GI Flashcards
[Esophageal Disorders]
- Describe symptoms of esophageal disease
- Workup for dysphagia
- Symptoms:
A. heartburn (pyrosis) - intermittent burning sensation behind sternum; after eating, exercise, lying flat
B. chest pain - shared nerve plexus between heart and esophagus –> pressure in mid-chest, arm, jaw; have to rule out cardiac source
C. regurgitation - return of food without nausea or wretching
D. odynophagia - pain that comes with or is worsened by swallowing; more common with infectious esophagitis than GERD
E. Dysphagia - difficulty swallowing; ALARM symptom
2A. Timing:
- oropharyngeal dysphagia - difficulty initiating swallowing
- esophageal dysphasia - swallowing for several seconds after initial swallow as if food is stuck
B. Solids? Liquids? Both
- dysmotility - both liquids and solids at onset
- mechanical - solids progressing to liquids
[Esophageal Disorders]
Describe esophageal motility disorders incl causes, pathophys, presentation, and diagnosis
1. Zenker diverticulum
2. Achalasia
- Zenker diverticulum - uncommon
A. Cause - altered esophageal motility
B. Pathophys - false diverticulum (does not contain all the walls of the structure, as opposed to Meckel diverticulum in bowel) - just mucosa and not muscular layer
- herniation of esophageal mucosa at Killian triangle in inferior pharyngeal constrictor
C. Clinical - in elderly males; halitosis, regurgitation, nocturnal aspiration
D. Diagnosis - barium swallow
- other types of diverticulum are traction (associated with cancer or granuloma) and epiphrenic (associated with hypertensive LES) - Achalasia - uncommon
A. Cause - autoimmune, infection with T. cruzi (chagas causes secondary achalasia) –> damages ganglion cells of myenteric (Auerbach) plexus in muscularis propria
B. Pathophys - damage to ganglion cells –> inability to relax LES –> high resting lower esophageal sphincter (LES) pressure + absent peristalsis (esophageal dysmotility) –> esophageal body dilates (“bird beak” on barium swallow)
C. Clinical - dysphagia for solids and liquids, regurgitations (of undigested food), halitosis, nocturnal cough/aspiration, heartburn
D. Diagnosis - endoscopy, manometry (measuring pressures) –> all pressures low except LES which is high
[Esophageal Disorders]
Describe esophageal motility disorders incl causes, pathophys, presentation, and diagnosis
3. Diffuse esophageal spasm
4. Nutcracker esophagus
- Diffuse esophageal spasm - uncommon
A. Cause - unknown
B. Pathophys - impaired innervation of inhibitory neurons; problem with nitric oxide synthesis –> loss of coordination of peristaltic wave –> simultaneous contractions of normal pressure amplitude
C. Clinical - dysphagia for solids and liquids +/- retrosternal chest pain
D. Diagnosis - barium swallow “corkscrew” esophagus - Nutcracker esophagus - uncommon
A. Cause - unknown
B. Pathophys - overstimulation of excitatory cholinergic neurons –> sequential peristaltic contractions with very high amplitude
C. Clinical - dysphagia for solids and liquids, otherwise asymptomatic
[Esophageal Disorders] Describe esophageal inflammatory disorders incl causes, pathophys, presentation, and diagnosis 1. GERD A. Cause B. Pathophys C. Clinical D. Diagnosis E. Treatment F. Complications incl Barrett esophagus
- GERD - gastroesophageal reflux disease –> reflux of acid-containing gastric secretions and/or bile into esophagus
A. Cause - due to anatomic position (hiatus hernia), SMC relaxation - transient sphincter opening (food, drugs), LES length (gastric distension)
B. Pathophys - decreased LES pressure / tone –> reflux of acid from stomach to esophagus
- risk factors: obesity, pregnancy, gastric hypersecretory state, delayed gastric emptying, disruption of esophageal peristalsis
C. Clinical - fleeting sx that can resolve spontaneously
- heartburn and substernal chest pain, dysphagia, voice changes
- adult-onset asthma + cough (1 of 3 MCC of chronic cough, others are asthma and postnasal drip)
- must rule out CAD (angina and GERD present similarly)
D. Diagnosis - EGD (upper endoscopy) or 24 hr pH probes
E. Treatment - risk mgmt: avoid foods that reduce LES pressure (fatty, alcohol, mint, tomato, coffee/tea), weight reduction, PPIs
F. Complications
i. erosive esophagitis (necrosis of surface layers of esophageal mucosa) –> ulceration with strictures (fibrosis healing process of erosive esophagitis)
ii. Barrett esophagus (metaplasia from non-keratizinizing SSE to non-ciliated columnar with goblet cells) –> ↑ risk of esophageal adenocarcinoma
[Esophageal Disorders]
Describe esophageal inflammatory disorders incl causes, pathophys, presentation, and diagnosis
- Allergic (eosinophilic) esophagitis
- Infectious esophagitis
- Iatrogenic (Lye, Pill)
- Eosinophilic esophagitis
A. Cause - immunologic (Th2 cell mediated) induced by food allergens; intraepithelial eosinophils
B. Pathophys - Th2 –> IL-13 and IL-5 –> eosinophils
C. Clinical - intermittent dysphagia for solid foods, food impaction, central chest pain, GERD sx refractory to GERD treatment
D. Diagnosis - stacked circular rings on endoscopy (like a cat esophagus) - Infectious esophagitis
A. Cause - Candida albicans or CMV (in HIV patients with CD4 < 100), HSV1 (in organ transplant patients)
B. Pathophys -
C. Clinical - odynophagia (pain with swallowing)
- oral thrush in Candida
- distal esophagus in HSV
D. Diagnosis -
- white mucosal plaques in Candida esophagitis (can be scraped off, as opposed to leukoplakia)
- well-circumscribed “punched out” volcano ulcers in Herpes esophagitis
- linear ulcers in CMV esophagitis - Iatrogenic (Lye, Pill)
A. Pill - due to esophageal hypomotility or incorrect method of swallowing pill –> pill adheres to esophageal wall –> acute onset chest pain, heartburn, and severe odynophagia (even to sips of water)
most common - tetracyclines, bisphosphonates (esp alendronate), KCl, NSAIDs
B. Caustic ingestion
i. Alkali (e.g. lye) - causes liquefactive necrosis –> full thickness injury –> esophageal strictures
ii. Acid - causes coagulative necrosis –> superficial injury that damages stomach
[Esophageal Disorders] Esophageal cancer 1. Common clinical presentation 2. Esophageal adenocarcinoma 3. Squamous cell carcinoma
- Esophageal cancer - presents late in course
- dysphagia progressing from solids to liquids –> weight loss
- hematemesis –> iron deficiency anemia due to chronic blood loss
- tracheobronchial fistulas
- squamous cell –> hoarse voice (recurrent laryngeal nerve) or cough (Tracheal involvement) - Esophageal adenocarcinoma - most common in US
A. Cause - associated with GERD and Barrett esophagus, as well as smoking
- NOT associated with helicobacter (causes gastric cancer)
B. Pathophys - malignant proliferation of glands
- most commonly occurs at GE junction (distal third of esophagus) –> spreads to celiac and gastric lymph nodes - Squamous cell carcinoma - most common worldwide
A. Causes - associated irritation of mucosa –> smoking and alcohol, hot liquids, achalasia, esophageal webs (eg Plummer-Vinson syndrome), esophageal injury (Eg lye ingestion)
B. Pathophys - malignant proliferation of squamous cells
- most commonly arises in cervical and thoracic esophagus (upper or middle third) –> spreads to cervical or mediastinal/tracheobronchial lymph nodes
[Esophageal Disorders] Esophageal structural disorders 1. Webs 2. Rings 3. Hiatus hernia 4. Paraesophageal hernia
- Webs- proximal (cervical) esophagus; mucosal fold that protrudes into lumen
- associated with Plummer-Vinson syndrome (iron deficiency anemia, dysphagia, esophageal web) with spoon nails, atrophic glossitis - Rings - distal esophagus; Schatzki ring is most common; constant luminal size
- associated with hiatal hernia and GERD; causes intermittent solid food dysphagia - Hiatus hernia - type 1 (sliding) hernia; 50% of pts with GERD have hiatal hernia; GE junction rises above the diaphragm (supposed to be below)
- Paraesophageal hernia - type 2 hernia; GE junction in right position but fundus herniates into the chest
- gastric volvulus - whole stomach goes into the chest and rotates –> ischemia and perforation –> borchardt triad:
i. sudden severe pain in chest
ii. persistent retching but little vomit
iii. inability to pass nasogastric tube
- can hear bowel sounds in lower lung fields
[Esophageal Disorders] Describe esophageal mechanical injury incl causes, pathophys, presentation, and diagnosis 1. Mallory-Weiss tear 2. Boerhaave syndrome 3. Sclerodermal esophageal dysmotility
- Mallory-Weiss tear
A. Cause - longitudinal tear/laceration of mucosa of lower esophagus due to severe vomiting (alcoholism, bulimia)
B. Pathophys - self-limited cause of upper GI bleed
C. Clinical - retching and then vomiting red blood (hematemesis); usually painless, but there can be epigastric or back pain
- risk of boerhaave syndrome - Boerhaave syndrome
A. Cause - esophageal rupture associated with vomiting (Eg Mallory Weiss tear) –> spill esophageal contents into chest
B. Pathophys - most common in left distal esophagus
C. Clinical - excruciating retrosternal chest pain immediately following vomiting; air in mediastinum and neck –> subcutaneous emphysema (crackling noise)
- sepsis –> death high mortality - Sclerodermal esophageal dysmotility
A. Cause - Esophageal smooth muscle atrophy –> decreased LES pressure and dysmotility –> acid reflux and dysphagia
B. Clinical - stricture, Barrett esophagus, and aspiration
[Stomach Disorders]
- Describe pathophysiology of injury/inflammation to stomach
- Most common risk factors for ulcers
- Four layers of an ulcer
1A. Failure of mucosal defense barrier - mucous maintains physiologic pH around the cells (7) while outside is pH 2
B. Acid hypersecretion
2A. Helicobacter pylori- most common chronic bacterial infection in humans; MCC of gastritis in kids
B. NSAID use - one of most commonly used OTC drugs
- Four layers of an ulcer: debris, inflammation, granulation tissue, fibrosis
[Stomach Disorders] Risk factors for ulcers 1. H. Pylori A. Virulence B. Clinical i. Acute ii. Chronic C. Diagnosis
- H. Pylori
A. Virulence - Gram (-) curved rod with flagella that allow motility - penetrates mucous gel layer and epithelium
- urease, oxidase, catalase (+) –> urease converts NH3 into NH4+ CO2 –> creates alkaline environment to neutralize low pH in stomach
- adheres to epithelium through virulence factors (Type IV secretion system, exotoxins) –> mucosal and epithelial damage; does NOT invade
B. Clinical - causes 90% of all gastric ulcers and 80% of all duodenal ulcers
i. Acute infection - mild transient sx incl nausea, vomiting, intense neutrophilic infiltrate (pathologic diagnosis)
ii. Chronic infection -
- antral gastritis most common –> infection confined to antrum with decreased bicarbonate secretion –> duodenal ulcer
- gastritis of body and fundus –> reduced parietal cell mass and acid secretion –> intestinal metaplasia –> ↑ risk of gastric adenocarcinoma (intestinal type)
- non-atrophic pangastritis (inflammation of entire stomach lining) –> lymphoid aggregates with germinal centers –> ↑ risk of lymphoma (MALToma)
C. Diagnosis - urea breath test (↑ C02) or mucosal biopsy (patchy intestinal metaplasia) during endoscopy; NOT cultured
D. Treatment - triple therapy
- PPI
- clarithromycin (macrolide)
- amoxicillin (or metronidazole if penicillin allergy)
[Stomach Disorders] Risk factors for ulcers 2. NSAIDs A. MOA B. Risk factors C. NSAID-induced injury
- NSAIDs
A. MOA - inhibitors of COX1 (housekeeping) and COX2 (inflammation); aspirin is irreversible and ibuprofen, naproxen are reversible
- membrane phospholipids (PLA2) –> Arachidonic acid –> prostaglandins via COX1 or COX2
- COX1 –> TXA2, PGI2, PGE2–> platelet aggregation / vasoconstriction, GI mucosal integrity, renal function (dilates afferent arteriole)
- COX2 –> PGI2 and PGE2 –> inflammation, bone formation, mitogenesis –> fever, pain, increased vascular permeability
B. Risk factors - prior h/o peptic ulcer disease, high dose or multiple NSAIDs, H. pylori infection, smoking, alcohol, corticosteroid use (synergistic)
C. Injury - direct toxicity, perturbs epithelial mucous barrier (decreased mucous, HC03 secretion) –> acute hemorrhagic erosive gastropathy (GI bleeding)
- acute kidney injury, renal papillary necrosis, acute interstitial nephritis
- Type 4 RTA (hypoaldosteronism)
- respiratory alkalosis, tinnitus, aplastic anemia
- gastric inflammation, ulcers
- child with viral illness given NSAID –> Reye’s syndrome (hepatic encephalopathy)
[Stomach Disorders] Congenital disorders A. Cause B. Risk factors C. Clinical
- Pyloric stenosis
- Duodenal atresia
- Jejunoileal atresia
- Pyloric stenosis
A. Cause - congenital pyloric smooth muscle hypertrophy; MCC of gastric outlet obstruction in infants
B. Risk factors - more common in firstborn males, associated with exposure to macrolides
C. Clinical - develops 4-6 weeks after birth –> non-bilious projectile vomiting immediately after feeding
- physical: palpable olive-like mass in abdomen, dehydrated (dry mucous membranes, flat fontanelle)
- labs: hypochloremic, hypokalemic metabolic alkalosis and elevated bilirubin - Duodenal atresia
A. Cause - congenital failure of duodenum to recanalize –> complete obstruction of lumen
B. Risk factors - associated with Down syndrome, cardiac defects
C. Clinical - presents hours after birth
- prenatal- polyhydramnios in utero (baby cannot swallow amniotic fluid)
- bilious vomiting (emergency in newborn)
- blind loop of duodenum –> “double bubble” sign on X-ray - Jejunoileal atresia
A. Cause - associated with vascular accident eg disruption of mesenteric vessels –> ischemic necrosis
B. Risk factors - low association with chromosomal anomalies
C. Clinical - results in jejunal dilation with “apple peel” deformity of distal bowel
- also presents with bilious vomiting and abdominal distension
- multiple air-fluid levels and distended loops of small bowel on plain X-ray films
[Stomach Disorders] Inflammation disorders A. Cause B. Risk factors C. Clinical
- Acute gastritis
- Stress ulcer
Curling vs Cushing
- Acute gastritis
A. Cause - imbalance between mucosal defenses and acidic environment –> acid damage to stomach mucosa
- defenses: mucin layer of foveolar (surface mucous cells); HC03- secretion by surface epithelium; blood flow
- imbalance –> inflammation, erosion (loss of epithelium), or ulcers (loss of mucosal layer)
B. Risk factors - alcohol/smoking, NSAID use, bile reflux, stress ulcers
- Stress ulcer - shallow or deep erosions of gastric mucosa that cause acute gastritis
A. Cause - impaired mucosal protection (loss of mucous layer or ischemia) and hypersecretion of acid
B. Risk factors - patients in ICU setting with critical illness (usually have multiple ulcers)
C. Clinical
i. Curling - severe burn –> hypovolemia –> mucosal ischemia
ii. Cushing - brain injury –> increased intracranial pressure –> vagal stimulation –> ↑ ACh –> ↑ H+ production
[Stomach Disorders]
Inflammation disorders
3. Chronic gastritis A. Cause B. Location C. Clinical D. Sequelae
- Chronic gastritis - chronic inflammation of mucosa with patchy intestinal metaplasia
A. Cause
i. H. pylori (90%) - antibodies to H pylori
ii. autoimmune (10%) - mucosal atrophy of gastric parietal and chief cells via CD4+ T cell response (Type 4 HSN) –> loss of acid secretion (achlorhydria) –> hypergastrinemia (loss of negative feedback) –> ECL cell hyperplasia (gastrin stimulates ECL cells to release histamine)
- result is antibodies to IF (made by parietal cells)
B. Location
i. H. pylori - antrum involved
ii. Autoimmune - antrum spared - damage is in body and fundus (where gastric parietal cells are)
C. Clinical
i. H. pylori - epigastric abdominal pain + hyperplastic polyps
ii. Autoimmune - megaloblastic (pernicious) anemia
- (decreased B12 due to lack of IF) –> reversible glossitis, irreversible peripheral neuropathy, irreversible cerebral dysfunction (memory loss, personality change, psychosis)
D. Sequelae
i. H. pylori - peptic ulcer disease, MALToma, gastric adenocarcinoma
ii. Autoimmune - gastric adenocarcinoma, carcinoid tumor; associated with other autoimmune diseases (Hashimoto’s, DMI, Graves)
[Stomach Disorders]
Inflammation disorders
- Peptic Ulcer Disease - differentiate between duodenal and gastric ulcers
A. Cause B. Location C. Clinical D. Complications E. Treatment
- Peptic Ulcer Disease
A. Cause - break in the mucosal surface associated with chronic gastritis
i. Duodenal ulcer - H. pylori, in younger adults
ii. Gastric ulcer - H. pylori, NSAIDs, bile reflux, in adults >60 yo
B. Location - usually solitary (multiple - think ZE)
i. Duodenal (90%) - usually in first portion of duodenum
ii. Gastric (10%) - usually in lesser curvature of antrum
C. Clinical - benign ulcers - sharply “punched out” lesions with radiating folds of mucosa; most common cause of upper GI bleed
i. Duodenal - epigastric pain that improves with meals
- hypertrophy of Brunner’s glands
ii. Gastric - epigastric pain that worsens with meals
D. Complications - bleeding most common complication –> melana, hematemesis
i. Duodenal - if ulcer arises in posterior duodenum –> rupture –> bleeding from gastroduodenal artery, or acute pancreatitis
- 99% benign (don’t need to worry about cancer)
ii. Gastric - bleeding from left gastric artery
- DDx is gastric adenocarcinoma (large, irregular ulcers) - do biopsy
bleeding via coffee-ground emesis, melana, or occult bleeding
E. Treatment - treat H. pylori, avoid NSAIDs, acid suppressive therapy with PPIs (eg omeprazole)
- diagnose via upper endoscopy
[Stomach Disorders]
Gastric neoplasms
1. Gastric adenocarcinoma - differentiate between intestinal vs diffuse types A. Cause B. Risk factors C. Clinical D. Complications
- Gastric carcinoma - malignant proliferation of surface columnar epithelial cells –> adenocarcinoma
A. Cause -
i. Intestinal - chronic inflammation and continuous cycles of injury and repair –> atrophic gastritis –> metaplasia –> dysplasia –> carcinoma
ii. Diffuse - infiltrative cancer with invasion of “signet ring” cells (due to large mucin vacuoles) through gastric wall
B. Risk factors -
i. Intestinal - intestinal metaplasia (due to H pylori and autoimmune chronic gastritis), nitrosamines in smoked foods (Japan), blood type A
ii. Diffuse - not associated with any of above; in younger patients and has worse prognosis; cadherin mutations
C. Clinical - presents late with weight loss, epigastric abdominal pain, anemia, early satiety
- cutaneous paraneoplastic: (1) acanthosis nigricans (hyperpigmented plaques in axilla) and (2) Leser-Trelat sign (sudden onset of multiple keratoses)
i. Intestinal - large, irregular ulcer at lesser curvature of antrum
ii. Diffuse - “linitis plastica” stomach wall becomes thick and leathery; worse prognosis
D. Complications: 75% have spread to lymph nodes or distant metastases at time of diagnosis:
- Virchow’s node - swollen left supraclavicular node
- Sister Mary Joseph nodule (periumbilical region) –> intestinal
- Krukenberg tumor (bilateral ovarian metastasis) –> diffuse; mets have signet ring cells
[Stomach Disorders]
Gastric neoplasms
2. Gastric lymphoma A. Cause B. Risk factors C. Clinical D. Complications E. Treatment
- Gastric lymphoma
A. Cause - gastric MALToma is most common (mutation of “marginal zone” post germinal center memory B cell)
B. Risk factors - H. pylori (associated with chronic inflammation), most are gastric; associated with chromosomal translocations and constitutive activation of NF-kappaB
C. Clinical - peptic ulcer disease, abdominal symptoms, associated autoimmune disease
D. Complications - MALT associated with inflammation (thyroid MALT = Hashimoto’s, cutaneous = Borrelia, C. psittaci = Ocular, Sjogren’s = salivary)
E. Treatment - chemo and radiation; treat H pylori; can progress to DLBCL
[Stomach Disorders]
Gastric neoplasms
- Gastrointestinal stromal tumors
- Menetrier disease
- Diabetic gastroparesis
A. Cause
B. Clinical
- Gastrointestinal stromal tumors (GIST)
A. Cause - most common mesenchymal tumor of the abdomen (50% are gastric); arise from interstitial cells of Cajal (cells in gut muscle wall that are pacemakers for peristalsis, express c-KIT)
- associated with NF1
C. Clinical - overt or occult GI bleeding; tend not to metastasize
- solitary well-circumscribed masses with intact or ulcerated surface and spindle morphology
- treat with imatinib (Gleevec) tyrosine kinase inhibitor –> c-KIT positive tumors - Menetrier disease
A. Cause - diffuse hyperplasia of foveolar epithelium (Surface mucous cells) in gastric mucosa -> hypertrophied rugae (look like brain gyri)
B. Clinical - excess mucous production –> hypoproteinemia (mucous is a protein) and parietal cell atrophy –> malnutrition / weight loss, epigastric pain, diarrhea, peripheral edema
- can resolve spontaneously or regress - Diabetic gastroparesis
A. Cause - related to autonomic neuropathy –> loss of vagus nerve stimulation + loss of peristalsis
B. Clinical - epigastric pain, nausea, early satiety, vomiting
- will see retinopathy, peripheral neuropathy, and nephropathy
[Small intestine disorders]
1. Acute diarrheal illness
- Chronic diarrhea
A. Small bowel vs large bowel diarrhea
B. Malabsorption vs maldigestion - How do you measure osmolarity in stool in patient with watery diarrhea?
- Acute diarrheal illness - less than 2 weeks duration
- Causes - infectious, mostly viral –> Norovirus (single stranded RNA virus) and Rotovirus (dsRNA) - acute
- bacterial more likely with severe, fever, blood in stool, longer duration
- parasite most likely with travel, immunocompromised, culture negative, longer duration - Chronic diarrhea - more than 4 weeks duration
A. Small bowel diarrhea - bulky stools, infrequent and with less urgency
- Large bowel diarrhea - frequent small stools with urgency and tenesmus (cramping and spasm)
B.
i. Malabsorption - disease of intestinal mucous lining
- e.g. Celiac disease, environmental enteropathy, SIBO, Whipple disease, Giardia, Small bowel lymphoma
ii. Maldigestion - exocrine pancreatic dysfunction eg chronic pancreatitis (alcohol or cystic fibrosis) –> activation of trypsin in pancreas –> repeated insults –> calcifications on X-ray
- Both have weight loss, malnutrition, diarrhea, steatorrhea (mild in malabsorption, profound in maldigestion), muscle wasting, anemia, osteoporosis, and neurological issues
- Fecal osmotic gap = 290 - 2(Na + K)
<50 mOsm - secretory diarrhea
>125 mOsm - osmotic diarrhea due to agent eg colonoscopy prep
[Small intestine disorders] Describe the four categories of diarrhea including pathophys and causes: 1. Osmotic 2. Secretory 3. Inflammatory 4. Dysmotility
- Osmotic - driven by eating (and stops when oral intake stops) - excessive osmotic particles in gut lumen
- due to lactose intolerance, artificial sweeteners, mushrooms - Secretory - massive secretion of salt, sodium, and water irrespective of eating –> watery diarrhea
- due to infectious agents (cholera toxin, ETEC), neuroendocrine tumors (VIPoma), bile salts - Inflammatory - fever, dehydration, abdominal pain, bloody diarrhea with tenesmus, (cramping and spasm), urgency, nocturnal diarrhea
- due to ulcerative colitis, Crohn’s, invasive bacteria (EHEC, Shiga, Campylobacter) - Dysmotility - tissue transglutaminase negative (no Celiac) with normal IgA, no travel, HbA1C normal
- can be due to intestinal stasis (e.g. diabetic gastroparesis, scleroderma) –> SIBO (small intestine bacterial overgrowth) –> deconjugate bile salts and increased osmotic particles due to bacterial fermentation –> steatorrhea, diarrhea if severe
- confirm with early H2 breath peak on lactulose test
[Small intestine disorders]
Celiac disease A. Cause B. Pathophys C. Clinical D. Diagnosis E. Complications
Celiac disease eg Nontropical sprue
A. Cause - autoimmune; malabsorption type small bowel disease; associated with HLA-DQ2 and DQ8
B. Pathophys - gliadin (component of gluten) is deamidated by tissue transglutaminase (tTG) –> presented by APC via MHC II –> CD4+ T cells mediate tissue damage via inflammatory response –> villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes –> intestinal malabsorption and nutrient depletion
- affects mostly duodenum / proximal jejunum
C. Clinical- bloating/abdominal distension + chronic osmotic diarrhea (due to bile acid malabsorption), steatorrhea, megaloblastic anemia and secondary lactase deficiency
- Kids - failure to thrive (short stature, delayed puberty)
- Adults
i. Skin - dermatitis herpetiformis –> symmetric, pruritic herpes-like vesicles on extensor surfaces of extremities (elbows, knees); due to IgA anti-tTG deposition on tips of dermal papillae which form pustules/vesicles
ii. Bone - decreased bone density –> osteoporosis, arthritis
iii. CNS - ataxia, seizures
iv. Reproductive - infertility
D. Diagnosis - serology study to detect IgA antibodies against endomysium (connective tissue sheath around muscle fiber), tTG, or gliadin
- Sudan black stain for fecal fat
- D-xylose test - blood and urine levels of D-xylose (which is passively absorbed) are decreased –> malabsorption
E. Complications
- small intestinal carcinoma - v rare
- EATL (enteropathy-associated T cell lymphoma) - intestinal masses and lymphadenopathy
[Small intestine disorders]
- Environmental enteropathy i.e. Tropical sprue
- Short bowel syndrome
A. Cause B. Pathophys C. Clinical D. Diagnosis E. Treatment
- Environmental enteropathy i.e. Tropical sprue - malabsorption disorder
A. Cause - unknown infectious agent, seen in tropics e.g. Puerto Rico and India
B. Pathophys - unknown; occurs in jejunum and ileum (Celiac is in duodenum)
C. Clinical - same as celiac –> chronic diarrhea, steatorrhea, weight loss + megaloblastic anemia due to deficiencies (folate B9 absorbed in jejunum)
D. Diagnosis - small bowel biopsy shows flattened villi and mononuclear cell infiltrate in lamina propria, resembles celiac disease; returns to normal when they return to temperate area
E. Treatment - antibiotics (tetracycline), folic acid
*celiac does not respond to antibiotics - Short bowel syndrome - lack of adequate absorptive surface
A. Cause - surgical resection due to Crohn’s, malignancy, radiation, vascular insult
B. Pathophys + Clinical
i. jejunum - gastric hypersecretion (loss of GIP, VIP)
ii. ileum - B12 deficiency, bile salt malabsorption (>100cm resected) –> ADEK deficiency, steatorrhea, diarrhea (can be osmotic or secretory); SIBO (due to intestinal dysmotility)
Roux-en-Y gastric bypass –> leads to deficiency of thiamine B1 (encephalopathy, nystagmus, gait ataxia), B12 (megaloblastic anemia), + copper (neurological findings e.g. UMN spasticity, stocking glove neuropathy + anemia)
[Small intestine disorders]
3. Whipple disease
- Abetalipoproteinemia
A. Cause B. Pathophys C. Clinical D. Diagnosis E. Treatment
- Whipple disease
A. Cause - infectious agent Tropheryni whipplei (Gram + rods in Actinomycetes family)
- rare, predominately male
B. Pathophys - lamina propria of villi loaded with macrophages containing T. whippleii –> compress lacteals –> cannot transfer chylomicrons from enterocytes to lymphatics –> fat malabsorption
C. Clinical - more common in older men
- cardiac symptoms
- arthralgias (eg migratory arthritis)
- neuro sx (nystagmus, dementia, myoclonus)
- diarrhea, steatorrhea, weight loss occur later
D. Diagnosis - positive fecal Sudan stain, foamy macrophages that stain PAS (+) on small bowel biopsy; thickened small bowel with rapid transit time
E. Treatment - antibiotics - Abetalipoproteinemia
A. Cause - rare autosomal recessive deficiency of apolipoprotein B48 and B100; pediatric
B. Pathophys - cannot make chylomicron without B48; cannot make VLDL and LDL without B100
- acanthocytes - star-shaped RBCs
C. Clinical - presents in infancy as failure to thrive
- presents in childhood with steatorrhea, ataxia, retinitis pigmentosa, ADEK deficiency
Sketchies to review: Staphylococcus EHEC, ETEC Shigella Campylobacter Norovirus Salmonella Giardia Vibrio Entamoeba Schistosomiasis Cryptosporidium Ascaris Rotavirus
Staphylococcus X EHEC, ETEC X Shigella X Campylobacter X Norovirus X Salmonella X Giardia X Vibrio X Entamoeba X Schistosomiasis X Cryptosporidium X Ascaris X Rotavirus X
[GI Pharmacology]
I. Drugs that treat acid-peptic disease
- H2 receptor antagonists
A. MOA
B. Clinical indications
C. Adverse effects
I. Acid-peptic disease - peptic ulcers, GERD, stress-related mucosal injury due to imbalance between factors that are aggressive (acid, pepsin, bile) vs defensive (blood flow, mucous, HC03-, prostaglandins)
- H2 receptor antagonists - “-dines” eg ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), cimetidine (Tagamet)
A. MOA - competitive inhibitors of histamine on H2 receptors - most effective at reducing nocturnal acid secretion
- famotidine is most potent and no drug interactions
B. Clinical indications - being replaced by PPIs but OTC versions heavily used
i. GERD - for <3x week
ii. Gastric and duodenal ulcers (Peptic ulcer disease) - bedtime administration
C. Adverse effects - generally safe, most side effects with cimetidine (anti-androgenic –> galactorrhea, impotence, gynecomastia)
- GI effects
- lipophilic - cross placenta and breast milk –> do not use in pregnancy
[GI Pharmacology]
I. Drugs that treat acid-peptic disease
- Proton Pump Inhibitors (PPIs)
A. MOA
B. Clinical indications
C. Adverse effects
- Proton Pump Inhibitors (PPIs) - “azoles” eg omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid)
* other -azoles are antifungals eg ketoconazole
A. MOA - prodrug that is activated via protonation in acid –> forms covalent disulfide bond with the proton pump –> noncompetitive, irreversible inhibitor
- suppress fasting and meal-stimulated acid secretion better than H2 antagonists
B. Clinical indications - once daily dosing
i. GERD - first line - most effective for tx of GERD
ii. peptic ulcer disease - heal duodenal (and to lesser extent gastric) ulcers, faster healing and symptom relief than H2 antagonists
iii. H. pylori associated ulcers - heal ulcer and eradicate organism (triple therapy with amoxicillin + clarithromycin; quadruple therapy with metronidazole)
iv. NSAID-associated ulcers eg ibuprofen (Advil), naproxen (Aleve)
C. Adverse effects - generally safe, some GI side effects
- low bioavailability when taken with food - eat on empty stomach
- suppresses gastric acid barrier –> ↑ gastric bacterial concentrations –> ↑ risk of enteric infections (eg C. difficile), respiratory infections
- decreased Ca2+ absorption (needs acidic environment) –> worsens osteoporosis and bone fractures
[GI Pharmacology]
I. Drugs that treat acid-peptic disease
- Antacids
A. MOA
B. Clinical indications
C. Adverse effects
- Antacids
A. MOA - weak bases - Mg(OH)2, Al(OH)3, CaC03 (Tums) - that react with gastric HCl –> salt + water
- reduce gastric acidity as well as pepsin, which is inactive in pH>4
- work fast but weak in neutralizing ability
B. Clinical indications
i. intermittent heartburn
ii. duodenal ulcers - but no gastric
iii. GERD - antacid + alginic acid (Gaviscon)
C. Adverse effects - gassy, bloated
[GI Pharmacology] I. Drugs that treat acid-peptic disease 4. Sucralfate 5. Colloidal bismuth compounds 6. Misoprostol
A. MOA
B. Clinical indications
C. Adverse effects
- Sucralfate - sucrose + Al(OH)3
A. MOA - viscous substance that is insoluble in water and has weak buffering action –> selectively binds necrotic ulcer tissue –> acts as a barrier to acid, pepsin, bile –> reestablish pH gradient in mucous layer
B. Clinical indications - duodenal ulcers - prevention and healing; traveler’s diarrhea
C. Adverse effects - requires acidic conditions –> cannot be taken with PPIs, H2 antagonists, or antacids - Colloidal bismuth compounds - Pepto-Bismol
A. MOA - same as sucralfate
B. Clinical indications - H. pylori ulcers -direct antimicrobial activity, esp when combined with tetracycline and metronidazole - Misoprostol
A. MOA - PGE1 analog –> ↑ production of mucous barrier and ↓ acid production
B. Clinical indications - NSAID-induced ulcers
- off label to induce labor
C. Adverse effects - don’t give to women of childbearing age (abortifacient), dose-dependent diarrhea
[GI Pharmacology]
II. Drugs that promote gastrointestinal motility (Prokinetic agents)
- Metoclopramide (Reglan)
A. MOA
B. Clinical indications
C. Adverse effects
- Metoclopramide (Reglan)
A. MOA - blocks dopamine D2 receptors in area postrema (chemoreceptor trigger zone) –> increases esophageal clearance, raises LES pressure, and accelerates gastric emptying
B. Clinical indications
i. antiemetic - main use
ii. prokinetic - symptomatic relief in pts with post-op gastric motor failure or diabetic gastroparesis
iii. treats refractory heartburn - in combo with antisecretory agents (H2 antagonist, PPI)
C. Adverse effects - many CNS effects –> extrapyramidal sx (Parkinsonism), anxiety, depression
[GI Pharmacology]
II. Drugs that promote gastrointestinal motility (Prokinetic agents)
- Lubiprostone
- Linaclotide
A. MOA
B. Clinical indications
C. Adverse effects
NOT ON STEP 1
- Lubiprostone (Amitiza)
A. MOA - fatty acid from PGE1 that activates Type 2 Cl- channels in GI epithelial cells –> chloride-rich fluid secretion –> softens stool, increases motility, promotes BMs
B. Clinical indication
i. chronic idiopathic constipation
ii. IBS with constipation
C. Adverse effects - not for use in children (under 16)
- nausea, diarrhea, headache - Linaclotide (Linzess)
A. MOA - peptide agonist of guanylate cyclase that activates CFTR Cl- channel in GI epithelial cell –> chloride-rich fluid secretion –> softens stool, increases motility, promotes BMs
- reduces pain by decreased activation of colonic sensory neurons
B. Clinical indications
i. chronic idiopathic constipation
ii. IBS with constipation
C. Adverse effects - not for use in children (under 16)
- most common is diarrhea
[Abdominal Pain] 1. Visceral pain A. Development B. Innervation C. Triggers D. Characteristics E. Clinical features (how is pain perceived) F. Describe how persistent visceral pain can become referred
- Visceral pain - arises from irritation of visceral peritoneum, hollow viscera, and mesentery
* visceral peritoneum - peritoneal covering over mesentery and solid organs
A. Development - derived from splanchnic layer of lateral plate mesoderm
B. Innervation - autonomic; visceral pain afferents travel with splanchnic SNS nerves and do not lateralize –> visceral pain perceived in midline
- nerves run along blood vessels in mesentery - can associate location of pain with blood supply e.g. foregut (celiac), midgut (SMA), hindgut (IMA)
C. Triggers - sense mechanical (tension, overdistension, mesenteric traction, visceral muscle spasm) and chemical (ischemia, inflammation)
D. Characteristics -midline
- poorly localized (low density of pain receptors, convergence onto same level of spinal cord)
- not evoked equally from all organs (hollow>solid)
E. Clinical - dull, deep-seated discomfort, crampy/colicky, aching
- accompanied by autonomic sx (pain afferents run with autonomic nerves) –> diaphoresis, changes in HR and BP, nausea, diarrhea
F. Referred pain - visceral pain perceived in superficial somatic structures due to convergence –> visceral afferents synapse onto same neurons in spinal cord as somatic afferents
- diffuse (midline) –> then referred
[Abdominal Pain] 2. Somatic (parietal) pain A. Development B. Anatomy C. Triggers D. Characteristics E. Clinical features (how is pain perceived) F. Describe rigidity associated with somatic pain
- Somatic pain - arises from irritation of parietal peritoneum (peritoneal lining of abdominal wall, pelvis, diaphragm)
A. Development - derived from somatic layer of lateral plate mesoderm
B. Anatomy - somatic; parietal pain afferents are spinal afferent nerves - skin, muscle and parietal peritoneum of abdominal wall innervated by the same T7-L1 spinal nerves –> pain lateralizes
C. Triggers - detects peritonitis - inflammation of peritoneum secondary to illness in viscera (e.g. perforation)
- fluid in abdomen common
D. Characteristics - lateralized to specific quadrant
- many sensory nerves with dense meshwork of free nerve endings
- precise mapping of spinal nerves to spinal cord and cortex (not multiple organs coming to same level like the viscera)
E. Clinical features - severe, sharp, knife-like pain
- constant (not colicky), well-localized, worsens with movement
F. Rigidity –> involuntary guarding due to reflex arc –> pain afferents come into spinal cord and synapse onto motor neurons going to abdominal wall musculature
- differentiate from voluntary guarding bc patient cannot maintain that on inspiration
[Abdominal Pain]
1. GI inflammation (e.g. peritonitis, appendicitis, diverticulitis, cholecystitis)
A. Pathophysiology
B. Clinical progression
- GI inflammation
A. Luminal obstruction (eg stone, lymph node) –> response is secretion of fluid into lumen (distension) and reflex contraction –> increased pressure –> venous congestion and thrombosis of capillaries –> barrier disrupted and bacteria invade –> ischemia and inflammation –> focal abscess –> gangrenous necrosis and perforation
B. Dull, periumbilical pain and nausea with luminal obstruction –> increasingly severe pain with venous congestion / ischemia –> constant, sharp, localized pain when inflamed organ perforates –> leads to parietal peritoneum inflammation “peritonitis”
- appendicitis - RLQ
- diverticulitis (usually in sigmoid colon) - LLQ
[Abdominal Pain] 1. Small bowel obstruction A. Causes B. Symptoms 2. Large bowel obstruction
Bowel obstruction - cessation of BM and passage of gas, high pitched tinkling bowel sounds, colicky/crampy abdominal pain + nausea/vomiting
- Small bowel obstruction
- Causes, in order of likelihood:
A- adhesions (from prior surgery), B- bulges (hernia), C- cancer
B. Symptoms - obstruction leads to secretion of fluid into lumen and reflex contraction of smooth muscle to overcome obstruction –> abdominal distension - Large bowel obstruction
- Cause - MCC is malignancy. most common benign cause is sigmoid volvulus (sigmoid colon twists on itself), more common in elderly
[Abdominal wall disorders]
Congenital defects
1. Gastroschisis
2. Omphalocele
Congenital defects
- Gastroschisis - full thickness abdominal wall defect that occurs to the right of umbilicus
- due to abnormal folding of anterior abdominal wall during development (closes by 4 wks) –> exposure of abdominal contents / viscera (not covered by peritoneal sac)
- emergency, needs immediate closure; higher survival rate (even with poorer GI function) bc not associated with other anomalies - Omphalocele - persistent herniation of bowel into umbilical cord –> covered by peritoneum and amnion lining, usually larger than gastroschisis
- physiological herniation during development at 6 wks that allows bowels to develop then rotate and go back into the gut at 10 wks
- worse prognosis bc of high risk of associated anomalies e.g. neuploidy, structural anomalies eg VACTERL –> Vertebral, Anal, Cardiac, TE fistula, Renal, Limb
[Abdominal wall disorders]
Congenital defects
3. Meckel diverticulum
4. Diaphragmatic hernia
- Meckel diverticulum - most common congenital anomaly of GI tract; true diverticulum - outpouching of all 3 layers of bowel wall due to incomplete obliteration of vitelline duct (connects umbilicus to terminal ileum in utero)
Rule of 2’s:
-2” long
- found in distal ileum, within 2 ft of ileocecal valve
- 2% of pop
- presents at 2 yrs of age
- 2 main presentations: A) acute appendicitis or B) hematochezia –> copious brick-red painless rectal bleeding
- 2 epithelial types (pancreatic + gastric) - Diaphragmatic hernia - due to congenital defect of pleuroperitoneal membrane, more commonly occurs on left side where pericardioperitoneal canal is larger and closes later
- hypoplastic lung on affected side with pulmonary HTN and hypoxemia
- diagnosed on prenatal US, present at birth with respiratory distress (tachypnea, grunting, nasal flaring), cyanosis, absent bowel sounds, and scaphoid abdomen
[Abdominal wall disorders] Abdominal wall hernia 1. Indirect inguinal 2. Direct inguinal 3. Femoral
- Indirect inguinal hernia - goes through deep inguinal ring, superficial inguinal ring, and into scrotum –> covered by all three layers of spermatic fascia
- lateral to inferior epigastric vessels
- more common in younger males, due to patent processus vaginalis - Direct inguinal - goes through superficial inguinal ring and bulges through abdominal wall at Hesselbach’s triangle (inferior epigastric vessels, rectus abdominus, inguinal ligament)
- medial to inferior epigastric vessels
- more common in older men, due to weakness in transversalis fascia - Femoral - protrudes through femoral canal inferior to inguinal ligament, and medial to femoral vein
- more common in women, but most common hernia overall in women are inguinal
- more likely to present with hernia or strangulation
* (NAVEL from lateral to medial - nerve, artery, vein, empty lymphatic space)
[Abdominal wall disorders]
- Derivatives of ventral mesentery
- Pringle Maneuver
- Ventral mesentery - suspensory ligaments of liver (falciform, coronary, and triangular)
+ lesser omentum (hepatogastric + hepatoduodenal ligaments)
- all others are dorsal - Pringle Maneuver - compress hepatoduodenal ligament (which contains portal triad - portal vein, common bile duct, and proper hepatic artery) to control bleeding
[Inflammatory Bowel Disease IBD] Crohn's disease 1. Epi 2. Pathology 3. Macro/Micro 4. Clinical 5. Complications 6. Extraintestinal 7. Treatment
Crohn’s
- Epi - peak incidence in 20s, higher risk in smokers, genetic predisposition
- linked to Th1 immune response (cell mediated immunity via IgG, IFNgamma, TNFalpha) - Pathology - transmural inflammatory disease that affects ANY part of GI tract from mouth to anus; terminal ileum most common site; rectum is spared
- Appearance
A. Macroscopic - skip lesions with cobblestone mucosa; creeping fat; strictures with “string sign” on imaging
- Aphthous ulcers in mouth (i.e. canker sores)
B. Microscopic - noncaseating granulomas throughout all three layers - Clinical - systemic symptoms, pain, abdominal mass, and large bowel obstruction more common than with UC
A. Ileocolitis - RLQ pain with non-bloody diarrhea
B. Jejunocolitis - malabsorption –> steatorrhea, nutritional deficiency eg B12 deficiency
C. Colonic - large bowel diarrhea (tenesmus, bleeding, frequent small stools)
D. Perianal - fistula, fissure, abscesses around anus - Complications - fistula (due to persistent inflammation), small bowel obstruction (due to strictures)
- Extraintestinal - calcium oxalate kidney stones
- normally oxalate in lumen combines with calcium to be excreted in stool
- in Crohn’s, unbound FFAs take up the Ca2+, so oxalate is reabsorbed in the colon –> hyperoxaluria –> kidney stones - Treatment - corticosteroids (e.g. prednisone, budesonide), antimetabolite (azathioprine), antibiotics (metronidazole, cipro), anti-TNF Abs (infliximab / Remicade, adalimumab / Humira)
[IBD] Ulcerative colitis 1. Epi 2. Pathology 3. Macro/Micro 4. Clinical 5. Complications 6. Extraintestinal 7. Treatment
Ulcerative colitis
- Epi - peak incidence in 20s, smoking is protective, genetic predisposition
- linked to Th2 (humoral immunity via IgE, IL-4,5,10,13) - Pathology - chronic inflammation of the mucosa (epithelium, lamina propria, and muscularis mucosa) and occasionally submucosa –> continuous and superficial
- starts in rectum and extends proximally throughout colon - Appearance
A. Macroscopic - continuous, symmetric lesions (NO skip lesions) ONLY in colon; pseudopolyps (regenerated mucosa); loss of haustra with “lead pipe” sign on X-ray
B. Microscopic - crypt abscesses with neutrophils - Clinical - bloody diarrhea more common than with Crohn’s
- exacerbations and remissions; LLQ pain with bloody diarrhea [Crohn’s is RLQ without blood in stool]
- large bowel diarrhea with frequent small stools, tenesmus, and urgency
- severe disease - diffuse abdominal tenderness + systemic symptoms - Complications
- toxic megacolon - sudden onset fever, abdominal distension, no bowel function + severe bloody diarrhea, low BP and increased HR
- colorectal cancer - increased risk with extent (entire colon) and duration (10+ years of disease) - Extraintestinal - primary sclerosing cholangitis (inflammation of bile ducts), associated with p-ANCA
Treatment - 5-aminosalicylates (mesalamine), antimetabolite (6-MP), anti-TNF Abs (infliximab / Remicade)
[IBD] 1. Describe the extraintestinal manifestations common to both Crohn's and ulcerative colitis A. Dermatologic B. Ocular C. Arthritis
Common Extraintestinal Manifestations
A. Dermatologic
i. Erythema nodosum - tender subcutaneous nodules on lower extremities (eg knees); due to IC depositions in fat venules with vasculitis
ii. Pyoderma gangrenosum - neutrophil infiltrate of all layers of skin; inflammatory pustule that forms ulcer
B.. Ocular
i. Episcleritis - redness, burning
ii. Uveitis - inflammation of choroid and retina; floaters
C. Arthritis - nondestructive migratory arthritis; affects large joints
[Colon Diseases]
Describe causes and clinical sx of:
1. Appendicitis
2. Mesenteric lymphadenitis
- Appendicitis
A. Causes: obstruction of appendix due to fecalith, tumor, ascaris hookworm
- most common tumor of appendix is carcinoid tumor
- DDx for young children should include Meckel diverticulum
B. Clinical - obstruction –> dull visceral periumbilical pain (inflammation) –> ischemia, necrosis, perforation –> localized pain at RLQ McBurney point (peritonitis with guarding/rebound tenderness) with fever and nausea - Mesenteric lymphadenitis
A. Cause - Yersinia enterocolitica (Gram negative encapsulated bacteria with bipolar safety-pin staining) –> invades M cells to spread to lymph nodes and terminal ileum
B. Clinical - mimics appendicitis –> RLQ pain and bloody diarrhea
- commonly seen in toddlers if transmitted through puppy poop and milk products
[Colon Diseases]
Describe causes and clinical sx of:
3. Angiodysplasia
4. Colonic diverticula
- Angiodysplasia
A. Cause - AV malformation of submucosal vessels - connection between artery and vein with no capillary bed –> dilated, tortuous submucosal veins
- most commonly in cecum and right (ascending) colon
- associated with ESRD, vWD disease
B. Clinical - rupture of veins –> hematochezia (painless bright red blood in stool) in older adults - Colonic diverticula
A. Cause - outpouching of only mucosa and submucosa through muscularis propria and serosa (false diverticulum)
- due to wall stress (constipation, straining, low-fiber diet)
- most commonly in sigmoid colon at weak point of vasa recta perforation
B. Clinical - usually painless and asymptomatic, complications:
i. diverticular (arterial) bleeding –> painless copious hematochezia, can stop spontaneously
ii. diverticulitis - due to obstructing fecalith - inflamed diverticulum can cause microperforation of colonic wall –> appendicitis symptoms (peritonitis) but in LLQ
iii. colovesicular fistula - inflamed diverticulum ruptures and attaches to bladder–> pneumaturia (air in urine)
lower GI bleeding can also be due to vascular ectasias in patients 70+ years
[Colon Diseases]
Describe causes and clinical sx of:
5. Microscopic colitis
6. Irritable bowel syndrome IBS
- Microscopic colitis - collagenous colitis + lymphocytic colitis
A. Cause - biopsy shows increased intraepithelial lymphocytes or subepithelial collagen band
B. Clinical - chronic, non-bloody watery diarrhea in middle-aged female; colonscopy, images normal - IBS
A. Cause - disturbed intestinal motility; tests will be normal –> clinical diagnosis (can be confused with celiac disease); related to stress
B. Clinical - young adult female with relapsing abdominal pain with bloating, flatulence and changes in bowel habits (diarrhea alternating with constipation)
[Colon Diseases]
Describe causes and clinical sx of:
7. C. difficile associated colitis
8. Ischemic colitis
- C. difficile associated colitis (nosocomial)
A. Cause - Clostridium difficile (spore-forming Gram-positive obligate anaerobic); use of clindamycin
B. Clinical
i. Exotoxin A - binds to intestinal brush border –> cell death, inflammation –> watery diarrhea (toxin in stool)
ii. Exotoxin B - depolymerizes actin –> disrupts cytoskeleton –> pseudomembranous colitis (yellow-gray exudate)
- treat with oral vancomycin or metronidazole
- Ischemic colitis / bowel ischemia
A. Cause
i. mucosal - generalized hypoperfusion (SMA watershed areas - splenic flexure, sigmoid colon), shock/dehydration (low CO)
ii. transmural - acute vascular occlusion via embolus (afib) or thrombosis, atherosclerosis (superior mesenteric artery)
B. Clinical - severe, diffuse pain with pain out of proportion to physical findings; crampy abdominal pain + bloody diarrhea
- usually on left side (more likely to be obstruction bc of narrowing of lumen)
- benign physical exam –> no signs of peritonitis bc it takes time for damage to be transmural and affect parietal peritoneum
- ischemia –> infarction –> necrosis / perforation –> sepsis
[Colon Diseases]
Colonic polyps
- Familial adenomatous polyposis (FAP)
- Gardner Syndrome
- Turcot Syndrome - Juvenile Polyposis syndrome
- Peutz-Jeghers Syndrome
- Familial adenomatous polyposis (FAP)
A. Cause - AD mutation in APC (chromosome 5) –> ↑ beta catenin activity –> cell proliferation
- MYH gene mutation if AR, fewer polyps
B. Clinical - hundreds of adenomatous polyps throughout colon and rectum
- need to be removed or will develop colorectal carcinoma (but can develop cancers elsewhere)
C. Gardner Syndrome - FAP + fibromatosis + osteomas (benign skull tumor)
D. Turcot Syndrome - FAP + CNS tumors (medulloblastoma + glial) - Juvenile Polyposis syndrome
- multiple polyps in the stomach and polyp < 18 yo
- 2/3 develop colorectal carcinoma
- differentiate from sporadic, solitary hamartomas in kids <5 which are benign
* harmartoma - benign growths which contain all tissue elements but are disorganized - Peutz-Jeghers Syndrome
A. Cause - AD mutation
B. Clinical - hamartomatous polyps throughout GI tract + mucocutaneous hyperpigementation (Freckle-like spots) on lips, oral mucosa, and genital
- ↑ risk intussusception
- increased risk of colorectal and breast cancer
[Colon Diseases] Colorectal carcinoma 1. Lynch Syndrome (HNPCC) 2. Adenoma carcinoma sequence 3. Difference between right and left sided carcinomas
Colorectal carcinoma (colon cancer) - 3rd MCC of cancer death, 3rd most common site of cancer
- HNPCC - Hereditary non-polyposis colon cancer (Lynch Syndrome)
A. Cause - AD inherited mutations in DNA mismatch repair enzymes –> microsatellite instability
B. Clinical - de novo colorectal carcinoma, usually right sided (raised lesion) and in proximal colon; iron deficiency anemia
- increased risk for other malignancies eg ovarian
typical presentation: elderly patient with change in bowel habits or new onset iron deficiency anemia - Adenoma carcinoma sequence - second molecular pathogenesis pathway (first is mismatch repair)
- APC mutations (first and second hits) - increase risk of polyp formation
- K-RAS mutation - polyp formation
- additional cancer suppressor mutations (p53, DCC) + COX overexpression - progression of adenoma to carcinoma; aspirin protective
3A. Right-sided (ascending colon) - raised lesion; presents with iron deficiency anemia (occult bleed bc blood mixes with stool) + fatigue; metastases to liver (isolated ↑ in ALP and GGT imply liver involvement)
IDA microcytic anemia is a red flag in men and postmenopausal women
B. Left-sided (descending colon) - napkin-ring lesion, presents with LLQ pain and bloody stool (hematochezia); more likely to have obstruction bc of narrowing of the lumen
[Colon Diseases] 1. Fecal impaction 2. Anal fissure 3. Hemorrhoids A. External B. Internal
- Impaction - Hardened stool stuck in the rectum or lower colon
A. Cause - Due to fecal retention (children) or neuromuscular disorders eg Parkinson’s, ALS or chronic constipation (older adults)
B. Clinical - incontinence, rectal bleeding or itching; stool can be palpated on DRE - Anal fissure
A. Cause - tear in anal mucosa below pectinate line on posterior aspect of anal canal (area is poorly perfused)
- low fiber diets, constipation
B. Clinical - pain while pooping - Hemorrhoids - swollen and inflamed veins
A. External - below pectinate line, arterial supply from inferior rectal artery (branch of interior pudendal artery)
- somatic innervation from inferior rectal branch of pudendal nerve –> painful
- lymphatics - superficial inguinal nodes
B. Internal - above pectinate line, arterial supply from superior rectal artery (branch of IMA)
- visceral innervation –> not painful
- lymphatics - internal iliac nodes
[Small bowel Diseases] Pediatric small bowel 1. Midgut volvulus 2. Intussusception 3. Necrotizing enterocolitis
- Midgut volvulus
A. Cause - twisted bowel due to malrotation around SMA axis during fetal development
B. Clinical - presents few days after birth, rapid deterioration
- bilious vomiting + “apple peel”/corkscrew spiral sign on imaging
*sigmoid volvulus more common in elderly (large bowel obstruction) - Intussusception
A. Cause - telescoping of proximal segment of bowel forward into distal segment (usually at ileocecal junction) –> obstruction and disruption of blood supply
- kids - idiopathic, possibly viral infection (Rotavirus) –> lymphoid/Peyer’s patch hyperplasia –> lead point (Meckel diverticulum is pathologic lead point)
- adults - uncommon, due to lead point / tumor (malignant)
B. Clinical - intermittent, colicky abdominal pain with currant jelly stools and palpable abdominal mass
- bulls-eye on ultrasound - Necrotizing enterocolitis
A. Cause - unknown, seen in premature, formula fed babies with immature immune system
B. Clinical - necrosis of intestinal mucosa –> abdominal distension, vomiting, bloody stools
- perforation –> pneumatosis intestinalis (air gas cysts in bowel wall), air in portal vein
[Colon Diseases]
Pediatric large bowel
1. Bowel obstruction in newborn
2. Hirschsprung Disease
- Bowel obstruction in newborn - surgical emergency
Cardinal signs:
i. polyhydramnios
ii. bilious vomiting
iii. failure to pass meconium in first day
iv. abdominal distension - Hirschsprung Disease
A. Cause - congenital failure of neural crest ganglion cells to descend into Meissner (submucosal) plexus and Auerbach (myenteric) plexus –> bowel cannot relax
- associated with Down syndrome
- always involves rectum
B. Clinical - failure to pass meconium within 48 hours, bilious vomiting
- empty rectal vault on DRE
- abdominal distension + megacolon dilated with feces and gas
*meconium ileus is first manifestation of cystic fibrosis
Layers of GI tract: mucosa - muscularis mucosa - submucosa (Meissner submucosal plexus) - muscularis propria (Auerbach myenteric plexus) - serosa
[Pancreatic Diseases] Acute pancreatitis 1. Diagnosis 2. Pathogenesis 3. Clinical
Acute pancreatitis
1. Diagnosis:
A. Labs - high serum lipase (more specific) and amylase > 3x normal
B. Clinical - acute epigastric pain radiating to the back (pancreas is retroperitoneal)
C. Imaging - pancreas surrounded by edema (fluid in abdomen) –> body’s response to try to temper the pancreatic enzymes
- Pathogenesis - autodigestion of pancreas by pancreatic enzymes due to trypsin activation
- reduced intracellular protective mechanisms to prevent trypsinogen activation (low Ca2+, SPINK1 inhibitor)
- obstruction of of pancreatic duct due to tumor, mucus plugs due to CFTR mutation - Clinical -
- severe epigastric pain radiating to back
- nausea, vomiting, fever
- pain aggravated by food
- pain relieved by sitting up and leaning forward (relieves pressure on pancreas)
[Pancreatic Diseases]
- List causes of acute pancreatitis - I GET SMASHED
- Gallstones
- Hypertriglyceridemia
- Divisum
1. I GET SMASHED I-idiopathic G- gallstones *MCC E- ethanol T- trauma S- steroids M- mumps A- autoimmune disease S- scorpion sting H- hypercalcemia/hypertriglyceridemia E- ERCP endoscopy procedure D- drugs causing violent abdominal distress --> Didanosine (HIV antiviral), Corticosteroids, Valproic acid, Azathioprine (6MP), Diuretics (furosemide, HCTZ)
- Gallstones (MCC) - due to gallstones that block common bile and pancreatic ducts –> ascending cholangitis + biliary pancreatitis
alcohol - 2nd MCC (majority of acute pancreatitis is gallstones + alcohol)
- Hyperlipidemia - when TG levels > 1000 mg/dL
- eruptive xanthomas filled with chylomicrons with inflamed base (red ring); on extensor surfaces - Divisum - dorsal and ventral pancreatic ducts fail to fuse at 8 weeks
- most common congenital anomaly of pancreas
- usually asymptomatic but can cause pancreatitis
[Pancreatic Diseases]
1. Forms of acute pancreatitis
- Markers of disease severity
- Complications
A. Markers of organ failure
B. Pseudocyst
- Forms
A. Interstitial (80%) - swelling of cells, which are perfused –> diffuse enlargement and homogenous enhancement on imaging
B. Necrotizing (20%) - bv are squeezed and no perfusion –> non-enhancing
- can be sterile (70%) or infected (30%) - Markers of disease severity
- older age
- alcoholic pancreatitis - ↑ risk necrosis
- obesity
- ↑ BUN
- signs of systemic inflammation (organ failure)
- signs of fat necrosis and bleeding –> bruises
3A. Markers of organ failure: ↑ activation trypsin –> ↑ coagulation, complement –> vascular abnormalities
- shock - systolic BP < 90
- pulmonary insufficiency - Pa02 < 60 mmHg –> ARDS
- renal failure - Cr > 2 mg/Dl
- GI bleeding > 500 mL/24 hr
B. Pseudocyst - complication of acute pancreatitis; fluid collection surrounded by granulation tissue (not epithelium) –> persistently elevated amylase or early satiety
[Pancreatic Diseases] Chronic pancreatitis 1. Causes 2. Pathogenesis 3. Clinical
Chronic pancreatitis
- Causes - alcohol (60%), idiopathic (25%), autoimmune, obstructive, genetic
- in kids - most likely to be cystic fibrosis - Pathogenesis - chronic inflammation, atrophy, and calcification of the pancreas –> irreversible impairment of function; amylase and lipase may not be elevated
- Clinical
A. Early manifestation - recurrent epigastric pain associated with nerve involvement and/or dilatation of the duct
B. Late manifestations -
- steatorrhea (due to lack of lipase) + weight loss
- diabetes mellitus
- pancreatic calculi (dystrophic calcifications in pancreatic duct)
[Pancreatic Diseases] Pancreatic adenocarcinoma 1. Risk factors 2. Genetic causes 3. Clinical incl Courvoisier's law and Trousseau syndrome 4. Treatment
Pancreatic adenocarcinoma 1. Risk factors: A. Tobacco use B. Chronic pancreatitis C. Diabetes D. Age > 50
- K-RAS, p16, p53, and DPC4/SMAD4
- precursor lesion with neoplasia and progression, similar to adenoma-carcinoma sequence in colon cancer
- associated with CA 19-9 tumor marker - predicts course of disease
- pancreatic carcinomas like to invade nerves - Clinical
- persistent, aching abdominal radiating to back; increased by eating or lying supine (like acute pancreatitis)
- pancreatic head tumor –> obstructive jaundice with dark urine, clay stools
- extreme weight loss due to malabsorption + anorexia
- Trousseau syndrome - migratory thrombophlebitis (blood clot in vein) with redness and tenderness on palpation of extremities due to hypercoagulable state
- Courvoisier’s law - distended/palpable, nontender gallbladder + obstructive jaundice –> cancer of gallstone or pancreas - Treatment - Whipple surgery, chemo, radiation
[Neuroendocrine tumors] 1. NET characteristics 2. Associated clinical sx of the following Carcinoid ZE Insulinoma VIPoma Gucagonoma Somatostatinoma GRFoma Non-functioning
- Neuroendocrine tumors (NET) - originate from multipotential cells in gut crypts (Kulchitsky and ECL cells), can be GI or pancreatic
- small cells in sheets
- positive silver stain
- positive markers: neuron-specific enolase, chromogranin A, synaptophysin
2. Syndrome - Manifestations Carcinoid - diarrhea, flushing, wheezing ZE - severe PUD, diarrhea Insulinoma - hypoglycemia VIPoma - secretory diarrhea Gucagonoma - diabetes, migratory necrolytic erythema Somatostatinoma - diabetes, gallstones GRFoma - acromegaly Non-functioning - nothing
[Neuroendocrine tumors]
Cause, clinical, and treatment of the following NETs:
1. Insulinoma
2. Zollinger-Ellison
- Insulinoma - most common pancreatic NET
A. Cause - tumor of pancreatic beta cells
B. Clinical - overproduction of insulin –> hypoglycemia
- ↑ insulin and C-peptide levels with glucose < 40
- Whipple’s triad: hypoglycemia sx (sweating, tachycardia, weakness), low plasma glucose, sx relief when glucose increased
C. Treatment - surgical resection - Zollinger-Ellison syndrome
A. Cause - gastrin secreting tumor (gastrinoma) of pancreas or duodenum
- associated with MEN1
B. Clinical - chronic unexplained diarrhea (malabsorption) + intractable ulcer disease + abdominal pain (due to recurrent ulcers)
- positive secretin stimulation test –> gastrin levels are paradoxically elevated after giving secretin (gastrin inhibitor)
C. Treatment - PPIs; side effects are fractures (need H+ for osteoclast activity and bone turnover) and B12 deficiency (parietal cells make IF)
[Neuroendocrine tumors] Cause, clinical, and treatment of the following NETs: 3. VIPoma 4. Glucagonoma 5. Somatostatinoma
- VIPoma
A. Cause - excessive release of VIP from pancreatic tumor
B. Clinical - WDHA
Watery Diarrhea
Hypokalemia
Achlorhydria (no stomach acid production) - Glucagonoma
A. Cause - tumor of pancreatic alpha cells –> glucagon overproduction; pulling AA out of tissue to make glucose
B. Clinical - dermatitis (migratory necrolytic erythema), diabetes (hyperglycemia), DVT, declining weight, depression - Somatostatinoma
A. Cause - tumor of pancreatic delta cells –> somatostatin overproduction –> inhibition of cholecystokinin, glucagon, insulin, exocrine pancreas secretion
- duodenal somatostatinoma associated with NF1
B. Clinical - gallstones, diabetes, diarrhea (due to steatorrhea)
C. Treatment (for all)
- surgery, octreotide (somatostatin analog)
[Neuroendocrine tumors] Carcinoid syndrome A. Cause B. Clinical C. Treatment
Carcinoid syndrome
A. Cause - due to carcinoid tumor - slow-growing malignant tumor of neuroendocrine cells –> secrete serotonin (5-HT)
- in ileum (most common malignancy in small intestine)
- associated with hypergastrinemia (seen in ZE or autoimmune gastritis) –> Gastrin stimulates neuroendocrine ECL cells –> dysplasia
B. Clinical
i. only local tumor effects (bleeding, pain, obstruction) if tumor is limited to GI tract –> serotonin has first pass metabolism in liver
ii. if serotonin reaches systemic circulation –> carcinoid syndrome –> stimulates intestinal secretion and motility, inhibits absorption –>
- recurrent diarrhea
- facial flushing
- right-sided valvular heart disease (tricuspid regurg, pulmonic stenosis) - increases with inspiration
- bronchospasm –> difficulty breathing + asthmatic wheezing
- tryptophan depleted to make serotonin –> niacin deficiency –> pellagra (diarrhea/dementia/C3-4dermatitis)
- ↑ 5-HIAA in urine
C. Treatment - somatostatin analog (octreotide), surgery
[Gallbladder Disorders]
- Components of bile
- Functions of bile
- Function of gallbladder
- Bile - composed of bile salts (water soluble bc bile acids are conjugated to glycine or taurine), phospholipids e.g. lecithin, cholesterol, conjugated bilirubin, water, and ions
- bile acid synthesis in hepatocyte: RLS is catalyzed by CYP7A1, primary bile acids conjugated to glycine and taurine to become hydrophilic, polar, better detergents - Bile functions
A. Cholesterol excretion (body’s only mechanism)
B. Intestinal absorption of lipids and fat-soluble vitamins
C. Controlling bacterial overgrowth (via membrane disruption)
D. Hormone to regulate enterohepatic circulation - Gallbladder- concentrates hepatic bile
- micelles allow bile to stay isotonic to plasma despite increased concentration
- gallbladder is derivative of embryonic foregut; blood supply is cystic artery, branch of right hepatic
[Gallbladder Disorders]
Gallstones - pathophys + risk factors
1. Cholesterol
- Cholesterol gallstones (80%) - mostly composed of crystalline cholesterol, also some bile pigments; radiolucent
A. Pathophysiology - cholesterol supersaturation –> nucleation –> growth
B. Risk factors:
- female - ↑ estrogen ↑ hepatic secretion of biliary cholesterol; ↑ progesterone ↓ gallbladder motility
- fat - ↑ HMG CoA reductase activity
- forty
- fertile (pregnant) - or multiparity
+
- too much cholesterol (diet, dyslipidemia, obesity)
- reduced bile salt and phospholipids (lecithin)
- rapid weight loss
- Native American
[Gallbladder Disorders]
Gallstones - location, causes, risk factors
- Pigment
A. Brown stones
B. Black stones
- Pigment stones
A. Brown stones (18%)
i. Location - bile ducts (Eg common bile duct); radiolucent
- form in infected bile
ii. Cause - biliary stasis, deconjugated bilirubin (insoluble and precipitates as calcium bilirubinate, the main component of brown stones)
iii. Risk factors - biliary infections –> chronic parasitic infection e.g. Clonorchis, Ascaris - which produces beta-glucoronidase (deconjugates bilirubin)
B. Black stones (2%)
i. Location - exclusively in gallbladder; radiopaque
- form in sterile bile
ii. Cause - hyperbilirubinemia
iii. Risk factors -
- chronic liver disease (e.g. cirrhosis, Crohn’s)
- ineffective erythropoiesis (Vit B12/folate deficiency)
- hemolysis (e.g sickle cell, thalassemias)
- increased risk among patients with disease affecting terminal ileum (e.g. Crohn’s ileal resection)
[Gallbladder Disorders] Causes, clinical symptoms, and treatment of the following: 1. Biliary colic 2. Acute cholecystitis 3. Porcelain gallbladder
- Biliary colic
A. Cause - gallstone becomes impacted in cystic duct during gallbladder contraction
- pain goes away when gallbladder relaxes and obstruction is relieved
B. Clinical - sporadic episodes of epigastric or RUQ pain that radiates to right scapular tip + nausea/vomiting + diaphoresis
- postprandial, esp consumption of fatty food
- intense, dull, constant
- not relieved by anything - Acute cholecystitis
A. Cause - inflammation of gallbladder due to gallstone obstructing cystic duct
- gallbladder wall thickening
B. Clinical - constant, severe RUQ pain with radiation to scapula + nausea/vomiting + fever
- Murphy’s sign - inspiratory arrest on RUQ palpation due to pain
- use ultrasound or HIDA scan to diagnose - thick walls and pericholecystic fluid - Porcelain gallbladder
A. Cause - chronic cholecystitis
B. Clinical - incidental finding on imaging –> calcified gallbladder –> associated with gallbladder cancer
[Gallbladder Disorders] Gallstone complications 1. Ascending cholangitis 2. Gallstone pancreatitis 3. Gallstone ileus
- Ascending / Acute cholangitis
A. Cause - Choledocholithiasis (gallstone in the common bile) –> cholestasis –> dilatation and bacterial overgrowth (usually E. coli) –> ascending cholangitis (infection of the bile duct)
B. Clinical - Charcot’s triad with fever, RUQ pain, and jaundice
- increased WBCs, and LFTs
- hypotension, altered mental status (due to systemic infection) *emergency! can kill patients quickly - Gallstone pancreatitis
A. Cause - gallstone in distal common bile duct that obstructs common channel Ampulla of Vater –> bile reflux into pancreatic duct –> inflammatory process
B. Clinical - MCC of pancreatitis –> acute epigastric pain often radiating to the back, ↑ serum amylase/lipase - Gallstone ileus
A. Cause - chronic impaction of stone –> inflammation –> biliary-enteric fistula (gallbladder to duodenum) –> gallstone erodes into GI tract and obstructs ileocecal valve
B. Clinical - air in biliary tree pathognomonic
- mechanical bowel obstruction
[Gallbladder Disorders] Gallstone complications 1. Acalculous cholecystitis 2. Empysematous cholecystitis 3. Gallbladder cancer 4. Mirizzi syndrome
[Not on Step1]
- Acalculous cholecystitis
A. Cause - unclear; related to prolonged fasting or parenteral nutrition
B. Clinical –> pigment stone - Empysematous cholecystitis
A. Cause - Clostridia or E. coli
B. Clinical - rapidly progressive gangrene with gallbladder perforation; surgical emergency! - Gallbladder cancer
A. Cause - chronic inflammation due to gallstone, chronic infection due to Salmonella typhi, hereditary syndromes (eg Lynch), chemical exposures, calcification of gallbladder, primary sclerosing cholangitis - Mirizzi syndrome - gallstone in cystic duct compresses common hepatic duct –> obstructive jaundice (but common bile duct is normal)
[Pediatric GI]
Causes and clinical symptoms of:
1. Cleft lip and palate
2. Describe tracheo-esophageal fistulas (TEF) and clinical presentation
- Cleft lip and palate
A. Cause - holoprosencephaly (failure of left and right hemispheres to separate), vitamin A teratogenicity
B. Clinical - distinct midline facial defects that can occur together or alone, unilateral or bilateral
- cleft lip: failure of fusion of maxillary and median nasal processes (formation of primary palate); more common, M>F
- cleft palate: failure of fusion of lateral palatine shelves (formation of secondary palate); F>M - TEF
A. Cause - most common type –> esophageal atresia with blind esophageal pouch + distal fistula (connection) between esophagus and trachea
- due to failure of canalization
- associated with cardiac anomalies
B. Clinical
- polyhydramnios in utero
- 3C’s: coughing, choking, cyanosis
- neonates drool and vomit with first feeding
- unable to pass nasogastric tube into stomach
[Pediatric GI]
- Kwashiorkor
- Marasmus
- Kwashiorkor
A. Cause - protein deficiency, most common in toddlers bc they require high protein intake for growth
- occurs in developing countries
B. Clinical - soft, pitting painless edema with abdominal distension - Marasmus
A. Cause - caloric and protein deficiency
B. Clinical - muscle wasting, bradycardia, hypothermia, hypotension
[GI Pharmacology] 1. Laxatives A. Bulk-forming laxatives B. Stool softeners C. Osmotic laxatives D. Stimulant laxatives (cathartics)
- Laxatives
A. Bulk-forming laxatives (methyl cellulose, psyllium) - indigestible, hydrophilic colloids (plant fibers) that absorb water and form bulky gel –> distend colon and promote peristalsis
B. Stool softeners (eg docusate, glycerin suppository) -lubricate stool and prevent absorption of water from stool –> reduces straining and promotes passage
C. Osmotic laxatives (magnesium compounds e.g. Milk of Magnesia, lactulose, polyethylene glycol e.g. MiraLAX) - nonabsorbable substances that draw water into intestinal lumen –> distension –> peristalsis –> bowel movement
- used for colonic cleansing prior to GI endoscopic procedures
D. Stimulant cathartic laxatives (Senna, aloe vera) - stimulate enteric nervous system + secretion of colonic electrolytes + fluid into bowel –> induce BMs
- can cause melanosis coli
[GI Pharmacology]
2. Antidiarrheal agents
A. Opioid agonists
B. Somatostatin analog
- Antidiarrheal agents *contraindicated in pts with inflammatory diarrhea (treat underlying cause)
A. Opioid agonists
- diphenoxylate (Lomotil) - prescription, cross BBB so CNS effects at high doses and must be prescriped with atropine
- loperamide (Imodium) - OTC, does not cross BBB
i. MOA: activate mu-opioid receptors in the GI tract –> increased colonic phasic segmenting activity and colonic transit time
ii. Indications - diarrhea
iii. Adverse effects - constipation (increase hydration and fiber)
B. Somatostatin analog - octreotide
i. MOA - inhibits secretion of hormones:
- gastrin –> ↓ acid and pepsinogen secretion
- CCK –> ↓ pancreatic secretions, gallbladder contraction
- secretin –> ↓ pancreatic HC03- secretion
- motilin –> ↓ peristalsis –> slowed GI motility
- VIP –> ↓ intestinal fluid secretion and relaxation
+ inhibits GIP, GH, TSH, and prolactin
ii. Indications - secretory diarrhea due to VIPoma or carcinoid tumor
iii. Adverse effects - flatulence, abdominal pain, nausea
- impaired pancreatic secretion –> steatorrhea, ADEK deficiency
- inhibition of gallbladder contractility –> gallstones
- long term –> hypothyroidism
[GI Pharmacology]
3. Irritable bowel syndrome (IBS) drugs
A. Altered bowel habits
B. Pain and severe IBS
- IBS drugs
A. Altered bowel habits
i. predominant diarrhea –> opioid agonists to reduce frequency and urgency
ii. predominant constipation –> increased dietary fiber + Cl- channel activators (linaclotide), osmotic laxatives (PEG), bulk-forming laxatives (psyllium) to soften stool and reduce straining
B. Pain and severe IBS
- chronic abdominal pain –> low doses TCAs without altering mood
- severe diarrhea –> 5HT3 receptor antagonist (alosetron) to treat visceral pain bloating, nausea
[GI Pharmacology] 4. Inflammatory bowel disease (IBD) drugs A. 5-aminosalicylates B. Glucocorticoids C. Antimetabolites D. Anti-TNF therapy
- IBD drugs
A. 5-aminosalicylates (mesalamine) e.g. olsalazine
i. MOA - work topically on diseased GI mucosa
ii. Indication - first-line for UC
B. Glucocorticoids (type of corticosteroid)
- prednisone, prednisolone, budesonide (oral)
- hydrocortisone (enema, foam, suppository) - to minimize systemic absorption
i. MOA - suppresses immunity and inflammation
ii. Indication - Crohn’s
iii. Adverse effect - Cushingoid
C. Antimetabolites
A. MOA - purine antimetabolites
i. Indication - 6-MP for UC, azathioprine for Crohn’s
ii. Adverse effect - can cause hepatotoxicity
D. Anti-TNF therapy
i. MOA - inhibit TNF, key pro-inflammatory cytokine
ii. Indication - infliximab (Remicade) for both severe Crohn’s and UC
- adalimumab (Humira) for severe Crohn’s
iii. Adverse effect - opportunistic infection from suppression of helper T cells –> fungal (Candida, Aspergillus)
[GI Pharmacology] 5. Antiemetic drugs A. 5-HT3R antagonists B. NK1R antagonists C. H1R antihistamines
A. 5-HT3 antagonists - “setron” –> ondansetron, granisetron, dolasetron, palonestron
i. MOA - inhibits activation of 5HT3 receptors on vagal afferents by serotonin –> decreased vagal stimulation of nucleus tractus solitarius (medullary vomiting center)
ii. Indications - chemo-induced vomiting, post-op vomiting
- can cause constipation, headache, dizziness, or serotonin syndrome
B. NK1R antagonists - aprepitant
i. MOA - inhibit neurokinin 1 receptors in area postrema (chemoreceptor trigger zone)
ii. Indication - chemo-induced vomiting
C. H1 antihistamines - diphenhydramine (Benadryl), dimenhydrinate (Dramamine)
i. MOA - inhibit histamine H1 receptors; first generation
- vestibular system responsible for vertigo, motion sickness and contains H1 and M1 receptors
ii. Indications - motion sickness
[Liver Disease]
- Causes of jaundice and enzyme values
- Clinical sx of jaundice
- Causes of jaundice
A. Prehepatic e.g. hemolytic anemia - ↑ indirect bilirubin, normal ALT/AST, normal ALP
B-E have ↑ unconjugated AND conjugated bilirubin (no value in fractionating)
B. Hepatocellular inflammation e.g. acute viral hepatitis - ↑ bilirubin, ↑ ALT/AST (>500), ALP moderately high (<300)
* the only times AST/ALT ~ 1000 are acute viral hepatitis, ischemic hepatitis, and acetaminophen overdose
C. Hepatocellular failure e.g. chronic liver disease - ↑ bilirubin, ALT/AST moderately high (<300), ALP moderately high (<300)
D. Cholestasis (intrahepatic e.g. congenital or extrahepatic e.g. obstruction) - ↑ bilirubin, normal or moderately high AST/ALT, ↑ ALP (>300 or 3xnormal)
*ALP v high (>300) in liver infiltration e.g. tumor, TB while AST/ALT are normal
- Jaundice - clinical, seen when bilirubin > 3 mg/dL
A. yellowing of skin, sclera, mucous membranes (due to conjugated and unconjugated bilirubin)
- sclera detected first due to high elastin content
B. dark cola-colored urine (due to soluble conjugated bilirubin in the urine; obstructive jaundice)
- urine color changes precede yellowing of sclera
C. clay-colored stools (due to absence of stercobilin; obstructive jaundice)
[Liver Disease]
- Transaminases and relative numbers
- DDx for mild, moderate, severe elevations
- Liver injury pattern based on zones
- Transaminases - preformed enzymes produced by hepatocytes; released into plasma with hepatocellular necrosis and inflammation
ALT - most specific for liver; upper limit normal (ULN) 40
AST - found in liver but also muscle and RBC; ULN 40
LDH - much less specific; ULN 200
- usually ALT»_space; AST (AST>ALT in alcoholic disease) - AST and ALT elevations
A. Mild elevation (<150) - nonalcoholic fatty liver disease, chronic hepatitis, cirrhosis
B. Moderate (150+) - acute hepatitis, drugs, alcohol
C. Severe (800+) - acetaminophen, shock, fulminant liver failure
- in acute hepatic illness/injury – can go into the thousands - Zone 1: closest to portal triad (portal vein, hepatic artery, bile duct - where bile drains)
- viral hepatitis, ingested toxins e.g. cocaine
Zone 2: intermediate
- yellow fever
Zone 3: closest to central vein (where blood drains)
- first affected by ischemia
- contains CYP450 –> acetaminophen toxicity
- alcoholic hepatitis, metabolic toxins
[Liver Disease]
Describe causes of the following:
- Unconjugated (indirect) hyperbilirubinemia
- Conjugated (direct) hyperbilirubinemia
- Unconjugated (indirect) hyperbilirubinemia
A. Hemolytic anemia eg Beta thalassemia
B. Physiologic in newborns due to immature UDP glucoronyltransferase (UGT1A1) –> phototherapy to make UCB more soluble to be excreted
C. Crigler-Najjar syndrome (AR)
- Type I - no UGT –> UCB is toxic and goes to brain (kernicterus) –> jaundice, lethargy, poor feeding, hearing loss, neurodevelopmental delays, paralysis of upwards gaze –> die in few years
- Type II - less severe, responds to phenobarbital to increase bilirubin –> survive but jaundiced
D. Gilbert syndrome (AR) - mildly decreased UGT; mild jaundice with stress and fasting, totally benign
- Conjugated (direct) hyperbilirubinemia
A. Dubin Johnson (AR) - defective excretion of conjugated bilirubin from the hepatocyte into bile canaliculus; benign but grossly black liver
B. Rotor (AR) - same as Dubin-Johnson but liver is NOT black
[Biliary Tract Disease]
- Define cholestasis
- Biochemical markers
- Hepatic infiltration and biochemical results
- Cholestasis - deficient bile transit, can be complete or partial, macroscopic (due to obstruction) or microscopic (due to impairment of transport) –> biochemical markers identical
- Biochemical markers of cholestasis
A. ↑ alkaline phosphatase (ALP) - measured first; then gamma-glutamyl transpeptidase (GGT) –> ↑ in both suggests cholestasis
- alk phos sources: liver, bone, kidney, placenta
- GGT: sensitive indicator of alcohol use
B. Bile components
- bilirubin ↑ –> jaundice can have cholestasis w/out jaundice
- bile salts ↑ –> pruritus, can be first presenting symptom
- cholesterol ↑
- excretory products - copper ↑, higher drug levels
- water and electrolytes - renally compensated
- Hepatic infiltration - due to granuloma, abscess, or tumor –> similar to cholestasis but lacks elevated bilirubin, cholesterol, bile salts, or pruritus
- elevated alk phos and GGTP
- normal transaminases (~40)
- normal bilirubin (~1)
[Biliary Tract Disease]
- Primary sclerosing cholangitis
- Primary biliary cirrhosis
- Secondary biliary cirrhosis
Biliary tract disease - presents with cholestatic pattern of LFTs (↑ ALP, ↑ CB) and jaundice
- Primary sclerosing cholangitis
A. Cause - p-ANCA (+); ↑ IgM; “onion-skin” concentric bile duct fibrosis with beading (“beads on a string”) due to strictures/dilation of bile ducts –> obliteration of bile ducts –> cirrhosis
B. Clinical - in middle-aged men with ulcerative colitis
- ↑ risk cholangiocarcinoma and gallbladder cancer - Primary biliary cirrhosis
A. Cause - IgM anti-mitochondrial Ab (+)
- autoimmune reaction –> lymphocytic infiltrate + granulomas in portal tract–> destruction of intrahepatic bile ducts (which are part of portal triad in liver acinus)
B. Clinical - in middle aged women, associated with other autoimmune conditions (esp Sjogren, thyroid)
- RUQ pain, fatigue, pruritis, jaundice + ↑ ALP/GGT, lipid, cholesterol (xanthoma)
- cirrhosis –> ↑ risk hepatocellular carcinoma
- treat with Ursodiol (ursodeoxycholic acid) - bile acid that enterohepatic recirculation –> lowers hepatic cholesterol secretion and delays progression of PBC - Secondary biliary cirrhosis
A. Cause - extrahepatic biliary obstruction –> ↑ pressure in intrahepatic ducts –> injury/fibrosis and bile stasis
B. Clinical - seen in patients with known obstructive lesions (gallstones, biliary strictures, pancreatic cancer)
[NAFLD]
Nonalcoholic fatty liver disease
1. Progression
2. Two hit hypothesis
Nonalcoholic fatty liver disease (NAFLD) - most common liver disease
- Progression - reversible before cirrhosis
- healthy –> NAFLD (25% of US population) –> nonalcoholic steatohepatitis NASH (25% of them) –> cirrhosis (25% of NASH pts) –> hepatocellular carcinoma
- diagnosis of exclusion - need to biopsy - Two hit hypothesis
A. First hit - fat accumulation –> NAFLD
- metabolic syndrome: 3+ more of the following - hyperglycemia (>110 mg/dL), visceral/central obesity, dyslipidemia (>150 TAGs, <50 HDL), hypertension (>130/85)
- diet - hypercalorific, fatty diet
B. Second hit - inflammation –> NASH
- mitochondrial dysfunction
- omega-6 fatty acids and fructose –> pro-inflammatory (omega-3 is anti-inflammatory)
[Hepatitis]
1. Acute viral hepatitis
A. Causes
B. Clinical
- Describe serological markers for HAV, HBV, HCV
- Acute viral hepatitis - systemic infection that predominantly affects liver
A. Causes - Hepatitis viruses (A-E), other viruses (EBV, CMV, Coxsackie), IVDU, alcohol, ischemia, biliary tract disease
B. Clinical - subclinical –> malaise, nausea/vomiting, low-grade fever, diarrhea –> dark urine, jaundice, hepatomegaly
- pruritus due to cholestasis
- elevated AST and ALT levels (ALT»_space; AST)
- Serological markers
A. HAV - IgM Ab for acute hepatitis A infection; IgG Ab indicates prior infection or vaccine and is protective
B. HBV - in order of appearance
HBsAg - surface antigen; indicates infection
HBeAg - marker of active viral replication and infectivity, high HBV DBA in serum
anti-HBc - IgM (active infection) - seen during window period; IgG (prior exposure/chronic)
anti-Hbe - low transmitability, low HBV RNA
anti-Hbs - recovery / immunity
C. HCV - diagnose via anti-HCV Ab in serum, but most sensitive marker is HCV RNA in serum (v expensive test)
[Hepatitis] 1. Hepatitis A Virus A. Virus type B. Transmission C. Clinical D. Sequelae E. Treatment
- HAV (Acute, asymptomatic)
A. Virus type - (+) sense, naked, SS RNA picornavirus
- naked –> acid-stable (not destroyed by the gut)
B. Transmission - fecal oral
- developing countries - contaminated water supplies –> endemics
- developed countries - shellfish; outbreaks in daycare centers
C. Clinical - often asymptomatic
- acute viral hepatitis: low-grade fever, nausea/vomiting, hepatomegaly, jaundice
- no jaundice in kids
D. Sequelae - no chronic carrier state
E. Treatment - inactivated vaccine for high risk patients
[Hepatitis] 2. Hepatitis B Virus A. Virus type B. Transmission C. Clinical D. Sequelae E. Treatment
- Hepatitis B Virus (Blood, birthing, baby-making)
A. Virus type - circular, partially dsDNA virus with envelope, surface coat (HBsAg), inner core (HBcAg)
- host RNA polymerase transcribes mRNA –> HBV DNA polymerase reverse transcribes the RNA to dsDNA
B. Transmission - blood (needlesticks), birthing (during delivery), baby-making (sexual)
- endemic in SSA and SE Asia
C. Clinical
i. Most people are subclinical - mild serum sickness-like illness with fever, arthralgia, rash
ii. polyarteritis nodosa (type 3 HSN) - medium vessel “beads on a string” vasculitis
iii. membranous nephropathy - BM thickening with subepithelial “spike and dome” deposits
iv. MPGN - Type I with subendothelial IC deposits and “tram-track” appearance due to BM splitting (more likely with HCV)
D. Sequelae
- adults: 90% recover without sequelae (Anti-HBs)
- those that don’t get chronic/carrier hepatitis (HBsAg, no Ab) –> cirrhosis –> hepatocellular carcinoma
- fulminant hepatitis v rare
- babies: 90% progress to chronic infection
E. Treatment - recombinant hepatitis B vaccine to high risk groups and all children
- neonates / exposed people - HBIg (immunoglobulin) + vaccine
- pregnant women / chronic infection - NRTIs eg lamivudine, IFNalpha (treatment does not get rid of carrier state, only suppresses)
[Hepatitis] 3. Hepatitis C Virus A. Virus type B. Transmission C. Clinical D. Sequelae / extraintestinal manifestations E. Treatment
- Hepatitis C Virus (Cirrhosis, Cancer, Carrier)
A. Virus type - (+) sense, enveloped RNA flavivirus
- lack of 3’–>5’ exonuclease proofreading activity –> genetic heterogeneity in HCV envelope proteins
B. Transmission - primarily blood (IVDU, blood transfusions)
- HCV RNA in serum indicates infection
C. Clinical - mild presentation, majority asymptomatic
- acute viral hepatitis - jaundice, RUQ pain, ↑ ALT
- chronic - ALT normalizes, lymphocyte aggregates in portal tract - fatigue
D. Sequelae - >50% become chronic HCV –> cirrhosis –> small % get hepatocellular carcinoma
Extraintestinal manifestations:
- hematologic: Idiopathic thromboctopenic purpura, essential cryoglobulinemia (cryoglobulins of anti-HCV IgM that precipitate out in cooler temperatures)
- renal: MPGN (subendothelial tramtrack deposits)
- autoimmune: Sjogren’s
- dermatologic: lichen planus, porphyria cutanea tarda
E. Treatment - ribavirin + IFNalpha, protease inhibitors (can eradicate/cure carrier state)
- throw out any donated blood with anti-HCV
[Hepatitis] 4. Hepatitis D Virus A. Virus type B. Transmission C. Clinical D. Sequelae E. Treatment
- Hepatitis D Virus (Defective dependent)
A. Virus type - enveloped, circular (-) sense RNA deltavirus
B. Transmission - defective virus that requires HBV HBsAg (surface antigen) for infection; via IVDU, transfusion, or MSM
- anti-HDV in serum
C. Clinical
- co-infection of HBV and HDV - similar to HBV
- superinfection with HBV and then HDB –> worse prognosis; enhances severity of HBV with acceleration of chronic hepatitis –> cirrhosis –> hepatocellular carcinoma
D. Sequelae - N/A
E. Treatment - prevent in non-carriers with HBV vaccine (so HDV cannot be transmitted either)
[Hepatitis] 5. Hepatitis E Virus A. Virus type B. Transmission C. Clinical D. Sequelae E. Treatment
- Hepatitis E Virus (Enteric, Epidemic, Expectant)
A. Virus type - naked, circular RNA hepevirus
- naked –> acid-stable (not destroyed by the gut)
B. Transmission - fecal oral (like HAV)
- waterborne epidemics in developing countries
C. Clinical - short incubation period
- acute viral hepatitis - jaundice, nausea/vomiting, low-grade fever
D. Sequelae - no carrier state
- high mortality rate in pregnant women due to fulminant hepatitis (massive hepatic necrosis in absence of preexisting liver disease)
E. Treatment - self-limited
[Hepatitis]
Alcoholic liver disease
- Hepatic steatosis
A. Macrovesicular
B. Microvesicular - Alcoholic hepatitis
- Alcoholic cirrhosis
- Hepatic steatosis - can lead to cirrhosis
A. Macrovesicular - more common, big fat lipid droplets due to obesity (NAFL), diabetes, alcoholism
- more likely to be reversible
B. Microvesicular - small intracytoplasmic fat vacuoles –> foamy cytoplasm
- due to fatty liver of pregnancy, Reye’s syndrome, HCV - Alcoholic hepatitis - long-term consumption; swollen and necrotic hepatocytes with neutrophilic infiltration; Mallory bodies - intracytoplasmic eosinophilic inclusions (damaged keratin filaments)
- AST»ALT (2:1) - Alcoholic cirrhosis - irreversible
- shrunken liver with hobnail appearance
- sclerosis around central vein in zone 3
- chronic liver disease –> jaundice, hypoalbuminemia
[Hepatitis] 1. Budd-Chiari syndrome A. Cause B. Pathophys C. Clinical
- Budd-Chiari syndrome
A. Cause
i. pills and pregnancy - thrombophilic disorders, also Factor V Leiden
ii. platelets (essential thrombocytosis) and polycythemia vera - myeloproliferative disorders
iii. protein C deficiency and prothrombin mutations - hypercoagulable state
- associated with hepatocellular carcinoma
B. Pathophys - obstruction, congestion, necrosis –> hepatic veins are thrombosed or compressed
C. Clinical - congestive liver disease “Budd Chiari syndrome” –> sudden onset RUQ pain, ascites, and hepatomegaly +/- varices
- but no JVD (as in right heart failure)
- nutmeg liver (blood backing up) - can be seen in right heart failure or Budd-Chiari
[Hepatitis] 2. Reye's syndrome A. Cause B. Pathophys C. Clinical
- Reye syndrome
A. Cause - in children with viral infection (VZV, Influenza B) given aspirin
B. Pathophys - aspirin metabolites reversibly inhibit mitochondrial enzymes –> impairs oxidative phosphorylation and fatty acid beta oxidation in the liver
C. Clinical - rapidly progressive encephalopathy (confusion, seizures, hypoglycemia, vomiting) with hepatic dysfunction (hepatomegaly due to microvesicular fatty change
- can lead to coma and death
- only children with Kawasaki disease (most common childhood vasculitis) should be given aspirin
[Hepatitis] 3. Wilson Disease A. Cause B. Pathophys C. Clinical
Wilson disease
A. Cause - AR mutation ATP7B gene –> in copper-transporting ATPase in hepatocytes
B. Pathophys - inadequate excretion from liver into bile –> copper accumulates in liver, kidneys, brain, cornea, joints
- ↓ ceruloplasmin (primary copper-carrying protein in the blood), ↑ urinary copper
C. Clinical - presents in young adulthood, <40 yo
i. liver disease - acute liver failure, cirrhosis
ii. neurologic - parkinsonism (essential tremor)
iii. Kayser-Fleischer rings (deposits in cornea)
iv. renal - Fanconi syndrome (no reabsorption in PCT), hemolytic anemia
[Hepatitis]
4. Fulminant hepatic failure
- Fulminant hepatic failure
A. Cause - drugs/toxins (acetaminophen), Budd-Chiari, Wilson’s, microvesicular fat syndrome (e.g. Reye)
- hepatitis viruses (A-E) – most cases due to HBV
B. Pathophys - massive hepatic necrosis in absence of preexisting liver disease
- low AST and ALT bc no hepatocytes to dump out the preformed enzymes
- prolonged PT, increased bilirubin, shrinking liver
C. Clinical - confusion, disorientation, ascites, edema, jaundice
- high mortality
[Liver Tumors] Congenital 1. Embryology of bile ducts 2. Choledochal cysts 3. Biliary atresia 4. Caroli's disease
- Embryology - Bile ducts form from ductal plate
- Choledochal cysts (bile duct cyst)
A. Cause - congenital cystic dilatations of biliary tree
B. Clinical - baby (~6 months) presents with cholestasis (↑ bilirubin, ↑ALP, ↑ GGTP) and RUQ pain, fever, jaundice, palpable mass
- associated with cholangiocarcinoma (due to chronic inflammation) - Biliary atresia
A. Cause - fibroproliferative obliteration of the extrahepatic biliary system (bile ducts) –> then affects intrahepatic
- MCC of surgically correctible cholestasis and MCC of liver transplant in newborns
B. Clinical - presents from birth to 8 weeks –> newborn with persistent jaundice (scleral icterus, dark urine)
- usually isolated, can be associated with splenic malformation - Caroli’s disease - saccular dilatation of the intrahepatic bile ducts
- associated with ARPKD
[Liver Tumors] Benign lesions 1. Hepatic (cavernous) hemangioma 2. Focal nodular hyperplasia 3. Hepatic adenoma
- Cavernous hemangioma - discrete red nodules in liver (abnormal proliferation of blood vessels in a bed of fibrous connective tissue)
- most common benign incidental finding, usually in younger women
- solitary, asymptomatic, growth static
- biopsy contraindicated bc of risk of hemorrhage - Focal nodular hyperplasia - anomalous arterial structure in liver becomes hyperperfused –> hyperplasia of hepatic parenchyma containing biliary components and and subdivided into nodules by dense fibrous tissue
- asymptomatic, solitary, in women
- central stellate scar - Hepatic adenoma - uncommon benign epithelial tumor in otherwise normal liver; solitary, in right lobe
- typical presentation: young woman with h/o of OCP use
- risk factors: OCPs, anabolic steroids, pregnancy
- pathology: large, non-functional cells with loss of normal architecture (no bile ductules)
- clinical: incidental, but can rupture –> RUQ abdominal pain, hemorrhage + shock –> emergency!
- risk of malignancy - remove all
[Liver Tumors] Hepatic Cysts - infectious causes 1. Echinococcus granulosis 2. Entamoeba histolytica 3. Strep bovis 4. Klebsiella
Hepatic Cysts - most are incidental and benign, can be associated with ADPKD
- Echinococcus granulosus (sheep worm) - humans ingest eggs from dog feces; MCC worldwide
- solitary hydatid cyst with eggshell calcification
- rupture –> anaphylaxis and acute abdomen (sudden, severe abdominal pain) - Entamoeba histolytica (protozoa parasite)
- amoebic liver abscess with fever and dull RUQ pain, pus smells like anchovy
- plus there are flask-shaped ulcers in the colon, fecal-oral transmission - S. bovis (Gram + cocci) –> colon cancer –> pyogenic hepatic abscess
- fatal if untreated - Klebsiella (Gram - rod) - can cause liver abscesses as sole presenting clinical manifestation
- “currant jelly” sputum, urease positive, nosocomial pneumonia
3A’s - aspiration, alcoholics, abscesses
[Liver Tumors] Malignant lesions 1. Hepatocellular carcinoma A. Causes B. Spread C. Fibrolamellar type D. Clinical E. Metastatic disease
- Hepatocellular carcinoma - most common malignant tumor in adults; 3rd leading cause of cancer deaths worldwide; M>F
A. Causes
i. in areas with high chronic HBV infection, high carrier rates (due to vertical transmission)
ii. due to cirrhosis
- HCV
- alcohol
- metabolic diseases of liver –> hemochromatosis, alpha-1 antitrypsin deficiency, Wilson, NASH
iii. carcinogens - aflatoxin (aspergillus) - risk is peanuts
B. Spread
- spreads hematogenously (most carcinomas spread via lymphatics) and invades vessels
- can lead to Budd-Chiari syndrome (block hepatic vein)
C. Fibrolamellar type - genetic, in younger patients (<35yo), single hard “scirrhous” tumors, cells rich in mitochondria
D. Clinical - vague (malaise, fatigue, anorexia, fullness), jaundice, hepatomegaly (RUQ pain)
- ↑ alpha fetoprotein
E. Metastatic disease - most common tumor in liver is metastatic disease from another site –> multiple tumors
- in peritoneal cavity: colorectal, pancreas/stomach/ esophagus
- breast, lung, melanoma
[Liver Tumors] Malignant lesions 2. Hepatoblastoma 3. Cholangiocarcinoma A. Location B. Risk factors 4. Angiosarcoma
- Hepatoblastoma - most common childhood liver tumor
- associated with APC and beta catenin activity gene mutations
- tumor marker is alpha fetoprotein - Cholangiocarcinoma - malignant tumor of biliary tree, from bile duct cells
A. can be intrahepatic, perihilar (called “klatskin” tumor), distal
- painless jaundice (Courvoisier) ddx - pancreatic cancer, cholangiocarcinoma
B. Risk factors
- liver fluke infestation (opisthorchis, clonorchis, ascaris)
- primary sclerosing cholangitis
- chronic choledocholithiasis
- HBV, HCV
- NASH - Angiosarcoma - malignant tumor of endothelial origin
- associated with vinyl chloride (in PVC) and arsenic
[Cirrhosis] Cirrhosis 1. Symptoms 2. Lab findings 3. Varices
Cirrhosis - liver fibrosis
- Symptoms - general (nausea/vomiting, weakness, fatigue, anorexia)
- diarrhea, abdominal distension, vague RUQ pain
- pruritus - due to deposition of bile salts
- signs of GI bleed –> hematemesis (bleeding from esophageal varices), hematochezia (bleeding from rectal varices)
- confusion, sleep disturbance (mild hepatic encephalopathy)
- women - amenorrhea
- men - impotence, infertility - Lab findings - ↑ AST, ALT, ALP, GGT, bilirubin
A. Anemia - microcytic (blood loss), macrocytic (folate deficiency in alcoholics)
B. Pancytopenia due to hypersplenism (trapped in spleen) - especially low platelet count (thrombocytopenia)
C. Hyponatremic, hypokalemic alkalosis (due to RAAS)
D. Prolonged PT/INR (decrease in coagulation factors) –> 80% of liver has to be dead
E. Hypoalbuminemia (produced by hepatocytes) –> 80% of liver has to be dead - Varices - esp esophageal, due to portal hypertension
- prevent bleeding with non-selective beta blockers e.g. propanolol, nadolol
- treat acute hemorrhage with ADH/vasopressin (constricts mesenteric arteries) and octreotide (splanchnic vasoconstriction)
[Cirrhosis] Cirrhosis 3. Physical findings A. Vitals B. Dermatologic C. Fetor hepaticus D. Men
- Physical findings
A. Vitals - splanchnic arteriolar vasodilation –> hyperdynamic circulation –> ↑ resting HR and CO, ↓ SVR and BP
B. Dermatologic - jaundice - scleral icterus
- spider angiomata (telangiectasia)
C. fetor hepaticus - sweet pungent smell to breath due to ↑ dimethyl sulfide (indicates portal system shunting)
D. men - gynecomastia due to ↑SHBG (higher affinity for testosterone than estrogen), ↑ androstenedione synthesis (↑ aromatization to E1/E2), spironolactone, testicular atrophy (alcohol is direct toxin)
- altered sex hormone metabolism also causes palmar erythema
[Cirrhosis] Cirrhosis 3. Physical findings E. Ascites F. Caput medusae G. Hepatic encephalopathy
E. ascites - due to portal hypertension (also leads to varices) and plasma volume expansion –> decreased intravascular volume –> activates RAAS –> edema
- treat with Na+ restriction, spironolactone, paracentesis
- suspect spontaneous bacteria peritonitis if patient with cirrhotic ascites develops fever, increased PMN count
- portal HTN can also be caused by schistosoma
F. caput medusae - portal blood shunted to periumbilical veins –> umbilical vein –> abdominal wall veins
- DDx includes IVC obstruction, where veins are more lateral
G. hepatic encephalopathy - triggered by ↑ NH3 production (protein, GI bleeding, constipation) or ↓ clearance (renal failure, diuretics) –> confusion, memory loss, asterixis
- treat with lactulose (increased conversion to NH4+) and neomycin or rifaximin (kills bacteria)
[NOT ON STEP]
- Cruveilhier-Baumgarten murmur - epigastrium venous hum caused by collateral connections between portal system and remnant of umbilical vein
- Duputryen’s contracture - pinky and ring finger, due to tenseness of tendon
[Cirrhosis] Hemochromatosis 1. Cause 2. Pathogenesis 3. Clinical 4. Treatment
Hemochromatosis
- Cause - AR point mutation in HFE gene (C282Y in chromosome 6)
- can also be secondary to chronic transfusion therapy - Pathogenesis - abnormal iron sensing due to ↓ hepcidin (main iron regulator) –> ↑ ferroportin (export into blood) and ↑ intestinal absorption –> ↑ serum iron, ↑ ferritin (storage form), ↑ transferrin saturation (iron / TIBC) –> iron accumulates in liver, skin, heart, pituitary, joints, pancreas
- Clinical - presents after 40 yo
- triad: skin hyperpigmentation, bronze diabetes, cirrhosis
- dilated cardiomyopathy (reversible) –> mitral regurgitation (holosystolic murur at apex)
- hypogonadism –> fertility problems e.g. loss of libido, impotence, amenorrhea
- arthropathy (due to calcium pyrophosphate deposition)
- hepatomegaly –> cirrhosis –> hepatocellular carcinoma (cause of death) - Treatment
- hemosiderin on prussian blue stain
- phlebotomy, chelation with deferoxamine, deferasirox
*people with hemochromatosis at risk of infection with iron-eating bacteria: A) Listeria monocytogenes, B) Yersinia enterocolitica, C) Vibrio vulnificus
[Cirrhosis] Alpha antitrypsin deficiency 1. Cause 2. Pathogenesis 3. Clinical
Alpha antitrypsin deficiency
- Cause - ↓ apha antitrypsin; autosomal codominant disorder (PiMM normal, PiZZ is most common mutant)
- Pathogenesis -
- liver: misfolded gene product protein aggregates in hepatocyte ER
- lungs: ↓ alpha antitrypsin –> uninhibited elastase in alveoli –> ↓ elastic tissue - Clinical - liver + lung disease at a young age
- hepatic: fatigue, PAS (+) globules in liver –> cirrhosis
* Whipple disease uses PAS stain to visualize macrophages in the villi
- pulmonary: cough, dyspnea –> panacinar emphysema in lungs
[Cirrhosis]
End stage cirrhosis complications
1. Hepatorenal syndrome
2. Hepatopulmonary syndrome
- Hepatorenal syndrome - liver causes damage to kidneys
- poor blood flow to liver bc of fibrosis –> vasodilators released (prostaglandins and NO) –> dilation of splanchnic arterial beds –> worsens ascites and ↓ intravascular volume –> RAAS activated –> ↑ Ang II –> constricts BOTH efferent AND afferent arteriole –> ↓ GFR –> kidney failure
- treat with midodrine (alpha agonist) and octreotide - Hepatopulmonary syndrome
- PGs and NO also dilate pulmonary circulation –> create shunts –> V/Q mismatch (perfusion > ventilation) –> dyspnea, hypoxemia, and platypnea (SOB on standing, relieved by lying down; opposite of orthopnea)
