of magnesia, Mylanta, Gelusil) Pharmacologic Properties of Antacids a. Antacids react with gastric acid (HCl). b. *The basic group in the antacid neutralizes the acid to form water, carbon dioxide and chloride salts. c. Added simethicone decreases foaming and esophageal reflux.

Answer 193

Antacid Adverse Effects a. NaHCO3 & CaCO3: Formation of CO2 causes gastric distention and belching; Transient metabolic alkalosis – NaHCO3 & CaCO3 b. Consider sodium levels in CHF c. *GI Effects Al(OH)3 can cause constipation Mg(OH)2 can cause diarrhea Net effect of combination agents (e.g. Gelusil, Maalox, etc.) depends on the relative amounts of the two agents. d. Excessive use of Al and Mg antacids can lead to hypophoshatemia due to formation of insoluble metal phosphate salts. e. *In DECREASED renal function, absorbed Al3+ and Mg2+ can lead to systemic toxicity. Antacid Drug Interactions a. *Altered gastric or urinary pH may affect rate of absorption or excretion and the bioavailability of some drugs. b. Altered GI motility by Al3+ or Mg 2+ or complex formation (Al) can alter absorption of some drugs. c. *Significant DECREASED bioavailability – many factors: iron, theophylline, quinolone antibiotics, isoniazid, tetracycline and ketaconazole.

Answer 194

Histamine H2 Receptor Antagonists (H2RA) a. Include: cimetidine (Tagamet), ranitidine (Zantac), nizatidine (axid) and famotidine (Pepcid). b. *Mechanism of Action: - Competitive antagonists of histamine at H2 receptors - DECREASED volume of gastric juice and [H+] content - DECREASED pepsin secretion c. Cimetidine was the initial agent in this class. Other agents are generally more potent than cimetidine and are longer acting. d. *Cimetidine, ranitidine and famotidine are biotransformed by the liver in varying amounts, while nizatidine is eliminated primarily by the kidney. e. All H2RA’s inhibit 60-70% of total 24hr acid secretion f. Especially effective at inhibiting nocturnal acid secretion (Histamine dependent acid secretion), but modest impact on meal-stimulated acid secretion (stimulated by gastrin, Ach and histamine)

Answer 195

Histamine H2 Receptor Antagonists (H2RA) Adverse effects 1. The incidences of adverse effects are low and generally minor. 2. Most common adverse effects (1-3%) are headache, itching, rashes, lethargy and confusion. The last two are seen most in elderly patients or patients with renal impairment. 3. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits E2. At high doses and long-term use may case impotence in men. Drug interactions 1. Similar interactions to antacids due to altered gastric acid secretion. 2. Cimetidine – inhibits CYP450 and alters the biotransformation rate of many drugs. May increase toxicity of second drug, if dose adjustments are not made. Other H2RAs have no effect on hepatic biotransformation of other drugs.

Answer 196

Proton Pump Inhibitors Mechanism of action: PPIs irreversibly inhibit the H+/K+ - ATPase in parietal cells to DECREASED basal and stimulated gastric acid secretion (>90%). [PPIs are administered as inactive prodrugs (acid –resistant, enteric-coated capsules or tablets). After passing through the stomach into the intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed (the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+/K+ - ATPase, irreversibly inactivating the enzyme.] PPIs inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, i.e. the proton pump. The drug is administered one hour before meal so that the peak serum concentration coincides with the maximal activity of proton pump secretion. Though the serum half life of the drug is only 1.5 hours, the acid inhibition lasts up to 24 hrs owing to the irreversible inactivation of the proton pump.

Answer 197

1. *Peptic ulcers – Compared to H2RA, PPIs afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and to a lesser extent, gastric ulcers. Note: eradicate H. pylori infection if present, to reduce recurrence of ulcer formation (see below for H. pylori treatment regimen). 2. GERD: PPIs are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease and extraesophageal manisfestations of reflux disease. Empiric treatment with PPI provides sustained symptomatic relief in 70- 80% of GERD patients compared with 50-60% with H2RA. 3. Zollinger-Ellison syndrome 4. NSAID associated ulcers: For patients with ulcers caused by aspirin or NSAIDs, either H2RA or PPI provide healing so long as NSAIDs are discontinued. If patients require continued NSAID therapy, treatment with once or twice daily PPIs are more reliable to promote ulcer healing.

Answer 198

Proton Pump Inhibitors a. Include : omeprazole (Prilosec), esomeprazole (nexium) and lansoprazole (prevacid). ADVERSE EFFECT 1. Generally well tolerated 2. Effects at 1.5-3% incidence include mainly GI effects (nausea, diarrhea, flatulence) and some CNS effects (headache, dizziness). 3. Long term use-warning about increased risk to fractures (reduced gastric acidity might interfere with calcium absorption) 4. QT interval prolongation and torsades de pontes (TdP) associated with severe PPI-induced hypomagnesia has been reported. Hypomagnesia is usually accompanied by hypocalemia and hypocalcemia, 5. Prolonged use of prescription strength PPI could lead to CKD and end-stage renal disease 6. Gastric cancers have been observed in animals. Human

Answer 199

Proton Pump Inhibitors a. Include : omeprazole (Prilosec), esomeprazole (nexium) and lansoprazole (prevacid). Drug interactions 1. Interactions due to altered gastric acid secretion similar to antacids and H2RA. 2. Omeprazole and esomeprazole– inhibits CYP450s (Cyp2c19). 3. Can increase serum levels of drugs metabolized by Cypc19 such as diazepam (Valium) 4. Omeprazole and esomeprazole can inhibit conversion of antiplatelet drug clopidogrel (plavix and generics) to its active form. (patients taking clopidogrel use other PPIs such a lansoprazole etc).

Answer 200

MISOPROSTOL (cytotec) a. A stable methyl analog of PGE1 b. Biological effects include; DECREASED acid secretion, INCREASED mucous and HCO3- secretion Therapeutic uses; prevention of peptic ulcer disease related to NSAID administration in high risk patients. Less effective than H2RA for other types of peptic ulcer disease.

Answer 201

SUCRALFATE (carapace) a. A sulfated sucrose and polyaluminum hydroxide complex. b. *Mechanism of action: At pH < 4, sucralfate forms polymers/cross-links to form a sticky gel that adheres to GI cells and ulcer craters. A protective barrier against acid.

Answer 202

Bismuth Compounds a. Colloidal bismuth subcitrate (GI ulcers) and bismuth subsalicylate (Pepto-Bismol) (ulcers and heartburn). Adverse effects - Can darken oral cavity and stool (bismuth sulfide from reaction with bacterial H2S).

Answer 203

Helicobacter pylori *** Impaired production of somatostatin by Δ cells, inhibition of gastrin production

Answer 204

GERD (Gastroesophageal Reflux Disease) 1. Also known as heartburn affects 10% of the US population. 2. Antacids (neutralize gastric acid, INCREASED lower esophageal sphincter tone and clearance). 3. H2RA and PPIs inhibit acid secretion and are preferred if problems persist with the use of OTC antacids. 4. PPIs are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease and extraesophageal manisfestations of reflux disease. 5. Empiric treatment with PPI provides sustained symptomatic relief in 70-80% of GERD patients compared with 50-60% with H2RA.

Answer 205

Metoclopramide (Regalan) *Metoclopramide has combined cholinergic agonist and dopamine (D2) antagonist activity. A prokinetic agent. MoA; - INCREASE esophageal clearance - INCREASE LES pressure and INCREASE gastric emptying - NET effect is to DECREASE REFLUX

Answer 206

CONSTIPATION - Constipation is characterized by dry stools that are often voided with excessive straining. Frequency of defecation is also reduced. - Can be caused by a wide range of causes, including drugs, stress, diet, and disease of the GI tract.

Answer 207

1. Bulk-forming laxatives (Dietary Fibers (DFs)) 2. Saline Laxatives 3. Osmotic laxatives - Osmotic effects retain water in the colon and soften stools**

Answer 208

1. Stimulant laxatives 2. Surfactant laxatives - *Docusates are mainly wetting and emulsifying agents that help soften the stool. - Castor oil - The oil of the castor bean contains a triglyceride ester of ricinoleic acid. - *Castor oil is cleaved to ricinoleic acid in the small intestine and can produce a purging effect with semi-fluid stools in 1-6 hours. Can be days before a normal defecation again. - *Ricinoleic acid is an anionic surfactant that DECREASED net absorption of fluid/electrolytes and stimulates peristalsis. 3. Mineral oil - *Can decrease the absorption of fat-soluble vitamins. - If aspirated, lipid pneumonitis can occur.

Answer 209

Lubiprostone (Amitiza ) (2012): * Adverse effects: nausea, abdominal pain diarrhea, some patients-dyspnea * Modestly effective also in treating opioid-induced constipation (exogenous opioids decrease peristalsis and secretion of fluid and electrolytes into the intestinal lumen).

Answer 210

Linaclotide (Linzess) (2013) (Plecanatide-Trulance-2017) - Increases intraluminal fluid and accelerates intestinal transit - Adverse effects: diarrhea, abdominal pain, flatulence; (black box warning against use in patients <18 years due to deaths in young mice.

Answer 211

Naloxegol (Movantik), (2014) • Naloxegel is a peripheral mu-opioid receptor antagonist. Pegylation reduces ability to cross BBB and makes it a substrate of the efflux transporter P- glycoprotein. • Adverse effects- dose related: abdominal pain, diarrhea, nausea, flatulence and vomiting

Answer 212

1. Used to: maintain soft feces, prevent straining during defecation and evacuation of the bowel before surgery or diagnostic procedures. 2. Contraindicated in patients with cramps, colic, nausea, vomiting, undiagnosed pain, or symptoms of appendicitis. 3. The laxative habit.

Answer 213

``` DIARRHEA; Characterized by watery stools and can be associated with an INCREASED frequency of defecation (> 3x/day). ``` Treatment 1. Nonspecific antidiarrheals – aim is to prevent dehydration and electrolyte imbalances. 2. If diarrhea is drug induced, change the dose of the drug or change to a new drug. Infectious diarrhea may require antibiotics.

Answer 214

Mechanism of action: Opioids stimulate the mu opiod receptors in the GI tract to: - DECREASE GI motility Which INCREASE transit time and absorption of water and salt - DECREASE secretion of water and salt Agents include; - DIPHENOXYLATE + atropine - DIPHENOXIN (active metabolite of diphenoxylate) + atropine - LOPERAMIDE *Atropine affects GI motility and secretion, but side effects discourage abuse of the opioid preparation. Loperamide has poor CNS penetration. *For moderate-to-severe traveler’s diarrhea; LOPERAMIDE + an appropriate ANTIMICROBIAL drug are preferred * * Adverse Effects a. Constipation b. With high doses of diphenoxylate + atropine, CNS effects can occur due to activation of central mu opiod receptors (opiod) and antimuscarinic effects (atropine)

Answer 215

1. Bismuth Subsalicylate A. *Pepto-Bismol - Used to treat mild-to-moderate traveler’s (infectious) diarrhea. B. Salicylate provides anti-inflammatory effects. C. Bismuth is antibacterial. 2. Octreotide A. A synthetic analog of somatostatin B. *Numerous effects on the GI tract including DECREASE in GI endocrine secretions, intestinal fluid and HCO3- secretion and smooth muscle contractility. C. Used to treat diarrhea caused by disease (e.g. chemotherapy, AIDS, refractory, diabetes), tumors and other disorders.

Answer 216

Inflammatory bowel disease (IBD) • Causes unknown; autoimmune disease? • Crohn’s Disease; inflammation anywhere in GI tract • Ulcerative colitis: inflammation predominately in colon and rectum Pharmacology • Involves drugs that belong to different therapeutic classes and have different non- specific mechanisms of anti-inflammatory action • Drugs chosen on the basis of disease severity, responsiveness and drug toxicity

Answer 217

**Treatment choice is predicted on both the severity of illness and responsiveness to therapy. MILD: 5-aminosalicylic acid (5-ASA) (UC or Crohn’s colitis) A. Topical corticosteroids (UC) B. Antibiotics (Crohn’s colitis or Crohn’s perianal disease) C. Budesonide (synthetic analog of prednisolone) (Crohn’s ileitis) MODERATE (pt that fail initial therapy of mild disease) A. Oral corticosteroid (promote disease remission) B. Immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission Anti-TNF antibodies) MODERATE (who fail above therapy) Or SEVERE A. IV corticosteroid B. Anti-TNF antibodies C. Surgery D. Natalizumab (ab-alpha 4 intergrin) or Ustekunumab (stellar IL12 and IL23) antagonist (those who have failed Immunomodulators or TNF antagonists) E. Cyclosporine (those with severe UC who have failed IV corticosteroids)

Answer 218

Jaundice; yellow discoloration of the skin due to retention of bilirubin Cholestasis; systemic retention of bilirubin and other solutes normally eliminated by bile Common causes of jaundice 1. Overproduction of bilirubin 2. Hepatitis 3. Bile flow obstruction

Answer 219

a. Dietary fat emulsification in the gut lumen via detergent action of bile salts b. Elimination of bilirubin, excess cholesterol and other waste products c. Consists mostly of bile salts (conjugation of bile acids with taurine or glycine)

Answer 220

1. BILIRUBIN (a) In blood, heme oxidized to biliverdin (by mononuclear phagocytic cells) (b) Biliverdin reduced to indirect (unconjugated) bilirubin which is bound to albumin and taken up by hepatocytes (c) In hepatocytes, indirect bilirubin is conjugated with glucuronic acid by bilirubin uridine diphosphate- glucuronyltransferase (UDPGT1A1) (d) Direct (conjugated) bilirubin is formed, transported into the bile canaliculi and secreted into the intestine (e) Intestinal bacteria deconjugate the direct bilirubin and eventually degrades it to urobilinogen ***Urobilinogen primarily excreted in the feces (small amount reabsorbed and excreted in urine) 2. BILE ACIDS (1) Major catabolic products of cholesterol (2) Primary human bile acids are cholic acid and chenodeoxycholic acid (3) Conjugated with taurine or glycine to form bile salts (4) Detergents that solubilize water-insoluble lipids in bile (5) Lipid carriers that remain soluble in water (6) Most are reabsorbed from the gut and returned to the liver by enterohepatic circulation

Answer 221

1. INDIRECT (unconjugated) (a) Virtually water insoluble at physiologic pH (b) Tightly complexed with serum albumin (c) CANNOT be excreted in urine (why not?) (d) Very small amount exists as albumin-free anion in blood (d) Elevated in severe hemolytic anemias, with certain protein- binding drugs and physiologic jaundice of the newborn (e) Can cause kernicterus in newborns (severe neurologic damage) 2. DIRECT (conjugated) (a) Water soluble at physiologic pH (b) Nontoxic (c) Loosely bound to albumin (d) CAN be excreted in urine (e) Elevated in deficiency of canalicular membrane transporters and impaired bile flow **CLINICALLY evident when bilirubin levels >2.0 to 2.5 mg/dL ** Occurs when the balance between bilirubin production and clearance is disturbed by: (1) Excessive extrahepatic bilirubin production (unconjugated) (2) Reduced hepatocyte uptake (unconjugated) (3) Impaired conjugation (unconjugated) (4) Decreased hepatocellular excretion (conjugated) (5) Impaired bile flow (conjugated)

Answer 222

NEONATAL JAUNDICE (physiologic jaundice of the newborn) **May be aggravated by breastfeeding (Beta-glucuronidases in milk)

Answer 223

Crigler - Najjar Syndrome TYPE 1 * * Elevated serum indirect (unconjugated) bilirubin * *RARE

Answer 224

Crigler-Najjar Syndrome Type II * *Elevated indirect (unconjugated) bilirubin * *Treatment: Phenobarbital reduces indirect bilirubin levels

Answer 225

Gilbert Syndrome | ** Elevated indirect (unconjugated) bilirubin

Answer 226

Dubin-Johnson Syndrome | ** Increased direct (conjugated) bilirubin

Answer 227

Rotor syndrome | ** Increased direct (conjugated) bilirubin

Answer 228

Cholestasis a. Impaired bile formation and bile flow LEAD TO accumulation of bile pigment in liver Causes 1. Due to Intrahepatic or extrahepatic biliary obstruction OR 2. Defects in hepatocyte bile excretion Morphology • Accumulation of bile pigment within hepatocytes give a fine, feathery appearance (feathery degeneration) • Green-brown bile plugs in dilated canaliculi

Answer 229

LARGE BILE DUCT OBSTRUCTION ** Obstructive conditions in children: biliary atresia, cystic fibrosis, choledochal cysts, insufficient intrahepatic bile ducts May promote **ascending cholangitis** (1) Secondary bacterial infection of intrahepatic biliary radicles ducts due to obstruction most often caused by enteric organisms (coliforms, enterococci) (2) Fever, chills, abdominal pain and jaundice (3) Acute inflammation of the bile duct wall and into the lumen

Answer 230

LARGE BILE DUCT OBSTRUCTION Morphology (1) Bile duct distention and proliferation (2) Portal tract edema and periductular acute inflammation (3) Unrelieved obstruction may lead to portal tract fibrosis and possible biliary cirrhosis (4) Hallmark of ascending cholangitis: Influx of periductular neutrophils into bile duct epithelium and lumen *** Extrahepatic obstruction is amenable to surgery while intrahepatic is NOT

Answer 231

Cholestasis of sepsis - liver affected in 3 ways a. Direct effects of intrahepatic bacterial infection b. Ischemia from hypotension (cirrhotic liver is most susceptible) c. Response to circulating microbial products- ***Most common cause of Cholestasis of sepsis

Answer 232

NEONATAL CHOLESTASIS ** Due to prolonged increase in conjugated bilirubin levels Major causes - aka neonatal hepatitis 1. Extrahepatic biliary atresia or bile duct obstruction 2. Infections and toxins 3. Genetic disorders; alpha 1 AT deficiency and lots more 4. Miscellaneous 5. Idiopathic (10-15%)

Answer 233

BILIARY ATRESIA Pathogenesis of 2 forms (1) Fetal form (20%) (a) Associated with other anomalies (malrotation of abdominal organs, polysplenia, congenital heart disease) (b) Due to aberrant intrauterine development of extrahepatic tree (2) Perinatal form (most common) (a) Destruction of the normally developed biliary tree after birth (b) Possible etiologies include viral infection and autoimmunity

Answer 234

BILIARY ATRESIA Morphology (1) Inflammation and fibrosing stricture of the extrahepatic or CBD (2) Periductal inflammation and destruction of intrahepatic biliary tree (3) Cirrhosis develops in uncorrected cases in 3-6 months (4) Type I- disease limited to common bile duct; surgically corrected (5) Type II- disease limited to hepatic bile ducts; surgically corrected (6) Type III (90% of cases) - disease at or above the porta hepatis; NOT surgically correctable; may need a liver transplant

Answer 235

REYE SYNDROME - Acute hepatic failure and encephalopathy - Possible correlation between a febrile illness and aspirin therapy - Secondary to mitochondrial dysfunction in the liver and brain Morphology a. Liver- microvesicular steatosis without necrosis or inflammation b. Brain- edema without inflammation c. Skeletal muscle, kidney & heart with fatty change

Answer 236

Viral Hepatitis a. Systemic viral infections causing hepatitis include: (1) Infectious mononucleosis (Epstein-Barr virus) (2) Cytomegalovirus (CMV) (3) Rubella, adenovirus, enterovirus and herpes virus b. Term “Viral Hepatitis” reserved for specific hepatotropic viruses; A, B, C, D, E

Answer 237

Hepatitis A virus (HAV) Serology (a) IgM HAV Ab indicates acute infection (b) IgG HAV Ab appears after IgM HAV Ab indicating recovery and lifelong immunity Clinical (a) Asymptomatic to mild symptoms (fever, fatigue, anorexia, nausea, vomiting and jaundice) (b) Usually a sporadic illness in developed countries (c) Does NOT cause chronic hepatitis or a carrier state

Answer 238

Hepatitis B virus (HBV) *can be a precursor to HEPATOCELLULAR CARCINOMA Transmission by; i) Perinatal transmission in high prevalence areas (Asia, Africa) ii) Sexual transmission and IV drug abuse in low prevalence areas (North America, Western Europe, Australia)

Answer 239

``` Hepatitis B (HBV) Enveloped partially dsDNA Hepadnaviridiae virus which is a spherical double layered “Dane particle” ``` I. Nucleocapsid “core” proteins HBcAg and HBeAg II. Polymerase (Pol) with DNA polymerase and reverse transcriptase activity III. Envelope glycoproteins; large, middle and small HBsAg IV. HBx protein for viral replication and associated with the pathogenesis of Hepatocellular carcinoma

Answer 240

1. HBsAg 2. HBeAg, HBV-DNA and DNA polymerase 3. IgM HBcAb 4. IgG HBcAb - eventually replaces IgM HBcAb over period of months 5. HBsAb 6. HBeAb

Answer 241

(a) Continued production of HBsAg and possibly HBeAg, HBV-DNA and DNA polymerase (b) WILL not see production of HBsAb** or HBeAb NO HBsAb in CHRONIC HEPATITIS B **progression to chronic infections occur in ~5-10% of acute infections

Answer 242

1. About 70% with mild or no symptoms without jaundice 2. Most cases are self-limited and resolve without treatment 3. About 5-10% develop chronic hepatitis (20-30% cirrhosis) 4. Vaccine-induced mutants which alter recognition of HBsAg by HBsAb can also occur 5. Host immune response is the main determinant regarding disease outcome (strong response by virus- specific CD4+ and CD8+ cells associated with resolution of acute infection) 6. Age at time of infection best predictor for chronicity – younger, more likely to develop chronic infection 7. HBV does not directly injure hepatocyte, CD8+ cytotoxic T cells attack infected hepatocytes 8. Asymptomatic carrier state (>= 30% of chronic hepatitis) i) HBsAg in serum > 6 months ii) HBeAg negative iii) HBV DNA at < 100,000 copies iv) Persistent normal ALT and AST levels

Answer 243

HEPATITIS C Virus (HCV) (a) Most common chronic blood-borne infection in the US (B) majority (~80-90%) of patients develop chronic disease (20-30% develop cirrhosis) (d) Major route of infection in children: perinatal transmission (e) Enveloped ssRNA Flaviviridae virus i) Unstable virus with multiple genotypes ii) Envelope has variable regions which cause emergent strains to escape neutralizing antibodies (F) incubation period of 4-26 weeks (mean -9 weeks)

Answer 244

HEPATITIS C VIRUS (HCV) Serology 1. HCV RNA i) Detected in the blood with INCREASED serum transaminases II) Persist in chronic infection despite the presence of HCV antibodies 2. HCV Ab I) Detected in only 50-70% of patients with symptomatic acute infection II) In rest of patients, detected about 3-6 weeks after start of infection III) IgG HCV Ab does NOT confer lifelong immunity

Answer 245

(a) Most patients with asymptomatic acute illness (85%, less severe than acute hepatitis B) (b) Symptoms may include fatigue, anorexia, nausea, vomiting, muscle and joint pain (c) Strong immune response with CD4+ and CD8+ cells associated with the few self-limited infections (d) HCV infection usually produces persistent infection and chronic hepatitis (80-90% of cases) (e) Patients usually have episodic periods of liver damage and elevated transaminases with symptoms (f) Cirrhosis or hepatocellular carcinoma may develop (5-30 yr) (g) Genomic instability and antigenic variability hinder development of an effect HCV vaccine (h) Treatment with drugs targeting viral protease and polymerase shows 90% success

Answer 246

Hepatitis D virus (HDV) A. ACUTE CO-INFECTION - with acute Hep B i) Follows exposure to serum with both HBV and HDV ii) HBV infection needed to establish first to provide HBsAg for development of complete HDV virions iii) See IgM HBcAg and IgM HDAg (then IgG of each) iv) Clinically indistinguishable from acute hepatitis B v) Usually self-limited infection (as in hepatitis B) B. SUPERINFECTION with chronic Hepatitis B patients i) Persistence of HBsAg and HDV Ab (IgM & IgG) ii) Chronic HDV occurs in 80-90% of patients iii) May present as severe acute hepatitis in an HBV carrier or exacerbation of preexisting chronic HBV iv) Almost all these patients develop chronic HDV infection which progresses to cirrhosis and sometimes HCC

Answer 247

HEPATITIS E Virus (HEV) Clinical (a) Mostly a self-limited illness (b) Mostly seen in young and middle-aged adults (c) High mortality (20-25%) in pregnant women (d) HEV RNA and HEV virions found in stool and blood before the onset of clinical illness (e) Symptoms, elevated aminotransferases and IgM HEV Ab occur at the same time (f) Symptoms usually resolve in 2-4 weeks (g) NOT associated with carrier state or chronic infection except in AIDS and transplant patients

Answer 248

HEPATITIS G VIRUS

Answer 249

Acute asymptomatic infection with recovery (1) Incidental finding of minimally elevated serum transaminases or presence of antiviral antibodies (2) Hepatitis A and B infections frequently subclinical in childhood Acute symptomatic infection with recovery * * Four phases: (a) Incubation period (b) Symptomatic preicteric phase (NO JAUNDICE) (c) Symptomatic icteric phase i) Increased conjugated bilirubin levels ii) Dark urine and acholic stools iii) Pruritis (d) Convalescence ** Peak infectivity- last days of incubation period and early days of acute illness

Answer 250

ACUTE LIVER FAILURE **Treatment; supportive, transplant

Answer 251

CHRONIC HEPATITIS A. Laboratory studies: May see elevated serum transaminases, prolonged PT, increased immunoglobulins, hyperbilirubinemia, elevated alkaline phosphatase B. Occ. in HBV & HCV, see immune-complex disease such as vasculitis (which one? - PAN polyangitis nodosa) and glomerulonephritis C. Best determinant of chronic disease- age of the patient D. Vertical transmission is a major risk for chronic HBV infection

Answer 252

Carrier State (1) Asymptomatic patient +/– non-progressive liver damage who harbors and can transmit the virus (2) Best example is with hepatitis B infection (3) Inactive carrier with HBsAg, no HBeAg, HBeAb, low HBV DNA, normal LFTs and lack of significant inflammation and necrosis on liver bx (4) Infection early in life e.g. vertical transmission in endemic areas, > 90% become carriers (5) Carrier state is probably not stable but may be activated by co-infection, alterations in immune function, etc. HIV and Chronic Viral hepatitis (1) Chronic HBV and HCV infections a leading cause of morbidity and mortality in HIV patients, even those on successful anti-HIV tx (2) Liver disease the 2nd most common cause of death in untreated or unsuccessfully treated AIDS patients

Answer 253

Acute Hepatitis (by HAV, HBV, HCV and HEV) (1) Common to all types (a) BALLOONING DEGENERATION - cytoplasm appears empty, cell eventually ruptures (b) Possible CHOLESTASIS with canalicular bile plugs (c) HEPATOCYTE NECROSIS leave collapsed reticulin framework and macrophage aggregates marking areas of lost cells (lobular disarray) (d) APOPTOSIS producing “COUNCILMAN BODIES” (shrunken, eosinophilic hepatocytes with pyknotic, fragmented nuclei) (e) Severe cases: confluent necrosis around central veins and BRIDGING NECROSIS (central-portal)

Answer 254

Chronic hepatitis (HBV, HCV, HBV + HDV) (1) Changes range from mild to severe disease (2) Mild disease: portal mononuclear inflammation only (3) Progressive disease: marked by interface hepatitis between portal tract and surrounding parenchyma (4) Hallmark of chronic disease: FIBROSIS (**remember hepatic STELLATE cells) (a) First in portal tracts (b) May eventually extend between portal tracts (bridging fibrosis) c) Continued scarring and nodule formation = cirrhosis (5) Increasing scarring coincides with stem cell activation (ductular reaction) (6) Clinical assessment of extent of damage requires liver biopsy (7) Specific changes A. HBV - “Ground glass” hepatocytes (ER is swollen by HBsAg) B. HCV - portal lymphoid aggregates and macrovesicular steatosis

Answer 255

1. The vowels (hepatitis A and E) never cause chronic hepatitis, only AcutE hepatitis, except HEV in immunocompromised hosts. 2. Only the consonants (hepatitis B, C, D) have the potential to cause chronic disease (C for consonant and for chronic) 3. Hepatitis B can be transmitted by blood, birthing, and “bonking” (as they say in the United Kingdom). 4. Hepatitis C is the single virus that is more often chronic than not (almost never detected acutely; 80% or more of patients develop chronic hepatitis, 20% of whom will develop cirrhosis). * *WE DO NOT TREAT ACUTE HEP C 5. Hepatitis D, the delta agent, is a defective virus, requiring hepatitis B co-infection for its own capacity to infect and replicate. 6. Hepatitis E is endemic in equatorial regions and frequently epidemic.

Answer 256

LIVER ABCESS (1) Usually in developing countries (echinococcal and amebic) (2) Most secondary to infection elsewhere in the body (E.g appendicitis in GI tract) (3) Organisms can enter the liver by portal vein, arterial supply, ascending infection, direct invasion or penetrating injury (4) In developed countries abscesses usually due to biliary tree or arterial supply in immunocompromised patients (elderly, chronic illness, immunosuppression, chemotherapy with marrow failure)

Answer 257

AUTOIMMUNE HEPATITIS 1. Chronic progressive hepatitis with features of autoimmune diseases: genetic disposition, association with other autoimmune diseases, presence of autoantibodies and therapeutic response to immunosuppression. 2. Strong HLA-associations, association with DRB1* alleles in Caucasians

Answer 258

AUTOIMMUNE HEPATITIS Clinicopathologic features 1. Highest incidence is in white, northern Europeans, 1.9:100,000 2. Female predominance (78%) 3. Two types a. Type 1 (1) Middle-aged to older individuals (2) Antibodies: Antinuclear (ANA), anti-smooth muscle actin (ASMA) b. Type 2 (1) Children and teenagers (2) Antibodies: anti-liver kidney microsome-1 (anti-LKM-1)

Answer 259

B = 1/90 1 x 1/2 x 1/45 = 1/90

Answer 260

1/70 = 1 x 1/35 x 1/2 = 1/70

Answer 261

D. 60% Penetrance = # phenotype / # genotype = 6/10 = 60%

Answer 262

E. 90% Penetrance = # phenotype / # genotype = 180/200 = 9/10 = 90%

Answer 263

1/75 1/4 x 2/3 x 1/12.5 = 1/75

Answer 264

1/6 1 x 1/4 x 2/3 = 1/6

Answer 265

1/3 1 x 2/3 x 1/2 = 1/3

Answer 266

Prob affected child = 1/2 x 1 x 1/2 = 1/4 Prob affected son/daughter = 1 x 1/2 x 1/4 = 1/8

Week 2 Flashcards

(292 cards)