Pathophysiology: GI

Disorders of Swallowing & Reflux Disease .............................................................................................................................. 2

Gastric Acid Secretion & Peptic Ulcer Disease ........................................................................................................................ 7
Fat Absorption & Malabsorption .......................................................................................................................................... 13
Mechanisms of Diarrhea ....................................................................................................................................................... 19
Celiac Disease ........................................................................................................................................................................ 25
Inflammatory Bowel Disease ................................................................................................................................................ 29
Gastrointestinal Motility ....................................................................................................................................................... 34
Functional GI Disorders / Irritable Bowel Syndrome (IBS) .................................................................................................... 39
Gallbladder ............................................................................................................................................................................ 42
Acute & Chronic Pancreatitis ................................................................................................................................................ 47
Pancreatic Cancer ................................................................................................................................................................. 53
Pediatric GI ............................................................................................................................................................................ 56
Liver Tests ............................................................................................................................................................................. 58
Hepatitis: Basics .................................................................................................................................................................... 63
Viral Hepatitis........................................................................................................................................................................ 66
Inherited and Metabolic Liver Disease ................................................................................................................................. 71
Cholestatic Liver Disease....................................................................................................................................................... 76
Autoimmune Hepatitis, Alcoholic Liver Dz, and Non-Alcoholic Fatty Liver .......................................................................... 81
Portal Hypertension & Cirrhosis ........................................................................................................................................... 86
Liver Transplant..................................................................................................................................................................... 93
Liver Review .......................................................................................................................................................................... 96

1
 Disorders of Swallowing & Reflux Disease
Introduction
 Humans swallow 600x / day; without apparent effort / forethought normally
 Swallowing involved in nutrition, oral hygiene, airway protection, social interaction

Physiology of Swallowing
Between swallows: nasal cavity / larynx in communication with pharynx (breathing)
 Upper esophageal sphincter (UES) tonically closed
o Esophagus sealed off; don’t fill with air on insp.
o Barrier to regurgitation
 Upper esophagus, pharyngeal constrictors = striated mm.
 Lower esophagus = smooth mm.

Deglutition: initiation of swallowing

1. Lips seal oral cavity
2. Blade of tongue moves contents up, back, through palatine arch
3. Nasopharynx closes (soft palate ↑, sup pharyngeal constrictors contract)
4. Airway closed (epiglottis deflects, larynx ↑, vocal cords approximate)
5. UES relaxes

Progressive peristaltic wave

 Starts in upper pharynx, moves down length of esophagus
 Contractile wave  pressure wave
o forces bolus down
o enough pressure to swallow standing on head
 Constriction below, dilation above bolus

Entry to stomach: LES relaxes so bolus can pass into stomach

Sphincters: Areas of higher pressure, relax in coordination

 Prevent regurgitation (LES)
 Regulate flow of air (UES - direct air into larynx)

Flow is determined by pressure gradient

𝚫𝐏 pressure gradient viscosity
𝑭𝒍𝒐𝒘 = = 𝑹𝒆𝒔𝒊𝒔𝒕𝒂𝒏𝒄𝒆 ≈
𝐑 resistance radius𝟒

Patient’s sensation of where problem is isn’t that specific

 Symptoms are always at or below where patient perceives it
 Food piles up above site of obstruction; spasm above level of problem, referred sx, etc

Mechanisms of Dysphagia
Structural disorders Motor disorders
 Paresis
 Luminal stenosis
 Sphincteric dysfunction
 Diverticular formation
 Spastic disorders

2
 Structural Disorders
Luminal Stenosis
Stenosis ≈ stricture ≈ narrowing
 Something narrowing the channel
Examples of stenotic lesions
 Inflammatory strictures – “ benign”
 Malignant strictures – often abrupt narrowing
 Schatzki’s rings – ≈ 10% middle aged individuals

Presentation:
 Pure solid food dysphasia
 Bolus-size related (sx only when can’t pass)
 Better after vomiting (undigested food) Luminal
Likelihood of symptoms
 ↓ Sx: avoiding difficult-to-chew foods, cutting/chewing diameter
well, washing down with lots of H2O < 12 mm everyone is symptomatic
 ↑ Sx: distracted & not able to control behavior 10-20 mm symptoms vary (severity / presence)
(eating out, booze, rushing, etc.) > 20 mm no one has symptoms
Sx only when lumen ≈ 50% compromised
Evaluation:
Barium swallow: First test to order on pt with swallowing disorder
 swallow radiodense material while radiologist takes X-ray snapshots
 Pharynx: whole event takes 1s; often use video recording for pharynx (esophagus slower, can do series)
 Info: where’s the problem; likely to be benign / malignant, motility disorders?

Endoscopy: Complementary to barium swallow (do 2nd – Dx, get tissue Bx, for treatment!)
 Left: secondary to chronic reflux and scarring
 Middle: tumor (looks like tissue); do Bx
 Right: Schatzki’s ring (shelf of tissue)

Variance between these too; depend on behavior / condition

Treatment: Esophageal dilators or surgical resection

 Dilation: lots of different ways (balloon, etc) – stretch the channel
 Resection: esp. if malignant
 Treat underlying problem: strictures will narrow again!
o E.g. reflux strictures: ↑ time to recurrence with PPI therapy

Diverticula
outpouchings coming out from esophagus
 NB: diverticulosis occurs in colon: totally different

Zenker’s diverticulum:
 1/10k-1/100k; mostly older people (more common than esophageal diverticula)
 occur in hypopharynx just above UES

Esophageal diverticulum: most often distal esophagus

Pulsion diverticulum: diverticulum that results in ↑ intraluminal pressure

 “wear & tear” phenomenon

3
Presentation:
 Dysphagia for solids & liquids with regurgitation of undigested food (lay down  spill out)
o Regurgitation often hours after ingestion
 Zenker’s – risk for aspiration – coughing during meals, at night, etc.
 Esophageal diverticula: usually relatively asymptomatic (down lower, not spilling out)

Pathogenesis: see two pathologies in both pictures

 Most result from downstream obstruction  keep pressing (on area of weakness?) above (“wear & tear”) 
o Bulge  pressure ↑ still  bulge grows  diverticulum!
 Also see: strictures below diverticula

Treatment
 Remove obstruction (will recur even with resection if obstruction not fixed)
 Surgical resection (diverticulectomy) usually needed too if severely symptomatic

Paresis
Neurologic dysphagia:
 Neurologic conditions (strokes, ALS, head/neck trauma, brain surgery)
 Neuromuscular disorders (MG)
 Myopathic conditions (polymyositis, MD)

Presentation:
 Dysphagia for liquids & solids
 Associated with airway penetration & regurgitation
o Penetration: material enters larynx but doesn’t get below vocal cords
o Aspiration: material gets below vocal cords into trachea
 Swallowing: usually protects respiratory system; in paresis, not clearing out material!

Normally during swallowing: many systems working to protect breathing (see above)
 Inhibition of respiration, elevation of larynx, approximation of vocal cords, inversion of epiglottis, pharyngeal clearance

Note that this is a really important mechanism: lots of redundancy

 After epiglottectomy – pts don’t always aspirate!

Sclerodermatous esophagus:
severe weakness of esophagus is the problem
(vs. neurogenic where nerves are problem)
 Affects smooth muscle of esophagus
o Pharynx, upper 1/3 esophagus work fine
(striated mm)
o Lower esophagus looks flaccid
(no contraction: smooth muscle)
 LES weak too (poor clearance + fulminant reflux)

Diagnostic approach
1. Barium studies (most helpful) – barium radiography w/ spot films
a. videopharyngoesophagram if pharynx is problem (pharynx too fast for spot films)
2. Manometry (assess contractile strength)

Treatment: drugs aren’t too effective for striated muscle

 Treat GERD if LES weak

4
Sphincteric Dysfunction (Achalasia = prototype)
 If the sphincter doesn’t relax, then it behaves like a stricture
 “ Functional obstruction” (not anatomical)
 Rest of this applies to achalasia (other forms possible too)

Pathogenesis: selective loss of inhibitory neurostimulation to myenteric plexus ganglion causes…

 Paresis (esophagus affected)
 Sphincteric dysfunction (↑ LES pressure, LES can’t relax)

Presentation:
 Dysphagia for solids & liquids
 Delayed regurgitation of recognizable food eaten hours before,
especially if they lie down is CLASSIC

Evaluation
 Barium swallow
o narrowing, column of barium
o air-fluid level, solid food retained
 Endoscopy:
o normal folds, just narrows dramatically,
o need to rule out stricture
 Manometry:
o aperistalsis of esophageal body
o failure of LES relaxation

Treatment: directed at weakening / tearing the muscle

 large diameter balloon dilatation (common – tear / rupture muscle) – see pic above
 surgical myotomy (also common – cut away some muscle)
 Smooth muscle relaxants (Ca channel blockers, etc – experimental, some success)
 Intrasphincteric botulinum toxin (safe, but only lasts ≈ 1 yr)
o Ach, substance P are excitatory (contraction)
o VIP, NO are inhibitory (relaxation)
o in achalasia: problems with inhibition
o Botox: ↓ contraction (degrades SNAP-25, ↓ vesicle release), restores balance

Cornflake study: way to measure the degree of esophageal retention

 Follow transit of food with radioactive labeling (e.g. cornflakes)
 Less radiation than barium esophagram – good for assessing response to Tx

Esophageal Spasm
 Diffuse esophageal spasm (DES): one extreme of esophageal dysmotility
 Tertiary contraction: individual abnormally coordinated contraction (also in normal, asx people)

Presentation:
 Dysphagia for liquids & solids
 Regurgitation immediately after swollowing
 ± chest pain (squeezing phenomenon), often sharp, radiates to back (can mimic angina too!)

Pathogenesis: unclear!
 Similar sx seen in pts with abnormally high but peristaltic contractions (nutcracker esophagus)
 May be related to visceral hyperalgesia (abnormally ↑ levels of sensory perception)

5
Treatment of DES:
If idiopathic:
 Nitroglycerine / Ca channel blockers
o to relieve idiopathic spasm / chest pain
o Side effects! (smooth muscle relaxants, ↓ BP)
 Tricyclic antidepressants may help with visceral hyperalgesia
 Surgery (long myotomy: use sparingly – cut esophageal smooth muscle down its length)
If secondary: usually GERD (treat GERD!)

Gastroesophageal Reflux Disease (GERD)

Reflux itself: occurs in majority of people on daily basis
GERD (disease): causes symptoms on recurring basis (how much, how frequently, how long does it stay in esophagus)

Presentation:
 BURNING PAIN IN CHEST & SOUR MATERIAL IN MOUTH are classic, esp at night
 Chest pain, dysphagia, sore throat, hoarseness, cough, asthma too

Pathogenesis:
 Weak / deficient anti-reflux barrier
o Anatomy of esophago-gastric junction (barium study / endoscopy)
o Strength / function of LES (manometry)
 ↓ saliva (Sjogren’s) – can’t neutralize acid
 Stomach emptying problems, frequent transient relaxations, impaired
esophageal clearance, impaired gastric emptying, etc. also involved

↑ anatomic risk: (↑↑ if both!)

 Hiatal hernia (EG junction displaced above diaphragm)
 Low LES resting pressure

Evaluation:
 Continuous reflux monitoring (best test available)
o pH or esophageal impedance + pH
 “PPI test”: give PPI to see if symptoms relieved (empiric trial with high dose PPI)
 Barium esophagram; endoscopy: not too sensitive
Erosive esophagitis &
stricture
Continuous reflux monitoring: pH monitoring
 Cath down through nose, measure pH and/or impedance
o Impedence: can detect non-acidic reflux!
 Normal physiologic reflux occurs during day, after eating, rapidly cleared
 Pathological reflux:
o more prolonged periods, at night
o esophagus stays acidic (not clearing)

Treatment:
 Dietary / life style modification
o Coffee, tea, chocolate, fatty foods, alcohol, smoking, smaller meals
o Avoid lying down after eating, elevating the head of the bed.
 Acid suppression (H2RAs, PPIs)
 Prokinetics (in theory – improve stomach emptying): Erythromycin, , metoclopramide, , domperidone, tegaserod
 Surgery: fundoplication (wrap lower end of esophagus with stomach, produces artificial barrier)
6
 Gastric Acid Secretion & Peptic Ulcer Disease
Normal Anatomy & Physiology of the Stomach
4 regions
 Cardia
 Fundus
 Body
 Antrum

Rugae = folds
 contain gastric pits  open into 4-5
gastric glands

Greater, lesser curvatures

Insets: endoscopy

Role of Stomach in Digestion

• Holds ingested food
• Degrades food (chemically /physically)
• Delivers chyme to the small intestine
• Enzymatically digests proteins (pepsin)
• Secretes intrinsic factor required for absorption of vitamin B12

Cell Types in the Stomach

By Location
Cardia Fundus and Body (oxyntic mucosa) Antrum and Pylorus
 Parietal cells
 Gastrin cells (G cells)
 Chief cells
 Mucous cells  Mucous cells
 Mucous neck cells
 Endocrine cells  Endocrine cells
 Endocrine cells
 D cells
 Enterochromaffin-like cells (ECL)

Note that ECLs secrete lots of stuff: Gastrin, Histamine, Endorphins, Serotonin, cholecystokinin (CCK), somatostatin

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Microscopic anatomy of stomach

Stomach lining / protection

 Exposed to harsh conditions: HCl (pH 2), pepsin, but pH ≈ 7 at cell surface
 Mucosal protection (see above right)
o Bicarbonate-rich mucous is secreted and coats the stomach wall
o Epithelial cells are joined by tight junctions
o Gastric glands have cells impervious to HCl
o Damaged epithelial cells are quickly replaced
 Prostaglandins are main mediators of protection
o ↑ mucosal blood flow, mucous secretion, bicarb secretion, restitution
o If mucosal prostaglandin synthesis impaired (NSAIDs), protective
mechanisms are impaired!
o Pathogenesis of NSAIDs: both direct toxicity & inhibition of prostaglandins

Acid Secretion

Parietal cells in lower / middle oxyntic glands

 Basal state: lots of tubulovesicles in cytoplasm
 Stimulation  tubulovesicles fuse  form secretory canalicular complex

Canuliculi: long microvilli with H/K ATPase enzymes on apical cell membrane
 Require lots of energy (lots of mito)
 H+ from carbonic anhydrase (CO2 + H 2O  H2CO3  H+ + HCO3-)
 Cl enters canuliculi via Cl channels (net: make HCl)
 K channels allow K to flow back out of cells (for more exchange for H)
o Basal state: not many K channels open
o Secretory state: K channels open, K returned to cell, HCl secreted

Net result: 100-160 mmol HCl secretd (pH ≈ 1) – 2.5L/day

 Also secrete: water, Na, HCO3, mucus

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Regulation of Gastric Acid Secretion

Molecule Released from Binds to Effects

Stimulation of Gastric Acid Secretion

ECL cells (oxyntic glands) H2 receptors (parietal cells) ↑ acid secretion

Histamine
Mast cells (lamina propria) H3 receptors (D-cells) ↓ somatostatin release (↑ acid secretion)
M3 receptors (parietal cells) ↑ acid secretion
Vagal nerve endings
Acetylcholine ECL cells ↑ histamine release (↑ acid)
(postganglionic parasymps)
D-cells ↓ somatostatin release (↑ acid secretion)
Parietal cells Proliferate, release acid
Gastrin G-cells (gastric antrum)*
ECL cells ↑ histamine release

Inhibition of Gastric Acid Secretion

Somatostatin D-cells (gastric antrum)** Parietal cells ↓ acid production / secretion
* Gastrin secreted in response to gastrin-releasing peptide (GRP), presence of food (esp AA) in gastric lumen
** Somatostatin secreted in response to ↓ pH in gastric lumen (protective! Shut off acid!)

Molecular mechanisms

Parietal cell stimulation

1. Histamine  H2 receptor  Gs protein 
↑ adenylate cyclase  ↑ cAMP
2. Ach  M3 receptor  ↑ Ca release

Both cAMP / Ca ions activate protein kinases

 Shape transformation of parietal cell
 Release of gastric acid

Vagal nerve:
 Direct Ach action and
 ↑ GRP production (↑ gastrin release)

Gastrin:
 Stimulates parietal cell directly
 Gastrin receptors on ECL  ↑ histamine  activates parietal cell indirectly

Parietal cell inhibition

 Somatostatin  Gi protein  ↓ adenylate cyclase  ↓ cAMP

o Prostaglandins: similar mechanism to inhibit parietal cells
o Also: somatostatin  inhibits ECL cells  ↓ histamine release

 Vasoactive intestinal peptide (VIP), secretin also inhibit parietal cell function

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 Physiology of Gastric Acid Secretion
Basal (fasting) acid secretion
 Gastric acid secreted continuously under fasting conditions in diurnal pattern
o Lowest secretion in morning, highest in evening
o ↑ vagal tone  basal hypersecretion in some people; also temporary hypersecretion in stress
o Women secrete less acid in basal state than men!

Physiologic acid secretion (3 phases)

Phase Timing Mediated by Acid secreted in response to Inhibition from…
 Loss of appetite
Prior to food
Cephalic Vagus nerve Sight, smell, taste or thought of food  Depression
entry
 ↓ parasymp stimulation
 Distention of the stomach by food
(stretch receptors)
Once food  pH < 2
Neural reflex  Direct action of food on gastrin release
Gastric enters  Emtional upset
pathways  Direct stimulation of the G cell
stomach (overrides parasymps)
(by amino acids and digested food)
 Chemoreceptors (peptides, caffeine, ↑ pH)
 Distention of duodenum
As partially
 Digested proteins in the small intestine  Presence of fatty, acidic, or
digested Release of
Intestinal*  Direct stimulation of parietal cells hypertonic chyme
food enters gastrin
(by absorbed amino acids)  Duodenal irritants
duodenum

* entry of gastric contents into duodenum also leads to inhibition of gastric acid secretion (via secretin release)

Gastric Contractile Activity

 Peristaltic waves (3/min) in stomach
 Basal electrical rhythm: from interstitial cells of Cajal (“gastric pacemakers”)
 Most vigorous mixing / peristalsis: near pylorus
 Chyme: with each contraction, either
o delivered through pylorus in small amounts to duodenum or
o forced back into body for further mixing

Gastric Emptying
Regulated by: neural enterogastric reflex and hormonal (enterogastrone) mechanisms
 Inhibits gastric secretion / duodenal filling

CHO-rich chyme: moves quickly to duodenum

Fat-rich chyme: digests slowly (food stays in stomach longer)

Peptic Ulcer Disease

Risk factors:
• H. pylori gastritis • NSAIDS • Family history
• Aspirin • Smoking • Acid hypersecretion (Zollinger-Ellison syndrome)

Diagnosis: clinical; lots of other stuff is similar

 can use upper GI endoscopy / barium studies too

10
Pathogenesis of PUD:
 Causative: H. pylori, acid, NSAIDs / ASA, Pepsin
 Protective: prostaglandins, mucous production, bicarb, mucosal blood flow

Complications of PUD: Bleeding, perforation, obstruction

Treatment of PUD:
 If bleeding: upper endoscopy (treat bleeding), give IV PPI
 If perforated or endoscopy doesn’t stop bleeding  surgery
 If H. pylori present: treat with abx + PPI
o Clarithromycin + amoxicillin + PPI
o Metronidazole + tetracycline + bismuth + PPI
 Avoid: NSAIDs, aspirin, smoking
 Treat with PPI / H2RA

Pathogenesis of PUD: NSAIDs

Double effect; big cause of PUD (esp. gastric ulcers)
 Local caustic effect (local cell toxicity)
 ↓ prostaglandin synthesis  ↓ cytoprotection, mucous secretion
o Inhibits arachadonic acid pathway (inhibit COX-1  ↓
prostaglandin synthesis  ↓ production)
COX-1: constitutive expression, involved in tissue homeostasis
COX-2: inducible expression, involved in inflammatory response

↑ Risk for adverse GI events with NSAIDs:

• Prior GI bleeding • Steroid use • Older age
• Anticoagulant use • Higher dose

Pathogenesis of PUD: H. pylori

 Extremely common (2B worldwide, 30% in developed countries); have detectable IgG
 Fecal oral transmission  colonizes gastric mucin (NOT invasive into mucosa)
 ↑ gastric acid production
o Releases cytotoxins, chemotatic factors  ↑ PMNs  chronic inflammation
o ↓ antral D cells  ↓ somatostatin  ↑ acid
o Also makes histamine analog (H3 agonist  ↓ somatostatin release)
o Makes urease (helps protect from HCl)

Complications of H. pylori (most are asymptomatic!)

 Gastritis  Gastric lymphoma (MALT lymphoma)
 Peptic ulcer disease (gastric / duodenal ulcers)  Gastric acenocarcinoma

Diagnosis of H. pylori
 Histology  Fecal H. pylori antigen test  Serology – IgG
 Rapid urease test  C13 or C14 urea breath test o Can’t distinguish between
 Culture current and past infection

Eradicate h. pylori in pt = cure H. pylori gastritis / PUD

11
Duodenal ulcer
 Deep, non-healing defect in mucosa of duodenum
 Most commonly in duodenal bulb
 90% caused by H. pylori (↑ acid in stomach  into duodenum)

Symptoms: epigastric pain, indigestion, nausea

 Worse with fasting (2-3h post meals)
 May wake patient at night

Findings: ulceration, gastric metaplasia (leads to peptic duodenitis), gastrin mucin cell metaplasia
Treatment: H. pylori eradication, gastric acid suppression

Gastric ulcer
 Most in antrum
 70-80% H. pylori related
 NSAIDs (↓ prostaglandins) can be involved too

Symptoms: epigastric pain, nausea, ± wt loss (afraid to eat)

 Pain 15-30m after eating (vs duodenal – 2-3h)
 nocturnal pain / pain when fasting rare

Treatment: H. pylori eradication, gastric acid suppression

 NSAIDs are bad

Zollinger-Ellinger Syndrome / Gastrinoma

ZE syndrome: disorder of acid hypersecretion
 Gastrinoma: ↑↑ gastrin  ↑↑ acid Classic triad of ZE Syndrome
1. Basal gastric acid hypersecretion
Diagnosis of ZE 2. Postbulbar duodenal ulcer
 serum gastrin >1000 pg/ml (150 nL) 3. Pancreatic gastrinoma (islet cell tumor)
 Basal acid output measurements (↑)
 Secretin stimulation testing: measure serum gastrin before / after
o Normally: no ↑ in serum gastrin after IV secretin
o ZE: ↑↑ serum gastrin

Clinical Presentation
 Diarrhea in 1/3 (damage prox. intestinal mucosa, inactivate pancreatic enzymes: hyperacidity, ↑ fluid load - ↑ secretions)

May be related to Multiple Endocrine Neoplasia type 1 (MEN1) – 1/3 ZE pts

 Characterized by hormone secreting tumors: check parathyroid, pituitary
o Hyperparathyroidism (80%), islet cell tumors (50-60%), pituitary tumors (40-50%)
o In MEN1, gastrinomas are malignant and multiple

Treatment of ZE: PPI in high doses, most die of metastatic gastrinoma (50% at 10 yrs)

Stress ulcers
 Common in ICU, typically single / multiple erosions/ulcers in fundus / body of stomach
Pathogenesis: related to ↓ mucosal blood flow (sepsis, burns, hypotension)
 ↓ mucosal blood flow  ↓ PG synthesis  ↓ mucous, bicarb secretion
Prevention: prophylaxis with H2RA / PPI

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 Fat Absorption & Malabsorption
Introduction / Definitions
 Absorption: passage of foodstuffs into the body; essential function of the GI tract
 Malabsorption: defects in this process.
o Generalized (e.g. celiac dz) – malabsorb CHO, proteins, fats
o Specific (e.g. pernicious anemia) – only malabsorb B12, for instance
o Steatorrhea: symptom of malabsorption of fat (Odorous, greasy, hard-to-flush stools)
 Fat: easy to detect in feces; colonic bacteria metabolize only a small fraction

Triglycerides: 40% of diet; 9 kcal/gm (concentrated calories); Fat is mostly triglyceride

 If you malabsorb fat, you also malabsorb fat-soluble vitamins (ADEK)

Overview of Fat Absorption

Purpose: ↑ lipid / H2O interface (where lipolysis happens)

Fat emulsified by gastric mixing
1. Emulsification  contractions against closed pylorus  jet spurts backwards
 Shearing forces emulsify; emulsion stabilized by other dietary constituents
Small intestine: peristalsis  more agitation, then stabilized by bile
Released from proximal small intestine (fatty acids & certain AA stimulate)
Acts on gallbladder & pancreas
2. Cholcystokinin-
Gallbladder: discharge contents into duodenum (contract GB, relax sphincter of Oddi)
pancreozymin
Pancreas: discharge zymogen granules into acini; ↑ synth of new enzymes
(CCK-PZ)
 Proenzymes activated by enterokinase on surface of small bowel mucosal cells
 Active enzymes: hydrolyze dietary fat  more FA  ↑ CCK-PZ release (self-perpetuating)
Pancreatic lipase: hydrolyzes dietary triglyceride
 Secreted in active form (not proenzyme)
 Absorbs to oil-water interface
3. Pancreatic  Partial hydrolysis
lipolysis (1-ester bonds only; makes 2-MG and 2 FAs)
 Works rapidly; pH optima in presence of bile acids 6-7 (duodenal pH!)
 10x excess (need to lose 90% pancreatic fxn to have steatorrhea)

13
 Colipase: secreted 1:1 with pancreatic lipase; activated by trypsin
 ↑ activity of pancreatic lipase 40-50%:
 associates with bile salts on micelle surface; “docking station” for pancreatic lipase

Other enzymes in pancreatic juice

 nonspecific esterase (hydrolyzes cholesterol esters / ester lipids)
 phospholipase (hydrolyzes lecithin, releasing 1 FA & soluble 1-lysolecithin)

Bile acid micelles:

 Lipolytic products (FAs, MG, etc):
insoluble in water; would stay in lipid droplets
 Soluble in bile acid micelles (↑1000x with ↑ *bile acid+)
note that TGs are NEVER soluble, no matter what [bile acid]

Bile acids (cycle = enterohepatic circulation)

4. Micelle  Synthesized in liver (from cholesterol, conjugated with taurine / glycine)
formation  Stored in gall bladder  secreted (CCK-PZ)
 Solubilize lypolitic products (which are absorbed in jejunum)
 Bile acids actively absorbed in ileum, returned to liver via portal circulation  re-excreted
EFFICIENT: Less than 5% bile acid lost into colon / day; bile salt pool makes 2 loops / meal

For micelles to form: need [bile acid] > critical micellar concentration (CMC, ≈ 2mM)
Cholesterol, vitamins ADEK need micellar solubilization but not lipolysis
Medium chain TGs need lipolysis but not micellar solubilization (lipolytic products soluble)

Micellar lipid taken up into enterocyte by carrier transport

5. Mucosal uptake
 favorable gradient: from fatty acid binding protein

Inside enterocyte: FA go to ER for TG resynthesis

6. TG resynthesis /
 Primary pathway: monoglyceride acylation (2-MG + 2 FA-CoA  TG + 2 CoA)
reesterification
 Fasting: secondary pathway (acylation of α-glycerophosphate, phosphatidic acid  TG / phospholipid)

Purpose: make newly resynthesized TGs aqueous-soluble

 Lipid droplets given lipoprotein coat
 Extruded through lateral, basal cell membrane
7. Chylomicron
formation

8. Lymphatic Chylomicrons are too big to go to capillaries  go to lacteals (small lymphatics)

transport  Lacteals  lymphatics  thoracic duct back to general circulation

14
 Defects in Fat Absorption
Stage Possible defects
Motility affected (think surgery) lose gastric churning or pyloric barrier
1. Emulsification  vagotomy, gastric resection, gastric motility dysfunction, gastro-jejunostomy
 Diabetes: stomach fails to contract like it should
2. CCK-PZ Fat doesn’t get to the duodenum (so ↓ stimulus for release)
release  Gastrojejunostomy: bypasses duodenum  ↓ secretin, CCK-PZ release

Exocrine pancreatic insufficiency

 Alcoholics (large quantities)  destroy exocrine pancreas (± endocrine too – DM)
3. Pancreatic  Chronic pancreatitis, CF, pancreatic duct obstruction, lipase inhibition, congenital deficiency too
lipolysis Low pH in duodenum (ZE syndrome) can inactivate pancreatic lipase
Note: Need pancreatic lipase < 10% of normal to have steatorrhea
 (lose 85% of function, might be fine; 90%  severe steatorrhea!)

Enterohepatic circulation affected

 ↓ bile acid secretion (liver dz, bile duct obstruction)
4. Micelle
 Interrupted enterohepatic circulation: surgical resection of terminal ileum (don’t resorb)
formation
 Precipitation of bile salts in intestinal lumen (↓pH, drugs – neomycin, cholestyramine)
 Deconjugation of bile acid (overgrowth of bacteria)

5. Mucosal Epithelial cell damage:

uptake  celiac disease, tropical sprue, intestinal infections, small intestine resections

Failure to synthesize protein coat (Abetaliproteinemia)

6. Chylomicron
 make TGs but get hung up in enterocyte (can’t get out); abnormal RBC membranes too
formation
 Anderson’s disease too (unknown etiology)
Interfere with transport of lipid from intestine
7. Lymphatic  Tumors / infections / trauma involving mesenteric / thoracic lymphatics
transport  Whipple’s disease: interfere with flow of lymph through villi, intestinal lymphatics
 Intestinal lymphangectasis: developmental hypoplasia of lymphatics

Clinical Evaluation of Malabsorption (in general)

When to suspect malabsorption?

Symptom Substance malabsorbed Symptom Substance malabsorbed
Weight loss Calories Edema Protein
Steatorrhea Fat Tetany Ca, Mg
Diarrhea OH-Fatty acids Osteoporosis Ca, protein
-
Bloating H2O, H2, CO2 (methane) Milk intolerance Lactose
Anemia Fe, B12, Folate Bleeding / bruising Vitamin K

Findings that suggest net malabsorption

• Hypoalbuminemia • Prolonged prothrombin time
• Hypocalcemia • Reduced carotene levels

15
 Evaluating Fat Malabsorption
Key question: why is fat being malabsorbed? Where’s the problem?
Intestine
Stomach Removal
Intraluminal Mucosal
2. CCK-PZ release
5. Mucosal uptake 7. Lymphatic system / to
1. Emulsification 3. Lipolysis (MGs/FAs)
6. Chylomicron formation thoracic duct
4. Micelle formation (biliary tract)

Categorization of Tests
Disordered phase Tests
Intraluminal  Lundh test meal / bentiromide test
 D-xylose absorption test  Small bowel series
Mucosal
 Lactose tolerance test  Mucosal biopsy
 Glucose hydrogen breath test  Schilling test
Intraluminal and/or mucosal
 Small bowel culture
Removal  Mucosal biopsy  Mesenteric lymphangiography
Specific Tests for Fat Malabsorption
Initial tests: is there net fat malabsorption?
Quick but not as precise
 Stain stool with “Sudan”
Stool Sudan staining  fat droplets show up yellow
 4+ fat droplets / HPF  steatorrhea

Better test, harder to do

72-hr fecal  Pt: ingest 100g fat / day; poop in paint can, keep in fridge, analyze for fat
fat collection Normal: Should absorb 95% of fat (see ≤ 5g/day in stool)
Abnormal: see > 5g/day (malabsorption)

Later tests: evaluate mucosa

Small intestine mucosa is good first step: easiest to evaluate!
Simple sugar: normally absorbed by intestine; doesn’t need intraluminal digestion
 Eat  absorbed (intestine)  liver  urine elimination (w/in 5 hrs)
 Measure: D-xylose in urine
D-Xylose
If intestinal mucosa abnormal:
 ↓ d-xylose absorption  ↓ d-xylose in urine
rd
Other causes of ↓ urine excretion of d-xylose: renal dysfunction, bacterial overgrowth, 3 space fluid (ascites)

Small bowel series: use barium contrast

 (outline mucosa, look for mucosal abnormality)
Small bowel
series  Floculation: dilution of barium (small bowel retaining fluid)
 Can see stricture, dilitation too
Capsule  picture: left is abnormal; flocculation/stricture present
endoscopy
Capsule endoscopy: swallow small pill
 send pictures to transciever on pt’s belt

16
 Endoscopy (peroral)  use pinch biopsy forceps to get small bowel mucosa
 Allows for pathologic evaluation of mucosal disease

Jejunal biopsy Findings can be:

 Diagnostic (Whipple’s dz, AB lipoproteinemia, intestinal lymphangectasia, amyloidosis, giardiasis, coccidiosis)
 Characteristic (Celiac dz, tropical sprue, eosinophilic gastroenteritis, Crohn’s)
 Non-specific / normal (pancreatic insufficiency, bile salt deficiency, bacterial overgrowth)

Examples of jejunal biopsy

 Villi absent
Celiac disease  Crypts elongated (trying to ↑ SA)
 Plasma cells, lymphocytes in lamina propria

 Villi abnormal but now present

Post-treatment  Crypts are gone
 Plasma cells / lymphocytes now absent

Later tests: evaluate intraluminal problems

Test for pancreatic insufficiency

 Chymotripsin (pancreas) cleaves PABA from
bentiromide

Bentiromide Give 500mg bentiromide, measure 6 hr urine sample

test  Normal pt (pancreas OK): free PABA released in duodenum 
absorbed  conjugated in liver  excreted in urine
 Severe pancreatic insufficiency (< 5% normal fxn)
↓ PABA excretion

Test for bacterial overgrowth of small intestine

 Ingest glucose, breath collected / analyzed
Glucose
Hydrogen If bacterial overgrowth:
Breath Test
 H2 produced by bacteria
 Detected in exhaled breath!

17
Vitamin B12 and the Schiling Test

Vitamin B12: normally (need IF & terminal ileum receptors to absorb B12!)
 Ingested, combines with R factor in stomach
 Duodenum: R factor hydrolyzed from B12 by pancreatic lipase
o Intrinsic factor then binds it (IF from parietal cells of stomach)
 B12-IF  taken up in ileum (specific receptors)

Schilling test:
1. Give 1000 g IM of nonradioactive B12 (both treat patient & saturate body stores so radiolabeled B12  urine!)
2. Give oral dose of radioactive B12
3. Collect 24 hr urine (normally > 7% will be excreted in urine)
a. If not absorbing: excreted in colon!

Parts of the test: distinguish why B12 absorption is messed up

Add __ with radioactive B12 Pernicous Anemia Ileal disease / resection
Part I Nothing (no IF) Abnormal Abnormal
Part II Intrinsic factor Normal (corrects!) Abnormal
Part III Broad spectrum abx Abnormal
Part IV Pancreatic enzymes Abnormal

 Note: if ileum missing, then can’t correct B12 absorption (pernicious anemia = no IF; add IF and it corrects!)
 Ilectomy – takes years post surgery to develop (big B12 stores)

Algorithm for Evaluation of Fat Absorption

18
 Mechanisms of Diarrhea
Epidemiology
Developing countries: Acute Diarrhea
 Mostly kids < 5yo: 3.2 episodes / yr, total burden not decreasing (population ↑)
 Mortality: 20% mortality of kids < 5yo (1.9x106 deaths / yr), 0.15% CFR (↓ with ORS introduction)

In USA
 2/3 of people get acute diarrhea in a year; 1/3 of those food related, 2/3 probably viral, etc.
 Chronic diarrhea: 3M yr (40% are irritable bowel syndrome – idiopathic), huge burden in cost
 Killer in USA too (esp. elder population; death rates ↓ with time in kids)
o Hospitalized old people: 3% with diarrhea die!

Normal GI & Water

Daily intestinal water balance
Intake Output
 Oral intake: ≈ 2L / day  Absorb 98% of water in intestine
 Organ secretion: ≈ 7L / day (majority!)  Only ≤ 200 mL out in stool!
o Gut both absorbs & secretes water (absorption ≫ secretion)
Secretion: water follows active electrolyte transport osmotically (aquaporins or tight junctions)
 Note: if no net sodium transport in gut lumen, still have hydrostatic pressure pushing water out into gut! (secretory state)

Definition of Diarrhea
 Too much water lost in stool!
o Normal stool water: 130 mL / 24h
o Diarrhea: > 200mL / 24h (3SD > normal)

Absorption & secretion (small intestine: right; colon: left)

 Absorption of sodium in villus
 Secretion of chloride in crypts

Epithelial cells: are vectorially oriented

 Apical or basal side, divided by tight junctions
 Asymmetric distribution of transport proteins

Small intestine Na absorption

Basolateral side: 3Na/2K ATPase, pumps sodium out
 Need energy!
 Makes lumen negative (electrochemical gradient)

Apical side: all transport proteins; several types, regional distribution

 Electrogenic: charge moves when sodium moves
o ENAC (colon): epithelial Na Channel
o Na/X : e.g. SGLT1 – sodium glucose linked transporter 1 (D-glucose, D-galactose taken up)
 Neutral: no net movement of charge
o Sodium/chloride cotransporter
o Na/H exchanger (NHE3); linked to Cl/bicarb exchanger
 Linked by carbonic anhydrase in brush border; H2O + CO2 H++HCO3-
 H+, HCO3- created  pumped out by the two pumps

19
Segmental Distribution of Intestinal Na Transport Proteins

Neutral: mostly in Ileum / colon

Glucose / AA: mostly in jejunum

Jejunum Ileum Colon

Na/D-Glu ++++ +
Na/L-AA ++++ +
Neutral NaCl + ++++ ++++
ENac + ++++

Glucose acting on SGLT1: stimulates NHE3 being put into apical membrane (linked)
 NHE3 is the key sodium absorption protein (neutral NaCl)
 Absorbs Na in exchange for extruding H+
 Coupled to Cl/bicarb exchanger

Neutral NaCl absorption in small intestine

1. Explains most basal Na absorption in small intestine in fasting
2. Explains ↑ ileal Na absorption in post-prandial state
3. Only process in Na absorbing cells inhibited in diarrheal diseases
4. ↑ in CF (contribute to meconium ileus?)
5. Linked to SGLT1 glucose transport?

Colonic Na absorption

SCFA = short-chain fatty acid / hydroxyl exchanger

Colon is more efficient than small intestine (compare to kidney)

 Small intestine: 9L in, 1.5L out
o Large volume, low efficiency (like proximal tubule)
 Colon: 1.5Lin, 0.13L out
o Small volume, high efficiency (like distal tubule)

Intestinal Cl Secretion
 same mechanism as lots of other places

Na/2Cl/K cotransporter and 3Na/2K ATPase in basal membrane

 Basal conditions: apical Cl channels not working
 Insert Cl channels  secretion
(Physiologic secretory state, diarrhea, other diseases)
 Note that K is required here

Intestinal secretogues (↑ secretion)

Some work from lumen, others in blood, others in mucosa / submucosa
Bacterial enterotoxins Humoral agents Laxatives
 Cholera  Vasoactive intestinal peptide (VIP)  Endogenous (bile acids, FAs)
 E. coli  Prostaglandin E  Exogenous (commercial)
 Staphylococcus  Calcitonin

20
 Dynamic Balance: Secretion / Absorption
 Normally absorption > secretion
 postprandial: brief shift (secretion > absorption) – don’t want to always have to run to bathroom real fast

What regulates balance? Neurohumoral environment

Inflammatory cells, COX, Lipoxygenase, nerves, cytokines, etc.
 Changes with eating
 Diarrheal diseases are exaggerations of this process

Diarrheal Disease
Diarrhea: in some part of digestive tract, the balance shifts: absorption > secretion

GI tract has EXTRA ABSORPTIVE CAPACITY

 Needs to overwhelm the absorptive capacity of remaining parts of digestive tract!
o Need much bigger problem to have diarrhea from proximal source!
o E.g. eat something, stomach starts secreting  stomach rumbles  can be absorbed by rest of GI tract
 Small intestine normally absorbs 7-9L but can handle 12L; colon normally absorbs 2-3L but can handle 4-6L

How was this determined?

 if you give nonabsorbable molecules during diarrhea & then perfuse, end up with more liquid (net secretion!)
 ↓ *noabsorbable test molecule+ concentration

Mechanisms of Net Intestinal Secretion

1. Inhibition of active electrolyte absorption
2. Stimulation of active electrolyte secretion
3. ↑ luminal osmolarity
4. ↑ tissue hydrostatic pressure

All diarrheal disease can be understood by these mechanisms! Most common: combination of #1 / #2

Cholera
 V. cholera  releases cholera toxin  ↑ cAMP  ↑ electrolyte secretion
o Lose up to 1L stool / hr! Would go into shock (need fluid replacement or ORS)
 Fecal-oral contamination (need 1M organism inoculum!)
o 10% get any diarrhea, 1% of those get this really bad diarrhea
 Can rarely see in US too – but good toilets are best way to go

Fluid replacement
 Cholera cot – collect bucket; measure volume with dipstick
 Need to replace fluids (ORS / IV)

Molecular pathogenesis

1. Production of cholera toxin (bacterial enterotoxin)

a. 1A/5B toxin (A=active, b=binding), released by bacteria
b. Binds GM-1 ganglioside receptor (brush border), A/5B subunits endocytosed
2. A/5B move into retrograde pathway (membrane  golgi ER)
3. In ER, A1 subunit (active) cleaved off, A1 subunit enters cytosol
4. A1 facilitates ADP ribosylation of adenylate cyclase’s Gs subunit (arginine)
a. Gα activated, so AC (on basolateral membrane) activated
b. Note that VIP activates AC in pancreatic cholera, but by a different mechanism
21
 5. ↑ AC  ↑ Cyclic AMP: activates PKA  p-lates stuff
a. PKA localized to different places in absorptive vs secretory cells
Absorptive cells: ↓ Na absorption Secretory cells: ↑ Cl secretion
 inhibits NHE3 (sodium absorption inhibition)  P-lates CFTR (insert Cl channel in apical membrane)
 only thing it does (PKA fixed to NHE3 by NHERF)  P-lates Na/K/2Cl (↑ insertion - ↑ activity)
 Na/substrate transport processes maintained –  P-lates K channels* (insert in apical membrane: K out
good for ORS!) with Cl, keeps cell electrically negative)
*lose A LOT OF POTASSIUM (BIG PROBLEM IN CHOLERA)

Bicarbonate ↓ in cholera
 Crypt: both Cl and HCO3- secretion via CFTR & Cl / HCO3- exchanger
 Villus: extra Cl in lumen from ↑ secretion exchanged for HCO3- - even more bicarb lost

Cholera: blood electrolyte findings

 ↓ K, ↓ HCO3 in blood
 Blood [Na] actually high (total body water ↓)

Oral Rehydration Salts

 Give glucose: can convert gut to absorptive state
 Na / glucose cotransporter NOT AFFECTED by cholera toxin
 Na, K, Cl, HCO3, glucose (or sucrose / starch / AA) to draw Na in
o Gatorade designed for loss of electrolytes in sweat (inadequate [electrolytes] for cholera)

Recent advances in ORS

 Hypo-osmolar solutions are better (≈ 220 mOsm/L) - ↑ absorption, ↑ effectiveness (solvent drag)
 Ceralyte (rice-based ORS): both starch & protein; may have anti-secretory effect, ↓ duration of diarrhea
 “Resistant (high maize) starch”
o ORS usually using just small intestine absorption
o non-metabolizable starch will enter colon  can take advantage of short-chain fatty acid transporter

22
Other mechanisms of cholera pathogenesis
 Affects enteric nerves
 Release intestinal prostaglandins
 Affects enteric serotonin-containing cells
o Large neural component!
Block serotonin cells  block 50% diarrhea
 Other cholera toxins (multiple!)
o Zonula occludens toxin: ↓ number of strands  makes
more permeable TJs (more water pulled through with chloride secretion)

Other diarrheal diseases work via ↑ cAMP too! Various ways to ↑ cAMP:
Prostaglandins UC, Crohn’s, medullary thyroid carcinoma, ganglioneuroma
Neurohumoral substances VIP Pancreatic cholera, ganglioneuroma, oat cell carcinoma of lung
Secretin Pancreatic cholera
Cholera toxin
Bacterial enterotoxins
Heat labile E. coli enterotoxin
Laxatives Bile salts, dioctyl Na sulfosuccinate, ricinoleic acid

cGMP, DAG, Calcium produce similar effects to cAMP: ↓ Na absorption, ↑ Cl secretion

cGMP: also ↓ Na absorption, ↑ Cl secretion
 Heat stable E. coli enterotoxin, Yersinia enterocolitica
 Heat stable E. coli toxin A: has AAs that are similar (basically simulating post-prandial state)

↑ intracellular calcium: also ↓ Na absorption, ↑ Cl secretion

 Neurohumoral substances (serotonin, AcH, neurotensin, substance P)
 Enterotoxins (C. diff, norovirus)
 Laxatives (senokot)

Diarrhea from ↓ Na absorption alone

Mechanism
Decreased Na absorption
Na absorptive cell damage
Increased motility
Decreased villus blood flow
Examples What’s going on?
Serotonin released in blood  inhibits NaCl absorption
Carcinoid syndrome
in small intestine (↑ calcium)
Celiac sprue
Can’t absorb Na
Viral gastroenteritis
Hyperthyroid Things moving too fast to absorb
Ischemic bowel Can’t take blood away fast enough

Celiac Disease
 “Villus Atrophy” – villi no longer there
 Sensitive to gluten, toxic reaction breaks down epithelial cells
 Bigger crypts, lots of inflammatory cells in lamina propria
 Secretion WORSE if you infuse glucose (epithelium can’t take it up, glc is osmotic agent to draw water out)

Celiac disease is more uniform (ORS doesn’t work well)

Viral diarrhea is more patchy (can still use ORS – works in intact areas)

Why diarrhea in celiac disease? Multiple mechanisms

1. ↓ brush border hydrolases (↑ unabsorbed osmoles) 3. Crypt hyperplasia (↑ secretion)
2. Villous atrophy  malabsorption 4. Inflammation  ↑ secretion

23
 Diarrhea due to ↑ luminal osmolarity
Disaccharidase deficiency
Lactase deficiency Very common (normal throughout world) – diarrhea after milk
Sucrase – isomaltase deficiency (primary / secondary) – diarrhea after table sugar
Trehalase deficiency Trehalose: diarrhea after mushrooms
Lactulose: synthetic disaccharide (no such thing as lactulase)
Cause diarrhea by ↑ delivery of osmoles!
Lactase deficiency
 Normal: Lactose’s β-bond broken by lactase in brush
border (proximal 3 ft of jejunum)  glucose + galactose
o Now two molecules: ↑ osmolality?
o Nope, normally: lactase found very close to SGLT 1
(glucose taken up right away)

 Lactase deficiency: lactose stays in lumen, ↑ osmolality

in colon (COLONIC DIARRHEA)
o Bacteria break it down to acid pH, H2+CO2,
short chain fatty acids - gassy

Note that malabsorption of fat doesn’t cause osmotic diarrhea

 forms micelles / precipitates, so doesn’t contribute enough to ↑ osmolality

Paradoxical Diarrhea: from ↑ tissue pressure

Normally: give ouabain (blocks all active transport); gut still secretes (hydrostatic pressure)

Paradoxical diarrhea: Partial small bowel obstruction can present with watery diarrhea
 ↑ hydrostatic pressure proximal to obstruction  diarrhea!

Pancreatic cholera (VIPoma) syndrome

Rare condition, a.k.a. Verner-Morrison Syndrome, not discussed in lecture

 Watery diarrhea (> 1L / 24h) which persists when patient fasts
 Hypokalemia
 Hypochlorhydria

Etiology: abnormality in non-B islet cells of pancreas

 Islet cell carcinoma, adenoma, hyperplasia
 Basically a VIPoma!
o ↑ VIP, other hormones  activates AC/cAMP system

Really rare (1/10 million per year, or about 670 cases worldwide)

24
 Celiac Disease
Key Points
 Gluten Induced Enteropathy, a.k.a. Celiac Sprue, Non-tropical Sprue
 Permanent, genetically determined auto-immune illness initiated by cereal prolamines (gluten/gliadin)
 Small bowel mucosal lesion causes intestinal malabsorption
o Villous blunting
o Intraepithelial lymphocytosis
o Chronic inflammation
 Clinical & histologic improvement on gluten withdrawal.

Clinical Overview
 Not rare (1:70-300; ↑ Europe, Argentina, ↑↑ Finland, 1:250 in Baltimore)
 Presentation: many ways (classically malabsorption + steatorrhea)
o Also: iron deficiency anemia, depression, osteopenic bone disease, ADEK loss sx
 Associated with autoimmune diseases
 Screening: with tTG IgA, CONFIRM dx with duodenal biopsy
 Treatment: avoid gluten; prognosis is good

Pathogenesis
Dysregulation of a usually suppressed T-cell response to gluten (HLA-DQ2 / HLA-DQ8 carriers)

Overview
1. Genetic basis (HLA-DQ2 / DQ8)

2. Gluten peptides taken up / processed

(DQ2, altered permeability, tTG involved)

3. Pathogenic CD4+ T-cells activated

(DQ2/DQ8 restricted T-cells, B-cells make Ab)

4. Tissue damage results

Genetic Factors
 Strong (70% MZ concordance, 10-15% in 1st degree relatives)
 Need HLA-DQ2 or HLA-DQ8 (In some pops, 30-35% are DQ2 or DQ8)
 Other genetic / environmental factors involved (only 2-5% gene carriers develop disease)
o 13 SNPs have also been implicated
o Cytokines during infection? Cross reactive AA sequences (HP, adenovirus)?

Environmental Trigger: Ingestion of Grain Products

Immunogenic peptides
 At least 11 peptides recognized by T-cells have been identified
 Not all subjects respond to all peptides (usually 1-5)
 No one peptide recognized by all celiac pts
Grain Prolamine
Grain prolamines: where immunogenic peptides come from! Wheat Gliadin
 Cereal prolamines initiate damage (not intrinsically toxic) Rye Secalin
 Corn / rice tolerated well (rice krispies, cornflakes OK) Barley Hodein
25
Processing of Grain Products  immunogenic peptides
 Need presence of HLA-DQ2 or HLA-DQ8
 Circulating Ab generated to enzyme (tissue transglutaminase, TG2)
o Most positive screening pts are asx
o Gliadin crosslinked to TG2  autoantigen

 TG2: deamidates certain gluten peptides  ↑ peptide affinity to HLA-DQ2 / HLA-DQ8

+
o Generates more vigorous CD4 Th1 T-cell activation
o Results in intestinal mucosal inflammation, malabsorption, 2° sx, autoimmune diseases
o Gluten: elicits innate immune responses that act in concert with adaptive immunity

Management of CD
Clinical Presentation

“Classical” presentation:
 Failure to thrive  Diarrhea, steatorrhea
 Weight loss  Abdominal pain
 Protuberant abdomen  Dramatic response to gluten
 Bloating (cranky kids) free diet

Varying forms (subtle deficiencies more common than classical presentation)

 Classical celiac disease (childhood)  Dermatitis herpetiformis
 Late onset, non-specific GI Sx  Asymptomatic c.d. (test relatives)
 Extra-intestinal presentations  Latent celiac disease
 Oligo-symptomatic

Represents a pathologic spectrum (see pic)

“Classical” case “Oligo-symptomatic” case
14yo M w/ diarrhea / anemia (2-4yo), undiagnosed. 34yo female, asx,
Delayed growth / puberty. Voluminous, foul-smelling, grey liquid stools. Unexplained iron deficiency anemia,
Anemia, low: FE /B12 / albumin /Ca /K /carotene. Osteopenia on scan, TG-2 positive
Cousin: CD; older sis / mom w/ thyroid dz, sis w/type I DM (autoimmune conditions) No FHx of celiac dz

Diagnostic Approach to CD
 Characteristic histological findings
 Response to a gluten free diet
o Clinical, serological, ± histological
 Endoscopy: scalloping of duodenal fold (suggestive)
 Duodenal biopsy (from endoscopy)

Clinical Presentation: remember, can be non-classical

Think about CD if you see unexplained…

 Anemia  Neuropsychiatric manifestations
 Osteoporosis  Related autoimmune conditions*
 Obstetrical problems  Dermatitis herpetiformis

* DM type I (3-8% have CD!), autoimmune thyroid dz (≈5%), Addison’s, alopecia areata, sjogren’s, dermatitis herpetiformis

26
Dermatitis Herpetiformis
 Erythematous macule > urticarial papule > tense vesicles
 Servere pruritis, symmetric distribution
 90% have no GI Sx, but 75% have villous atrophy
 Gluten sensitivity!

Non-specific GI symptoms:
 Altered bowel habit, bloating dyspepsia, abdominal discomfort, fatigue
 CD is 7x more common in IBS pts

↑ risk of Celiac Disease (and therefore ↑ index of suspicion) in…

 1 /2 degree relatives of CD pts  Autoimmune thyroid disease (5%)  IBS (3.4%)
st nd

 Down’s syndrome (12%)  Iron deficiency anemia (10-15% if sx, 3-6% if asx)  Chronic fatigue (2%)
 Type I DM (3-8%)  Microscopic colitis (15-27%)  Osteoporosis (1-3%)

Serologic tests
 tTG IgA (tissue transglutaminase IgA titer)
o Has high sensitivity / specificity for initial evaluation
o Good to monitor compliance / screen at-risk
o Can use to rule-out CD (high sensitivity if negative)
 ALL EMA / tTG positive pts should undergo small bowel (duodenal) biopsy
o gold standard for Dx
 HLA DQ Screening possible for screening too (negative can rule-out)
o DQ2/8 are susceptible to disease

Screening relatives is IMPORTANT!

Risk of Celiac Disease
General population 1.0%
Among people who are DQ2 or DQ8 positive 2-3%
st
People with unknown HLA and a 1 degree relative who has CD 10-15%
st
People with DQ2 or DQ8 and a 1 degree relative who has CD 20-30%

 Screen if
o Index case has proven celiac disease
o Relative willing to undergo diagnostic testing, treatment, will benefit from treatment
o If relative is symptomatic, approach should be DIAGNOSTIC, not screening!

Treatment
 Remove gluten from diet (GFD = gluten free diet) 3 Days surface epithelium damage reversed
2 weeks 70% have clinical improvement
Why seek a strict adherence to a gluten free diet? 6 weeks most have clinical improvement
 preventing, reversing and/or treating complications 4-6 weeks serological improvement (monitor compliance)
 Improved QOL (even for those detected by screening)  Corrects iron deficiency
 Improves unexplained infertility  Probably benefits overall cancer risk
 Improves osteoporosis  ? Effect on occurrence of autoimmune disorders

BAD grains GOOD grains

 Wheat  Rye  Couscous  Rice  Corn  Sorghum buckwheat
 Barley  Triticale  Kamut  Potato  Oats  Tapioca
 Bulgur  Spelt  Arrowroot  Soybean

27
Refractory Celiac Disease
80-90%: either ingesting gluten or have wrong Dx
 Type 1 refractory: respond to oral / topical steroids
 Type 2 refractory: pre-malignant condition
o 50% develop Enteropathy-associated T-cell lymphoma (ETAL) w/in 5 yrs!

Celiac disease & enteropathy-associated T-cell lymphoma

o 3x relative risk (in un-Rx’d CD) for ETAL
o CD on GFD > 5yrs: no ↑ risk ETAL / GI cancer (treatment = ↓ risk!)

Pathophysiology of Symptoms of Malabsorption

Fat malabsorption: steatorrhea
 Unabsorbed fatty acids are hydroxylated by enteric bacteria
o produce floating stools, rancid fats  foul odor
o Alter small / large intestinal fluid movement (net secretory diarrhea)
 Loss of calories  weight loss
 Loss of ADEK Vitamins (K- follow with PT)

Carbohydrate malabsorption
 Malabsorb sugars (e.g. D-xylose)
 Osmotic diarrhea: lose disaccharidases
 Gas, bloating, abdominal discomfort: from fermentative products
 Fatigue

Protein malabsorption
 Protein Losing  Edema
Enteropathy  Malnutrition

Vitamin / mineral malabsorption

Vitamin / Mineral Deficiency Absorption

Iron Anemia Duodenum (best)
B12 Anemia, glossitis* Ileum
A Night blindness
D Osteoporosis, hypocalcemia, tetany
Fat-soluble Vitamins With Fats**
E ↓ healing
K Bleeding
* Sprue = “sore tongue” in dutch (B12 deficiency  glossitis)
** ↓ absorption with overgrowth of bacteria (impaired motility, dilatation)

Celiac disease: dilated jejunum / ileum Glossitis: 2° to B12 / folate deficiency Tetany: 2° to Ca deficit (vit D)
 stasis  bacterial overgrowth

28
 Inflammatory Bowel Disease
Inflammatory Bowel Disease
(chronic relapsing / remitting disease of intestinal tract – 1M in USA)
Ulcerative Colitis Crohn’s Disease
Indeterminate
Ileitis
Proctitis (28%) Left-sided dz (25%) Pancolitis (47%) Colitis (10-20%) Ileocolitis (45%) Colitis (32%)
(22%)
% = % at time of diagnosis

Ulcerative colitis Crohn’s disease

Distribution

starts in rectum, moves more proximally, colonic only anywhere in GI tract (rare upper GI), mostly colon / Ileum
Endoscopy

 Edema, thickening of colon, loss of vasculature  Punched-out ulcers (apthae)

 Superficial ulcerations ± bleeding  Stellate or linear ulcers / cobblestoning (≈ street)
 Diffuse / continuous ulcers, can encircle colon  Patchy / focal / asymmetric distribution
 Severe: colon becomes tubelike  Severe: Macroulcerations & pseudopolyps

 Strictures RARE  Strictures COMMON

 Rectal involvement ALWAYS @ DX  Rectum commonly spared
Histology

Superficial mucosal ulceration Transmural inflammation

Less frequent Abdominal pain Frequent
Clinical manifestations

Frequent Bloody diarrhea Occasional

Never Abdominal mass Frequent
Never Intestinal obstruction Frequent
Almost never Perianal disease Frequent
Never Fistulae Common
PROTECTIVE Effect of smoking DETRIMENTAL
Less common Systemic Sx (EIMs*) COMMON
* see below for EIMs in Crohn’s
29
Crohn’s Disease (some extra info)
Progression of Crohn’s:
Inflammation Obstruction Fistulization

Ulcer goes the whole way through

 Abdominal pain
 Cramps  Diarrhea, pain
 Tenderness
 Distension  Air/feces in urine
 Diarrhea
 Vomiting  Enteroenteric, enterovesical,
 Weight loss
retroperitoneal, enterocutaneous

Extraintestinal manifestations of Crohn’s disease

 Aphthous stomatitis (canker sores)
o aphtha = ulcer
o stomatitis = inflammation of mucous lining of mouth
 Episcleritis, uveitis
 Arthritis
 Vascular complications
 Derm complications
o Erythema nodosum (tender red nodules under skin)
o Pyoderma gangrenosum (ulcers  grow  become necrotic
Therapy of IBD
Goals
 Induce remission & maintain remission
 ↑ QOL,
 Avoid long-term toxicity

Spectrum of therapies (balance efficacy with potential toxicity)

Antidiarrheals, bile sequestrants, antispasmodics,
Supportive agents
pain management, etc.

Aminosalicylates sulfasalazine, help with local inflammation

anti-inflammatory, ↓ immune system
Corticosteroids  prednisone, prednisolone
(doesn’t help maintain remission)
Antibiotics metronidazole, quinolones (see pathogenesis)
alter immune system work your way up
Immunomodulators  anti-TNFα, 6MP/azathioprine,
to more aggressive therapies!
methotrexate / cyclosporine, etc.

30
 Pathogenesis of IBD
Dysregulation of inflammatory response to a luminal pathogen in genetically predisposed patients
 Environment, microbes, epithelial barrier, microbial sensing, innate / adaptive immunity, leukocyte trafficking involved

Environmental factors
 Don’t know exactly how these work (from UC CD
epidemiology) Smoking ↓↓↓ ↑↑↑
 Smoking: ↑↑ Crohn’s, ↓↓ UC (best studies!) Appendectomy ↓↓ none
High sanitation level in childhood None ↑↑
Perinatal infection, breast feeding, OCP too? High refined CHO intake None ↑

Microbes
We know that bacteria are involved in IBD:
Animal IBD models require bacteria
 Specific bacteria ID’d
IL-10 knock-out mice
 Animal models require bacteria
 Grow in germ-free environment: no colitis
 Serum immune reactivity
 Grow in normal environment: develop colitis
 Efficacy of abx / probiotics for treatment!  Expose to only certain bacteria: still develop colitis

Normally:
 1014 cfu/g stool! Lots of bacteria & diverse species, 80% can’t be cultured
 Most: Firmicutes (mostly clostridia) & Bacteroides
 Hard to study (source material debated: feces / aspirates / mucosal biopsies?)

Altered intestinal bacterial flora levels in UC/CD pts

 Bacteroides, campylobacter, collinsella, clostridia, bifidobacteria, enterbactereacea, helicobacter (non-pylori)

Serology for IBD

Antibody Antigen NonIBD(%) CD (%) UC (%)
pANCA Histone H1 <5 15 65
ASCA Anti-saccharomyces cervisiase Ab <5 60 5
OmpC E. coli <5 38 2
Anti-I2 Pseudomonas fluorescens 19 54 10
All recognize bacterial antigens!
Antibiotics, probiotics help in IBD
 Abx shown to help in Crohn’s colitis, Crohn’s fistulas, pouchitis
 Probiotics shown to help in UC, Crohn’s colitis, pouchitis

IBD and the Immune Response

if we all have bacteria, why do only some patients get IBD?
Normally
Bacteria, intestinal mucosa have adapted to each other
Highly regulated innate, adaptive immune responses in GI tract
 Innate immunity: fast, less specific, no memory
 Adaptive immunity: slower, specific, memory response

Remember: Innate immunity responds first (PRRs, etc), then

primes adaptive immune response

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Innate Immunity & IBD
Epithelial cells: 1st point of contact with bacteria / line of defense against infection
Normally In IBD
 Barrier function Intestinal permeability defects in CD pts
 Produce cytokines / chemokines after bacterial invasion  (also in 10-15% 1 degree relatives; mouse models too)
st

 Interact with innate / adaptive immune cells Defects  IBD pts more prone to microbes

Pattern Recognition Receptors

 On innate immune cells; normally activated by PAMPs (pathogen-associated molecular patterns); 2 classes:
o TLRs: Toll-like receptors (on cell surface)
o NODs: Nucleotide oligomerization domain (intracellular PRRs)
 PRRs are dysregulated in IBD
o TLRs 2-6: bacterial lipoproteins, dsRNA, lipopolysaccharides, flagellin
o NOD2: bacterial peptidoglycan
 ↑ activation of downstream immune responses (↑ cytokines, antimicrobials)

Specific innate immune genes & IBD (Crohn’s, specifically)

Gene What product does More
1st gene associated with CD
 Predictive of early onset, ileal dz, ↑ structuring / fibrostenosis
 Localized in Mϕ, dendritic cells, paneth cells (distal small intestine – like CD!)
o Paneth cells: make defensins (natural antimicrobials)
NOD2 Intracellular PRR
Defect in NOD2:
 can’t eradicate intracellular organisms (lose controlled response)
 ↓ defensin production
IRGM Autophagy* “Immune-related GTPase”; expression levels influence efficacy of autophagy
ATG16L Autophagy* Mutations: impaired anti-bacterial autophagy
*autophagy = self eating (digest / recycle proteins / organelles, encapsulate & destroy bacteria)

Adaptive Immunity & IBD

Remember the CD4+ T helper cells?
Role Proinflammatory cytokines produced
Th1 Mediates cellular immunity (Mϕ driven) IFNγ, TNFα
Th2 Mediates humoral immunity (B-cell driven) IL-4/5/6/13
Th17 Manages transition between innate / adaptive immune responses TNFα, IL-6/17
 Regulated by Treg cells (suppressive T-cells)

Original theory
 CD is Th1-mediated, UC is Th2-mediated
 But TNFα antibodies are current top line therapy for BOTH CD & UC
o In this theory, only Th1-mediated CD should respond to anti-TNFα therapy

IL-23 Receptor
 SNPs in IL-23R are associated with both UC & CD (one is protective, another confers risk for both)
 IL-23: inflammatory cytokine produced by activated Mϕ / dendritic cells
 IL-23R: found on Th17 cells, Mϕ, and dendritic cells (NOT Th1/Th2)
o In clinical trials: IL23R Ab for Crohn’s!

32
New theory: Th1 ↑ in Crohn’s, Th2 ↑ in UC, Th17 ↑ in both!

Normal: T-cell differentiation in homeostasis IBD: balance shifts towards inflammation

Gut Homing of Inflammatory Cells

 Normally: inflammatory cells use integrins to traffick to gut
o α4β7 integrin interacts with gut endothelium’s MAdCAM-1 (roll, arrest)  diapedese, etc.

 Natalizumab being used to treat Crohn’s (also MS) – anti-α4 integrin antibody
o Stops leukocytes from homing to gut endothelium (and bbb)
o Remember PML can be a complication (not cool)

Pathophysiology: KEY POINTS

 Bacteria influence the development of colitis.
 IBD patients are genetically predisposed to disease
 IBD patients have compromised intestinal barriers
 IBD is likely influenced by aberrant sensing and processing of microbial antigens
o Altered PRR function: PRRs (TLRs and NODs) influence microbial sensing and are associated with IBD.
o Autophagy compromised: IRGM and ATG16L (autophagy genes) are associated with Crohn’s.
o 3 of 4 known CD genes are directly related to bacterial sensing or processing.
 A dysregulation of the T-cell balance contributes to IBD
o Th1 (Crohn’s), Th2 (UC), and Th17 (both) cells are all implicated in IBD
 Blocking T-cell activation or gut homing is effective in treating Crohn’s disease

33
 Gastrointestinal Motility
Regulation of GI motility: Normal Physiology
Segment Function Motility
Proximal  Accumulation, storage  Tonic movement of chyme
(fundus, body)  Regulates intragastric pressure  No phasic motor activity
Stomach
Distal  Grinding of food Phasic motor activity
(antrum)  Responsible for emptying (≈ 3 contractions / min)
Fed state Digest, absorb nutrients Mix / absorb
Phasic
Small Intestine Keep swept clean of bacteria / other Propel non-absorbed
Fasting state (≈12 / min)
residue residue
Contractions not as organized
 Absorb excess fluid  Mixing: Intermittent short segmental to-
 Salvage unabsorbed nutrients and-fro patterns
Colon (via bacteria)  Storage (next): relatively quiescent
 Permit defecation  HAPC (high amplitude peristaltic
 Transit time: 36 hours contractions ): promote defecation
(Intermittent ; ≈ 5/day)
Store feces & eliminate
Anorectum See below
(in a “socially acceptable manner”)

Anorectum
Storage:
 Rectum is storage reservoir
 Puborectalis, internal/external anal sphincters:
tonic contraction

Defecation:
 Response to voluntary defecation or ↑ rectal pressure
 Puborectalis relaxes
 Internal & external anal sphincters open

Enteric nervous System

Extrinsic component: parasympathetic & sympathetic innervations
Intrinsic component: 500 million neurons embedded in bowel wall
 Myenteric (Auerbach’s) plexus
 Submucosal (Meissner’s) plexus
Note: you can get reflexes from intrinsic system without CNS input!

5 groups of cells:
1. Smooth muscle
2. Enteroendocrine cells
3. Nervous tissue cells (neurons & glia)
4. Inflammatory cells (mast cells, lymphocytes, macrophages, granulocytes)
5. Interstitial cells of Cajal
o Non-neural elements
o Communicate with neurons and smooth muscle
o Intrinsic myoelectric frequencies
o Control frequency and propagation of contractions

34
Signalling in enteric nervous system
 Most molecules still unclear
 Serotonin: major stimulatory neurotransmitter
o Stored in enteroendocrine cells
o Released in response to intestinal stimuli
 Others: acetylcholine, substance P, etc.

Electrical Activity
 Rhythmic electrical activity
 Interstitial cells of Cajal  membrane depolarization 
hit threshold, fire AP repolarization  contractions Migratory motor complex

Fasting state Fed state

Migratory motor complex (MMC) Slow contractions in stomach / small intestine
 Clears stomach / intestine of residual food / debris ≈ 90 min  Stomach (3/min)
o Triggered by motilin (erythromycin)  Small intestine (12/min)
o Blocked by gastrin infusion  Colon: disorganized, but stronger

 Less pronounced in colon  Duration of fed state ↑ with ↑ calories, fat

 Lose MMC  bloating, distension (bacterial overgrowth)  Disrupted by opiates

Disorders of GI Motility (Overview)

 Gastroparesis  Irritable bowel syndrome
 Functional dyspepsia  Constipation
 Small intestinal bacterial overgrowth  Chronic intestinal pseudo-obstruction
o anything that disrupts MMC will ↑ growth / stasis o ↓ rhythmic contractions in fed state
o bloating / malabsorption o As if they were obstructed, but no focal point
(small bowel just not contracting)

Gastroparesis
Delayed emptying of stomach in absence of mechanical obstruction

Symptoms
 nausea  dyspepsia  bloating  weight loss
 vomiting of undigested food  epigastric pain  heartburn
Symptoms: severity can be highly variable, can be intermittent

Pathogenesis:
Destruction of gastric enteric nerves / interstitial cells of Cajal
Normal Gastroparesis
 Proximal stomach expands to accommodate food;
 Loss of fundic accommodation (bloating, early satiety)
maintains intragastric pressure
 Altered or absent antral phasic contractions (delayed emptying)
 Solids broken down (1-2 mm particles) by contractions
 Visceral hypersensitivity (pain)
 Gastric emptying: 50% in 2 hours, 90% in 4 hours

Etiology
Systemic disease Neuro / psych disorders Iatrogenic Idiopathic
 diabetes: 29%  autonomic dysfunction  Surgery
 (36%)
 paraneoplastic syndromes  spinal cord injury (vagectomy, partial gastrectomy: 13%)
 connective tissue disorders  Parkinson disease  Drugs (anticholinergics, tricyclics,
Post-infectious??
 anorexia dopamine agonists, opiates; radiation)

35
Diagnosis of gastroparesis
Physical examination: Prevalence of Gastroparesis:
 Early: normal  Not known
 Late: ± sucussion splash, wt loss, signs of dehydration  Women > men (7:1)
 30-50% of DM pts have delayed gastric
Laboratory tests: emptying (autonomic neuropathy?)
 No blood test
 use CBC / metabolic profile, amylase, pregnancy test, TSH to exclude other conditions

GI structural tests:
• Upper GI series (exclude obstruction)
• Endoscopy (exclude obstruction / gastric inflammatory process)

Gastric Motility tests

 Gastric emptying study: Scintigraphy
o Give egg substitutes & bread with nuclear tracer, take images over 4 hours
o Calculate how much emptying is going on
o Normal: > 90% emptying @ 4 hours
 Antroduodenal manography, electrogastrogram (EEG) – not widely available

Management of gastroparesis

 Dietary modification
o smaller, frequent meals (less stomach expansion  less discomfort)
o ↓ fat (fat slows gastric emptying)
o ↓ fiber (can sit in antrum, form large “vegetable balls”)
o Liquid supplements (don’t need as much churning, empty faster)

 Glycemic control: high glucose can slow emptying

 Medications: antiemetics and prokinetics

 Less frequently used: endoscopic therapy (botox?), gastric electrical stimulation (only works in some patients), percutaneous
gastrotomy / jejunostomy (bypass stomach), total gastrectomy (last resort)

Medications:
 Erythromycin:
o macrolide; stimulates motilin receptor; no known antiemetic effect
o Stimulates antral contractions & initiates MMC

 Metoclopramide
o Dopamine antagonist, also affects serotonin receptors
o Central antiemetic effects
o Induces antral contractions, fundic relaxation, ↑ antroduodenal coordination
o Side effect: tardative dyskinesia (low but very serious risk)

 Domperidone
o Peripheral dopamine antagonist (similar effects to metoclopramide)
o Central antiemetic effect (unclear why)

36
 o Not FDA approved

Constipation
Unsatisfactory defecation characterized by infrequent stool and difficult stool passage
 Symptom, not a disease!
 infrequent defecation alone is NOT SUFFICIENT to define constipation
o If you’re going infrequently but no problems – not constipation

Stool:
 Typically variation (normal!)
 Most stool should normally be type 3 or type 4
 On average: transit takes 36h through colon, 50-150g stool/day

Physiology: Normal
1. Segmental to-and-fro contractions to mix stool
2. Long quiescent periods for storage
3. Infrequent high amplitude propagating contractions (HAPC) to move stool (5/day)
4. Successful relaxation of anorectum to expel stool
Problems with any of these can lead to constipation!

Etiology of constipation: common (20% American adults); multifactorial

 Endocrine disorders  Neurologic conditions  Obstruction

(hypothryroidism, diabetes)  Connective tissue disease  Hirschsprung’s disease
 Metabolic derangements  Medications (over 100 listed)  Defecatory disorder
(hypercalcemia, hypocalcemia)  Functional

Hirschprung’s Disease
 Normally, neural crest cells migrate caudally towards anorectum during development
o Arrested in Hirschprung’s  absent ganglion cells in distal bowel
 Loss of internal anal sphincter relaxation with rectal distention
 Associated with constipation but symptoms variable based on length of involvement
 Usually detected in childhood but not always

Clinical Classification of Constipation

Normal transit constipation
Functional constipation (> 60% cases)
 stool frequency normal, but pts feel
constipated
 Probably due to perceived difficulty
w/ evacuation or hard stools
 Bloating, abd. pain, discomfort
 Fiber / osmotic laxative helps
Slow transit constipation
A.k.a. colonic inertia
 More common in young women
 Infrequent bowel movements
 ↓ # neurons and ICC
 Delayed emptying of proximal colon &
fewer HAPCs
Defecatory disorders
A.k.a. pelvic floor dysfunction, functional
outlet obstruction, dyssynergy
 Inability to extrude formed stool from
anorectum
 Can’t coordinate muscles or structural
abnormality
 Treatment: retrain muscle
(biofeedback) or correct structural
abnormality

Clinical Evaluation of Constipation

 History & Physical:
o Sx, stool frequency, stool form, any maneuvers they have to do to get stool out
o Eliminate other systemic conditions
o Rectal exam (tone, etc)

37
  Lab testing (TSH/Ca) – usually don’t do
 Radiography / endoscopy to exclude obstruction (colonoscopy, barium enema)
 Physiologic tests if needed

o Colonic scintigraphy

o Radiopaque marker transit study (Sitz marker study)

 Swallow radiopaque capsule; look at transit speed over time

o Anorectal manometry
 Catheter across sphincter; ask pt to bear down
 Look at pressure inside sphincter (pic: L = rest, R = squeeze)

o Barium defecography
 Put paste in rectum; have pt squeeze it out
 Not popular with pts

Management of Constipation
For normal transit constipation:
 Lifestyle modification:
o ↑ activity (if you’re more active, bowel activity ↑ too)
o ↑fluid intake
o Defecate early in morning / after meals (when activity is normally highest)
 Fiber (main 1st therapy)
 Osmotic laxative (2nd therapy usually)
 Colonic stimulants
 Prokinetics (don’t work well in colon)
 Chloride channel activators (new meds – like inducing mild, controlled cholera)
 Enemas, suppositories (last resort)
o injecting something into stool helps soften it
o ↑ pressure  ↑ contractions

For slow transit constipation

 Same as previous slide, but fiber makes symptoms worse! (more bloating,e tc)
 Surgery to remove colon can be considered

For defecatory disorders

 Direct treatment to underlying disorder
 Biofeedback if functional
 Surgery if structural

38
 Functional GI Disorders / Irritable Bowel Syndrome (IBS)
Functional GI disorders: a group of disorders of the digestive tract that are characterized by
 chronic abdominal complaints
 without a structural or biochemical cause that could explain symptoms.
For instance: do a whole workup; no cause found; sx interfere with life, etc.

Why are they important?

 Affect up to 70% of the population
 Contribute to a lower quality of life compared to “structural” GI disorders
 Challenging to manage (can’t just use Rx)

Case example: 21 yo F; CC: post-prandial bloating and intermittent diarrhea

 HPI: travel to asia 1 yr ago, developed severe diarrhea x 3 wks. Dx: amebic dysentery
 Never fully back to normal stooling; now diarrhea 4xday, small volume, watery, mucous
 No nocturnal episodes / wt loss / food intolerances / fever / chills
 Meds: acidophilus; SH: “stressful”, no EtOH/smoking/etc; ROS / PE nL, labs nL
Formerly caused “mucous colitis”, spastic colitis, etc. – now irritable bowel syndrome

Irritable Bowel Syndrome

Symptoms:
 Bloating  Diarrhea (can be intermittent)
 Abdominal pain  Constipation (can alternate with diarrhea, etc)

Formal definition (Rome III) recurrent abd pain or discomfort 3d/month in last 3 months with 2+ of the following
 worse with defecation
 onset associated with change in frequency of stool
 onset associated with change in form of stool

IBS epidemiology
 20% of Western pop (70% don’t see health care provider)
 Women 2:1 vs men
 30-50yo @ 1st presentation (really rare to have 1st presentation in elderly)

Impact:
 lots of cost; 28% all physician visits (top 10); big economic impact (missing work)
 ↓ QOL (60% say sx are severe); health related quality of life worse than GERD / DM / ERSD

Clinical groups
 IBS-D (diarrhea predominant) IBS is NEVER associated with
 IBS-C (constipation predominant)  Weight loss
 IBS-Mixed  Anemia / rectal bleeding
 Diarrhea waking pt up at night
Pathogenesis
Theory: IBS pts have visceral hypersensitivity (enteric nervous system sensitivity ↑)
 Inflate balloon in rectum: IBS pts have more discomfort vs controls
 Women: ↑ sensory perception with balloon inflation (more urge to defecate, discomfort, pain)

39
Serotonin
 Key mediator of visceral sensitivity / motility
 Stimulation  serotonin released  binds to 5-HT3, 5-HT4
receptors

5-HT3 receptor: visceral sensitivity (sends signal up to brain)

5-HT4 receptor: ↑ peristalsis (synapses onto intrinsic enteric nerves)

Genetic polymorphisms
 Serotonin reuptake transporter (SERT) – determines what
active pool of serotonin is
o Maybe ↑ activity (↑ serotonin availability) in IBS?
o Also associated with ↑ visceral pain sensation

Brain function
 Maybe there’s a different cerebral response to rectal stimuli in IBS pts
 Different areas triggered in IBS vs controls (fMRI)

Why more common in women

Physiology
 Females perceive somatic pain differently, ↓ pain thresholds, ↓ tolerance, etc.
 Estrogen? Central administration of estrogens: ↑ pain response (may bind opiod receptors to ↓ analgesic
response)
Cultural
 Men: less willing to report pain; women more likely to seek health care
 Women: more self-conscious & ashamed about GI symptoms
Sexual abuse
 Up to 50% of IBS pts have history of sexual abuse

Other things associated with IBS: Migraine, chronic pelvic pain, fibromyalgia, depression, anxiety

Management of IBS
 Education, diet, pharmacology, mind/body therapies

Diet
 ↑ sensitivity / pain to colonic gas distension, so any foods that ↑ gas is bad
 Bad foods: high fiber / fat, caffeine, lactose (if lactose intolerant)
o Gassy vegetables (beans, anything with raffinose – not broken down readily – humans have no α galactosidase)
 Beano, other tricks can help
o Lactase deficiency: lactose  gas  pain; tons of people have it (esp worldwide)
o Fructose malabsorption: exacerbates IBS (malabsorbed  fermented by colonic flora  gas
 Typical American: 100g fructose / day (can only metabolize 50g/day!)

Pharmacologic therapy:
 Meds to: ↓ intestinal spasm, treat constipation / diarrhea, ↓ visceral hypersensitivity (new)
 But most pts with IBS are dissatisfied with pharm therapy (side effects, meds not good, not well educated)
 Serotonin-directed therapies
o Tegaserod (5HT4 agonist for IBS-C - constipation)
o Aloetron (5HT3 receptor antagonist for IBS-D - diarrhea)
 RCPTs not working: 40-70% placebo response rate!

40
Mind-body therapy
 “Gut directed hypnotherapy”
o Aim: return GI fxn to normal
o Reduces absenteeism, ↑ QOL, ↓ symptoms, ↓ med use / consultations
o 84% remain well 1-5 yrs after initial treatment
o Physiologic effects: normalizes rectal sensitivity in IBS pts who are hypersensitive
 Improvement correlates with better abd pain / depression

 Cognitive behavioral therapy

o “teaches IBS pts how to reframe and adjust how they evaluate and judge their symptoms”
o Better than 80% improvement at 4 yr follow-up
o Expensive, difficult to obtain (insurance doesn’t cover it)

Post-infectious Irritable Bowel Syndrome

 May be responsible for 25% of all IBS
 Reported after outbreaks of salmonella, shigella, giardia, campylobacter
o Bowels don’t go back to normal

Risk factors: long duration of diarrhea, female, psychological factors

Pathophysiology:
 ↑ T-lymphocytes, mast cells in lamina propria
 Release of tryptase, histamine  excite visceral sensory nerves

Natural history of IBS

 50% report symptoms for more than 10 years; 16% more than 20 years
o Symptoms severity: may wax and wane
 1/3 of patients initially diagnosed with IBS report complete disappearance of symptoms @ 12 years
o Maybe the post-infectious subtype?

Summary (from notes)

• IBS is associated with altered visceral sensation and motility mediated by disturbances in serotonin metabolism
• 25% of IBS is post-infectious, suggesting its pathophysiology is related to intestinal inflammation
• Pharmacologic agents targeting serotonin metabolism may allow better symptomatic control
• Currently, there are few therapies with strong evidence for reducing global IBS symptoms
• Cognitive behavioral therapy is associated with good long-term response
• Sex and gender differences are important in the pathophysiology and treatment of IBS;
these differences should impact how IBS is managed

41
 Gallbladder
Normal Anatomy of the Gallbladder
 in RUQ / epigastric region
 infrahepatic (between quadrate & right lobes)
 pear-shaped fundus (body) with hollow vicus

Ducts:
 hepatic duct from liver
 cystic duct to /from gall bladder
o cystic duct has spiral valve (of Heister) to control it
o 3-4 cm long normally
 hepatic / cystic duct join inferior to porta hepatis to form common bile duct
o Sphincter of Oddi around it
 common bile duct joins pancreatic duct @ duodenal ampulla (of Vater)

Gallbladder: has own blood supply (cystic artery)

 from right hepatic artery, a branch of proper hepatic artery (off of common hepatic artery)

Gallbladder epithelium
 Two functional layers; inner columnar epithelium participates in bile concentration
 Tight junctions well developed (resistance to passive flux of solute; passive loss of bile molecules)
 Goblet cells: secrete protective mucus

Bile
Production of Bile
Made in liver (synthesized in canalicular cells lining bile canals)
 drains into hepatic bile ducts, which coalesce (R/L hepatic ducts)
 250-1500 mL bile /day made & secreted by liver

Components of bile:
 water, electrolytes, proteins, lipids,
 bile salts
 bile pigments (bilirubin)
 pH neutral or slightly alkaline

Bile Salts
 Bile ACIDS (mostly cholate, chenodeoxycholate) are made from cholesterol (liver)
o Major pathway of cholesterol breakdown in body
 Bile acids combined with glycine / taurine  bile SALTS
 95% bile acids are absorbed by ileum

Functions:
 Aid digestive enzymes
 Emulsification (↑ total surface area of fats for more efficient digestion by lipases)
 ↑ absorption of fatty acids, cholesterol, vitamins ADEK
st
o 1 clinical sign of bile acid deficiency often vitamin K deficiency (clotting disorders!)
o Also fat malabsorption too!

No bile salts: poor lipid absorption & vitamin deficiencies

42
Bile Pigment (Bilirubin)
 Bilirubin is breakdown product of heme (from RBC)

RBC hemoglobin  Heme + Fe+2 (hemolysis: spleen, liver, bone marrow)

 Iron: recycled to bone marrow

 Heme  biliverdin  bilirubin  conjugated in liver 
o Bilirubin eliminated in bile, excreted in feces

Control of gallbladder

Liver isn’t capable of making bile in an “on-demand basis”, so GB stores bile

Between meals: storage of bile

 Gallbladder fills (from hepatic secretion pressure)
o closed sphincter of Oddi & relaxation of gallbladder smooth muscle

During meals: secretion of bile

 Fat in chyme enters duodenum  CCK released 

bile expelled
o sphincter of Oddi relaxes (smooth muscle)
o gallbladder contracts

 Nitric oxide, VIP, Ach help serve as 2° mediators

Concentration of bile
via active ion transport across tight gallbladder epithelium

 1° transport at apical membrane (Na/H exchanged)

 Carbonic anhydrase generates protons for exchange

 End result: NaCl absorbed into bloodstream  water follows  concentration

of bile

Enterohepatic circulation
Compounds recirculate between liver intestine

 Taken up through small intestine  hepatic portal blood

 Various exogenous compounds secreted by liver into bile ducts

o These compounds can be excreted again into intestine via bile
o Example: 95% bile acids are absorbed by ileum

43
 Gallbladder Diseases (overview)
 Cholelithiasis = stone(s) in GB
 Cholecystitis = inflammation of GB
 Choledocholithiasis = obstruction
 Cholangitis = infection

Sample Case: Acute Emphysematous Cholecystitis

34 year-old AA F in the ER presenting with > 18 hours of progressively worse RUQ discomfort
associated with abrupt onset of chills, nausea and vomiting. Nothing makes pain better;
breathing/movement make pain worse; similar sx in past, always go away on own. Obese,
sickle thal trait, otherwise nL. Exam: a little febrile, HR 125 (tachy), BP↓, RR↑, looks
uncomfortable. RUQ tenderness, particularly on deep inspiration (Murphy’s sign), o/w
normal. Mild ↑ WBC (inflammatory process). CXR / abd X-ray clear. U/S: shows gallstones,
pericholecystic fluid (suggests inflammation)

Murphy’s sign: pain worse on inspiration

Cholelithiasis
Cholesterol is major source of gallstones

De novo synthesis of cholesterol

 made in liver; synthesis under control of HMG CoA-reductase
 Partially esterified by ACAT,
 Secreted as VLDL cholesterol or stored in liver

Dietary cholesterol
 taken up by intestinal ABC transporter 
 transferred to apoA1 particles
 ApoA1 particles then taken up by HDL receptor
o Minor amounts of cholesterol: from LDL / chylomicron remnants, taken up by LDL receptor

Metabolism into bile acids

 Once cholesterol’s in the liver (dietary / de novo), can be metabolized to bile acids
 Classical, neutral pathway (CYP7A1, CYP8B1) is key
o CYP7A1 is KEY regulatory enzyme for synthesis
o ABC pumps pump out cholesterol & bile salts
o Liver can take up bile salts via specific transporters
 Alternative pathway (less important)

Main things to remember

 Cholesterol made in liver
 Goes through blood stream, taken back into liver
 Broken down  make bile acids (main key: make cholesterol water-soluble for excretion)

Key concepts in cholelithiasis

 Gallbladder storage of bile results in changes in its composition, (bile acids become the dominant anions)
 Bile remains isotonic during this process (bile acid monomers are rapidly incorporated into mixed micelles)
 The relative proportion of biliary lipids is largely unchanged, although the high concentration of cholesterol in
human bile makes us vulnerable to cholesterol precipitation and thus to gallstones.
 Cholesterol gallstones are common in humans, and may cause pain and cholestasis.
 The gallbladder is not essential to normal digestion, and symptomatic gallstone disease can be largely treated
by removal of the gallbladder.
44
Gallstones: predisposing conditions
 Age (lose ability to make hydrophobic material)  Gallbladder hypomotility
 Female gender, OCP, pregnancy (↑ estrogen)  Genetics
 Obesity o Responsible for 25% all gallstones (sole risk factor)
 Rapid weight reduction o ↑ in parts of Chile
(changing relative balance of bile components)

Cholesterol Stone formation

Failure of any of the mechanisms of cholesterol homestasis can change balance
between solute / solvent in bile  lead to gallstones (precipitation)

Need:
• Cholesterol supersaturation of bile
• ↑ cholesterol secretion or ↓ bile salt / phospholipid secretion
• Gallbladder hypomotility – no flow makes it easier
• Pro-nucleating protein factors (form little nidus for crystallization)

Pigmented stones
A small proportion of gallstones are black-pigment stones
 Made of calcium bilirubinate (↑Ca, ↑unconjugated bili)
 Can be due to excessive heme breakdown
o Vitamin B12 or folic acid deficiency: ineffective erythropoesis
o Chronic hemolysis (e.g. liver cirrhosis, malaria)
o Crohn's disease with severe ileal manifestation or ileal resection:
bile salt malabsorption, leading to increased intestinal bilirubin absorption +/-vitamin B12 malabsorption
o Liver cirrhosis: decreased bile salt synthesis, bile salt malabsorption, gallbladder hypomotility, chronic hemolysis
Other Gallbladder Disease
Gallbladder Disease Etiology
Symptomatic cholelithiasis Intermittent blockage of cystic duct
 Wax/waning postprandial epigastric/RUQ pain
 due to transient cystic duct obstruction by stone
 no fever/WBC, normal LFT
 Can resolve or lead to acute / chronic cholecystitis
Acute cholecystitis More continuous blockage of cystic duct  GB inflammation
 Persistent RUQ pain +/- fever, ↑WBC, abnormal liver enzymes
 Positive Murphy’s sign (↑ pain on inspiration)
Chronic cholecystitis Recurrent bouts of biliary colic /acute cholecystitis 
chronic GB wall inflamm/fibrosis.
Acalculous cholecystitis GB inflammation due to biliary stasis (infrequent) without stones.
Choledocholithiasis Gallstone in common bile duct
 May originate in the CBD(primary) or migrate from GB (secondary)
Cholangitis Infection within bile ducts due to obstruction of extrahepatic bile ducts.
 Can result from choledocholithaisis
 Charcot triad: (RUQ pain, jaundice & fever) often present

45
Cholecystitis
Basic pathogenesis:
 Stone blocks cystic duct 
 ↑ pressure, backflow  chemical irritation, inflammation 
 disruption of mucosal lining  exposure to bile salts (destructive!)

Symptoms:
 Brief impaction: can cause pain only
 Prolonged impaction: leads to inflammation (usually sterile)
o 2° infection can occur
Course:
 Wall of gallbladder can undergo necrosis & gangrene
o Emphysematous cholecystitis: gas in wall/lumen of gallbladder (bact. superinfection with gas-forming bacteria)
 Can perforate without treatment (RUQ abscess, peritonitis)

Choledocholithiasis
Pathogenesis
 Stone forms in common bile duct (either 1° or passed from cystic duct to CBD)
 Promoting factors:
o Bile stasis, bactibilia, chemical/pH imbalances
o ↑ bilirubin excretion, sludge formation
Course:
 Results in bile stasis  can lead to cholangitis

Cholangitis
Systemic bacterial infection/endotoxinemia as a result of biliary obstruction

Pathogenesis
Bile is normally sterile (flow dynamics, Sphincter of Oddi, local immune factors)
 Sphincter of Oddi disruption (instrumentation / endoprosthesis)
 Stones / tumors: Block bile duct  ↑ pressure in bile duct  flow restricted  retrograde ascent of bacteria
o Bactibilia results (bacteria in biliary tract)
o ↑ pressure  ↓ antibacterial defenses, too; cholangiovenous reflux  systemic infeciton

Etiology: Choledocholithiasis, Obstructive tumors, Others (ERCP, ascaris lumbricoides, strictures / stenosis)

Signs / symptoms / course

 Charcot triad: RUQ pain, jaundice & fever (70% pts)
 Can lead to life-threatening sepsis & septic shock

Treatment:
 Correct ECV  Emergent decompression
 Give Abx (ERCP / percutaneous transhepatic cholangiogram)
 Correct initial cause

Acute Biliary Pancreatitis

 Pathophysiology poorly understood
 Common channel theory: gallstone @ ampulla of Vater
o Obstruction theory: ↑ pancreatic duct pressure  ductal HTN, cell damage
o Reflux theory: Maybe gallstone disrupts sphincter  activated pancreatic
enzymes reflux, start activating stuff

46
 Acute & Chronic Pancreatitis
Acute pancreatitis Chronic pancreatitis
 Acute inflammation  Chronic inflammation
 Acute abdominal pain  Chronic abdominal pain
 ↑ pancreatic enzymes in serum  Progressive loss of pancreatic endocrine / exocrine
 Self-limiting function

Acute Pancreatitis
 Acute episode of pancreatic inflammation  Results from autodigestion of part of pancreas
 Very common (#3 for GI hospital admits in US)  Generally resolves completely

Diagnosis (need 2 of 3)
 Abdominal pain characteristic of acute pancreatitis
 Serum amylase and/or lipase ≥ 3x upper limit of normal
 Findings of acute pancreatitis on CT

Pathogenesis of Acute Pancreatitis

 Zymogens activated; inflammatory mediators generated, ischemia results
 Lots of local inflammation involved
 Etiologies: most commonly alcoholic & biliary (gallstones)
o can also be idiopathic

Alcohol: multiple mechanisms

 Toxic metabolites of alcohol  CCK / secretin release
 Spasm of sphincter of Oddi stimulated

Gallstones: Temporary obstruction of common duct (tx with removal of gallstone)

 See pic: gallstones; lots of fluid around pancreas

Microlithiasis (tiny microscopic gallstones)

 can’t see except for under microscope
 Sludge: can happen with prolonged fasting; can be gritty 
o Predisposes to chronic pancreatitis
 Can also cause recurrent acute pancreatitis
 Treatment: sphincterotomy (drain bile duct)

Ultrasound: gallstones vs microlithiasis

 Gallstones have characteristic acoustic shadow behind them
 Microlithiasis (sludge) is more amorphous

Other causes of acute pancreatitis:

 ERCP: Endoscopic retrograde cholangio-pancreatography (can irritate  cause pancreatitis!)
o Stent pancreatic duct (e.g. post-ERCP) to prevent
 Variations in duct anatomy
o E.g. pancreatic divisum: improper drainage (ducts don’t form properly); predisposes
 Hypertriglyceridemia
o TGs have to be really high (>1000 mg/dL) –e/g/ familial dyslpidemia
o Can cause chronic pancreatitis too
 Genetics (e.g. young onset, recurrent acute pancreatitis, chronic pancreatitis) – examples below
 Others: Autoimmune, drugs / iatrogenic, IBD-related, infectious, inherited, trauma, vascular, toxic, cancer, etc
47
Etiology: Genetics (probably FYI only)

PRSS1: Protease, serine 1

 Mutations in cationic trypsinogen gene result in hereditary pancreatitis (aut-dom)
 Gain-of-function trypsinogen (↑ activation, ↑ survival)
 Shifts balance to active trypsin
 Early onset (teens) recurrent acute pancreatitis
o ↑ lifetime risk of pancreatic adenocarcinoma (30-60%)

SPINK1: Serine protease inhibitor, Kasal Type 1

 Polymorphisms in this gene (1:400) are ↑ in childhood chronic pancreatitis, idiopathic pancreatitis
 Acts as disease modifier

Cystic Fibrosis (CFTR)

 Homozygous  classic CF (pancreatic insufficiency)
 Compound heterozygous: mild CF or minimal CF features  ↑ risk of chronic pancreatitis (modest increase - dz modifier)

Note: Pancreatic cancer risk ↑ in chronic pancreatitis (including CP due to genetic forms)

Etiology: Drugs
Whole big list – almost everything you can think of; stronger associations listed below
 Azathioprine  Thiazide diuretics  Exanatide (Byetta)  Valproic Acid  L-asparaginase
 6-MP  Furosemide  Corticosteroids  Pentamidine  Octreotide
 Sulfonamides  Estrogens  Tetracyclines  IV lipid infusions

Etiology: Infectious diseases

 Mumps is classic; coxsackie too; CMV, others esp. in immunocompromised host
 Occasionally see viral etiology in kids

Presentation of Acute Pancreatitis

 Abdominal pain  Low grade fever  Jaundice
 Nausea / vomiting  Abdominal guarding (if backing up into liver)
 Tachycardia  Loss of bowel sounds

Diagnosis of Acute Pancreatitis

 Serum labs (very helpful) – use 2-3x normal as cutoff; moderate specificity
 Ultrasound: specific, best for gallstones, poor sensitivity
 CT (esp. IV contrast): good sensitivity, specificity, can detect necrosis

Serum labs: Amylase & lipase

 Amylase can be elevated in other conditions (parotiditis, tumors, etc)
o Macroamylasemia: some people just have ↑ amylase all the time
 Lipase rarely elevated in conditions other than pancreatitis (more specific)

48
Course / Prognosis
Mortality (remember, most cases are mild)
 ≈ 10% overall in hospitalized pts; 20-30% if necrotic pancreas
 Mortality from:
o Early: systemic inflammatory response syndrome, MOF
o Late: MOF, pancreatic infections, sepsis

How to follow clinical course?

 Bedside assessment tends to underestimate severe dz  Imaging criteria (fluid collections, necrosis)
 Scoring systems can be helpful (more objective)  Serum markers (CRP, cytokines – often nonspecific)

Early indicators of severity

 Tachycardia, hypotension  Oliguria
 Tachypnea, hypoxemia  Encephalopathy
 Hemoconcentration

Systemic responses to acute pancreatitis

 Systemic inflammatory response syndrome (SIRS): Bad for prognosis
o 2+ of: Temp (> 38 or <36), tachypnea, tachycardia, WBC (> 12k / <4k or >10% bands)
o Without infection
 Multiple-organ dysfunction syndrome:
o dysfunction of more than 1 organ requiring intervention to maintain homeostasis
 ARDS: with severe onset; delayed onset, more common with hyperlipidemia

Grey-Turner / Cullen signs

 Ecchymosis (bruising) in one or both flanks (Gray-Turner) or periumbilical (Cullen)
 Indicates extravasation of pancreatic hemorrhage into those areas
 Acute pancreatitis; means poor prognosis

Ranson’s criteria: Help predict severity of acute pancreatitis

Management of Acute pancreatitis

 Supportive care, pain control, pancreas rest, nutrition, assess / treat complications
 Treat underlying cause (e.g. gallstones)
o Gallstones: extract from common bile duct with little basket
o Difficult surgery (often pretty inflamed)
 CT: assess severity / complications – dx, prognosis, complications
 Jejunal tube: bypass stomach / duodenum → pancreatic rest
o Probably better than TPN
 Usually don’t advocate prophylactic abx (but debated)

CT in Acute Pancreatitis (FYI)

Fluid collections, necrosis, pseudocysts, abscesses
 Fluid collections: common, may be complex, usually resolve spontaneously, should drain if infected / symptomatic
 Necrosis: pancreas doesn’t enhance well (not perfusing), leads to systemic complications
o Can lead to hemorrhage / infection
o Can be sterile or infected (infected  necrosis with gas)
 Pseudocysts in pancreatitis
o No epithelial lining (unlike cysts), need to ddx vs neoplasms, non-neoplastic cysts
o Localized collections of fluid, > 4wks after disease onset
o Ductal disruption, necrosis can be causes
o Complications: Pain, obstruction, infection, erosion, bleeding, rupture
 Management: pancreatic rest, wait for healing (make sure not neoplastic!); drain endoscopically now
49
 Acute fluid collection Necrosis (↓ enhancement) Severe necrosis (no enhancement)

Infection: necrosis with gas Pseudocysts Acute Pancreatitis with

(gas-producing bacteria) hemorrhage

Chronic Pancreatitis
 Gradual fibrotic destruction of pancreatic tissue
 Recurrent acute pancreatitis can lead to chronic pancreatitis (but could also have no Hx of AP)

Pathogenesis: proposed mechanisms

 Intraductal plugging, obstruction  Necrosis – fibrosis
 Direct toxins, toxic metabolites  Immune dysregulation
 Oxidative stress  Really unknown

Clinical features
 Abdominal pain (recurrent / chronic pain, really bad, often narcotic addiction)
 Don’t want to eat (avoid pain), ± steatorrhea  malnutrition
 Psychosocial decline, work-loss, big health care expenditures

Remember: need >90% pancreatic compromise before steatorrhea starts (lots of functional lipase reserve)

Histology: see fibrosis, loss of acinar tissue

Pathogenesis
 Most alcoholic
 Idopathic or other (CF, hereditary pancreatitis, hypertriglyceridemia,
autoimmune, tropical) – see next few sections

Alcoholic chronic pancreatitis

 Heavy & prolonged use (150g/day x 5 yrs)
 Males ≫ F (peak age 35 yo), but females can get it with less alcohol use
50
Signs, symptoms
 Recurrent attacks (70%)  Calcifications, ductal changes common
 Pain more severe than other CP causes  Progresses to pancreatic insufficiency faster than non-etOH etiologies

Mechanisms
 Calcification  plugging of ducts  ↓ blood flow
 Direct toxic effects, fibrosis  Cytotoxic lymphocytes

Idiopathic chronic pancreatitis

10-30% of chronic pancreatitis; bimodal presentation
 Early onset: 1st/2nd decade with severe abdominal pain; structural / functional changes later
 Late onset: 30/40 yo with minimal pain but pancreatic insufficiency, calcifications

Autoimmune pancreatitis
Lymphoplasmacytic infiltration of pancreas (lymphocytes & plasma cells!)
 Milder pain than other chronic pancreatitis
 Classic: diffuse pancreatic enlargement
 Associated with autoimmune conditions
(Sjogren’s, PBC, thyroiditis, PSC, interstitial nephritis, SLE)

Labs: serum IgG4, hypergammaglobulinemia

Imaging: looks like sausage, big, can look like mass

TREATMENT: STEROIDS!
 IMPORTANT: this is one you can actually treat!

Histology: periductal lymphoplasmacytic infiltrates (lymphocytes, plasma cells)

Tropical chronic pancreatitis

 Endemic to developing world
 Young children & adults (<40 yo)
 Nutritional (dietary toxins – e.g. Cassava plant; nutrient deficiency: Zn/Cu/Se)
 Episodic pain with speedy progression to pancreatic insufficiency, calculi, ductal dilation

Diagnosis of chronic pancreatitis

 Can be more challenging than AP, especially early chronic pancreatitis
 Usually based on anatomic / functional test

Imaging: pretty much everything you can think of

Classification: used to grade with ERCP before, now maybe MRCP better?
 Minimal change CP: absent imaging findings, painful, hard to treat (don’t want to do surgery w/o cause!)
 Etiology-based classifications too

EUS: see calcification, echogenic strands

(whiter duct walls on U/S)

ERCP: mild chronic pancreatitis ERCP: severe chronic pancreatitis

(shouldn’t be able to see branches) (lots of dilatation, etc.) 51
Function tests
 Give secretin, measure bicarb production by gland (pretty accurate)
 If steatorrhea: see in stool (sudan test)
 Can measure pancreatic enzymes in stool (not as accurate)

Management of chronic CP
 Stop alcohol / smoking
 Analgesics: non-narcotics / narcotics
 Pancreatic enzyme therapy (treat steatorrhea / blunt pain, ↓ endogenous CCK, maybe resting pancreas?)
 Treatment of malnutrition

Pain management
 Destroying nerves (neurolytics) helps in pancreatic cancer
 Stone removal / duct decompression can help
 Analgesics too

ERCP (stone removal / stent placement); no proven long-term pain relief

Surgery:
 
nd
for pain + dilated duct (pancreaticojejunostomy) for pseudocyst repair (2 line)
 for pain + nondilated duct (resection)  for biliary stricture

How are symptoms caused?

Steatorrhea
 ↓ lipase / coplipase production (pancreas hurt)
 Duodenal pH changes (↓)
o Inactivate pancreatic lipase if pH < 4.5
o Bile salts precipitate at low pH
 End result: FA in stool

Pain
Pain: Etiology  Management
Etiology Treatment
Glandular damage Analgesia
 Fibrosis of tissue
 Small duct ischemia
Pancreatic duct blockage ERCP (how bad are Sx?)
Pancreatic pseudocysts Drainage

52
 Pancreatic Cancer
Epidemiology / Etiology
 th
Pretty rare (~ 1% lifetime risk) but 4 most common cause of cancer death in USA

Risk factors for Pancreatic Cancer

 Smoking (doubles risk – causes 26% pancreatic cancer)
 Family History
o 10% have positive FHx – may be good to screen
 Diet (vitamin B12, etc.)
 Obesity (~70% increase in risk)
 Diabetes Mellitus
o 2x increase if long-term diabetes
o 1% new-onset diabetes develop pancreatic cancer within 3 years
o Insulin maybe involved?
 Occupational exposure
 Chronic pancreatitis
 ABO blood groups (A/B > O) – no idea why

Inheritability
 Inheritance involved in 10-20% pts
 “Familial pancreatic cancer”: pancreatic cancer in 2 relatives

Specific Genes (syndromic causes)

 BRCA2 (breast cancer) (3.5-10x↑ risk)
o ~ 7% pts with “apparently sporadic” disease (BC is common!)
o ↑ in Ashkenazi Jewish pts
 PALB2 identified in GWAS, risk unknown
o Fanconi anemia gene
 Hereditary Pancreatitis (50-80x↑ risk)
 FAMMM (family atypical multiple mole-melanoma) syndrome (20-34x ↑ risk)
 Peutz-Jeugers
o Melanocytic macules in buccal mucosa, digits
o Multiple GI hamartomatous polyps
o ↑ risk GI/GU/lung cancer
o 132x↑ risk pancreas cancer
 HNPCC (Hereditary non-polyposis colon cancer syndrome)

Both genetic & epigenetic events in pancreatic cancer:

 Mutations, large deletions, amplifications, genetic instability, mitochondrial mutations, DNA methylation

Pathology of Pancreatic Neoplasms

 “Usual” ductal adenocarcinoma of the pancreas

 PanINs (Pancreatic intraepithelial neoplasia, commonest
 IPMN (Intraductal papillary mucinous neoplasm)
 Mucinous cystic neoplasm
 Islet cell neoplasms
 Rare (acinar, serous cystadenoma/adenoca), lymphomas, small cell

53
Pancreatic Intraepithelial Neoplasia (PanINs)
Most pancreatic cancer evolves this way

Histology Genetic changes

Early cuboidalcolumnar changes HER2, K-Ras
Later dysplasia p53, DPC4, BRCA2

↑ prevalence of PainINs with age (esp. low-grade)

Infiltrating adenocarcinoma:
 ductal structures stain (L)
 Propensity to invade nerve (middle) - painful
 Invasion (R)

Death from mets or local problems

Pancreatic Cystic Neoplasms

Often benign lesions but also represent larger cysts that can progress to adenocarcinoma
 Intraductal papillary mucionous neoplasms: via CIS stages, etc.
 Mucinous cystic neoplasms: have a classic ovarian
stroma that can lead to cancer

Incidentalomas
 Prognostic dilemmas, ↑ $$$
 ↑ prevalence with age
 E.g. pancreatic cystic neoplasms(above)

Prevention of pancreatic cancer

Not yet in wide clinical practice; in trials to try to detect / treat asx individuals
 Use imaging + biomarkers in combo
 Screen high-risk individuals with safest modalities
 Try to develop markers to ID advanced neoplasia

Clinical Presentation of pancreatic cancer

Varies (anatomical location, local extension, biology)
 Painless obstructive jaundice  Wt loss / cachexia
 Back pain (pancreas = retroperitoneal)  New onset DM

Generally a late diagnosis (only 15% present with resectable cancers)

 4% 5-year survival!
54
Diagnosis: Clinical + imaging; no good serum test yet

Management of pancreatic cancer

Many are inoperable; hard to treat with radiation (lots of vital structures around)
 Quickly progress to bad disease (lots of vital stuff around

Whipple procedure (pancreaticoduodenectomy)

Many patients not eligible (depends on extent)
 Take out head of pancreas, gall bladder, duodenum
 Stick pancreas to jejunem; hook up the bile or hepatic duct

Volume matters
 Pts do well (if doc & support staff experienced)
 Need to refer to HIGH VOLUME CENTER (% mortality ↓↓↓)

Even with resection: survival is poor (20% 5-year survival!)

 ~ 6mo survival w/o surgery

Oncology of Pancreatic Cancer

Staging: resectable, borderline resectable, locally advanced, metastatic
 Definitions based on involvement of arteries
o Surgeons need to have SMA available for resection
 Surgery if possible, chemo for advanced cancer
o Chemo: Gemcitabine, 5-FU (older), GTX, gem/abraxane, mitomycin C, PARP inhibitors (newer)

If you have Fanconi/BRCA mutations (e.g. PALB), ↑ susceptibility of cancer to dsDNA strand breaking agents

Complications of pancreatic cancer

 Malignant Biliary Obstruction  Weight Loss
 Malignant Duodenal obstruction  Depression/Coping
 Pain

Weight loss: Pain management:

 Pancreatic enzymes if duct blocked  Identify cause of pain
 Fish oils for cachexia (EPA)  Narcotics
 Appetite stimulants for anorexia  Celiac plexus neurolysis (palliate if not going to live long)

Hope is important (pts need to recalibrate life; help them enjoy what’s left)

55
 Pediatric GI

Case 1: Meckel’s Diverticulum

Young boy (<2yo), painless rectal bleeding
 red stool (guaiac + = blood), pale, tachycardia. WBC nL, ↓ Hct (normal RBC indices), clear radiography.

Diagnostic tests to do?

 Endoscopy: hard to do in children; don’t see whole GI tract (need to sedate!)
 Barium enema: can see whole GI tract!
 NG Lavage (upper GI bleeds) – good to look for sources; nurses can do, etc.

Dark-red to maroon blood in stool – probably upper GI tract (through acid) or means it’s been there for a while

Rectal bleeding in young boy

 Intussusception? (< 2yo) – but would be painful
 Anorectal fissure? (doesn’t make Hb go down)
 Meckel’s diverticulum

Intussusception
 One part of bowel folds into another (like telescope)
 Edema  swelling, pressure  ischemia
 Radiography  see where air stops!

Meckel’s Diverticulum
Embryological remnant of vitilline duct; becomes symptomatic if ulcerates into artery  bleeds

Rule of 2’s
 2% of population
 2 cm long
 Within 2 feet of ileocecal valve

Diagnosis: 99mTc-pertechnetate scan (“meckel’s scan”)

 Often missed by CT, abdominal X-ray, etc.

Case 2: Crohn’s disease

12yo M: intermittent abd. pain, early satiety & nausea over last year (worse last few mo), lost 5 lbs (weird for 12yo);
 No vomiting / hematemesis / diarrhea / constipation / melena / dysuria / jaundice
 Same size as 9yo brother (rough genetic estimate: probably should be bigger)
 PE: RLQ tenderness; 10th % for height, 5th for weight & has ↓ with time, anal fissure / skin tag on rectal exam
o Tender, nodular, erythematous lesions on bilateral shins
o Stool is guiac positive
o RLQ: appendix, ileocecal valve, colon are there

Check: allergies (food/drugs), skin rashes, joint pain, school attendance (social?), mouth ulcers, night-time awakening
DDx: Crohn’s disease, Hirschprung’s, Celiac, others
Tests to do: CBC & ESR (if elevated ESR & ↑ WBC, then probably Crohn’s!)
 Both come back positive: Crohn’s disease
 Confirm with: colonoscopy & upper GI endoscopy / EGD with biopsies (want to see both; distinguish CD/UC)

Case 3: Cystic Fibrosis

56
4mo Caucasian Male
 Poor growth, irritability, 3-5 malodorus, bulky, non-blood stools / day
o rectal protrusion (RECTAL PROLAPSE) 2 days prior to visit (spontaneously resolved)
o Has been consuming cow’s milk protein based formula
o Was full term at birth (95th %ile), no vomiting, healthy 3 yo sister
 PE: irritable, cachexic, visibly sucking at bottle

Rectal Prolapse: tissue that lines the rectum falls down into or sticks through the anal opening.
 Sx: reddish-colored mass that sticks out from the opening of the anus, especially following a bowel movement
o The lining of the rectal tissue may visible and may bleed slightly.

Diagnosis: Cystic Fibrosis

 Confirm with sweat chloride test

Case 4: Pyloric Stenosis

6wk M with 2wk Hx of recurrent nonbilious (not green, etc) vomiting 15-20m post-meals, 10th %ile weight, 50th %ile
length, normal birth weight (losing calories – normal baby; want ≈ 100 cal/kilo for babies)
 small firm mass in mid epigastric region (“olive”)
 reflux, gastroparesis, others could be on list of DDx

PYLORIC STENOSIS
 “olive” (small firm mass in mid-epigastric region is pathognomonic)
 More common in males

Diagnosis: abd. U/S, PE, upper GI series

 Hypochloremic metabolic alkalosis, hypokalemia associated
 Upper GI series: : muscle itself becomes thickened; see stream of barium going through

Therapy:
 Initially: correct fluid, electrolyte imbalances
 Surgery is treatment of choice (pyloromyotomy) – open up thickened muscle

Diagnostic Studies: overview

Upper GI: radiology stops in everything through 3rd portion of duodenum (including C-sweep)
 Need to see duodenum cross bowel twice to rule out malrotation
o bowel doesn’t rotate right – dysphagia, pain
Barium Enema: see whole colon up to terminal ileum
Esophagogastroduodenoscopy (EGD) = upper endoscopy: see through to duodenum
Colonoscopy: colon & terminal ileum
Endoscopic Retrograde Cholangiopancreatography (ERCP): inject contrast; visualize pancreatic / biliary tracts

57
 Liver Tests
Overview
Major roles of the liver (tests based on these)
 Metabolism  Storage
 Detoxification  Digestion (bile)

General Categories of Liver Tests

Test Measures…
Serum bilirubin Overall function
Serum enzymes Cellular injury, cholestasis
Serum albumin, Prothrombin time Biosynthetic capacity
14
C-Aminopyrine BT (research only), Urea synthesis Hepatocellular function
Autoantibodies, Viral Markers Specific tests for liver diseases

Usefulness of liver tests Limitations of liver tests

 Noninvasive screening for liver dz  Low sensitivity
 Pattern can alert recognition of general type of liver disease  Lack of specificity
 Indispensable for follow-up and management  No single test accurately assesses liver function

Bilirubin
Normal metabolism:
 Hemoglobin / myoglobin broken down  heme unit + Fe
 Heme converted to indirect / unconjugated bilirubin
o transported with albumin

 Uptake by liver & glucuronidation (conjugation) 

direct / conjugated bilirubin

 Direct bili now soluble; secreted into bile  gut

o Gives color in stool

 Colonic bacteria reduce some direct bili  urobilinogen

 Urobilinogen:
o 20%  reuptake  enterohepatic circ.  back to liver
o 2%  excreted in urine

Note that:
 ↑ indirect bilirubin (unconjugated) does not give you change of color in urine
 Direct bilirubin (conjugated) – gives you color in stool; gives dark urine if there’s impaired bile excretion
o < 20% of total bilirubin is normal
 Urobilinogens: some excreted in urine (but does not give color – need Ehrlich’s reagent to detect)
o Absent from urine in total biliary obstruction; ↑ in urine in hemolysis

DDx of Abnormal Bilirubin

↑ indirect bilirubin ↑ direct and total bilirubin
st
dark urine is 1 symptom (before jaundice)
 hemolysis (↑ RBC breakdown: sickle cell, etc.)  Acute & chronic liver diseases
 Gilbert’s syndrome (decreased uptake of bilirubin into liver)  Cholestasis (intra/extrahepatic)
 Crigler-Najjar syndrome (peds – probem with conjugation)  Dubin Johnson & Rotor syndromes
(prevent bilirubin from entering bile)

58
 Differential diagnosis of jaundice
Hemolysis Liver disease Biliary obstruction
Bilirubin (direct > 20%) No Yes Yes
Color urine nL Darker Dark
Color stool nL nL or light Light
Urine urobilinogen ↑ nL or ↓ ↓

Serum Aminotransferases (AST/ALT)

What determines usefulness (e.g. for a given disease?)
Specificity Sensitivity
 Content of enzyme in liver
 Presence of enzyme in liver as compared to other organs
 Synthetic rate
 Presence in subcellular organelles affected in the particular
 Ready release from subcellular organelles / cell
liver disease
 Rate of clearance from blood

Characteristics of AST/ALT as Diagnostic Tests

 Poor correlation between level of elevation and extent of liver cell necrosis (not a linear relationship)
 Rapid decline from high levels is consistent with a single episode of necrosis
o e.g. hypotension, fulminant hepatitis - big release of enzymes from necrosis, then cleared
o want to see them falling slowly
 Elevations > 500 I.U. are rare in extrahepatic obstruction
 In alcoholic liver disease, elevations are low (<300 I.U.) with AST > ALT
o Consider other causes (e.g. acetaminophen OD) on top of alcohol!
AST vs ALT
 More AST in mitochondria
 AST is cleared more rapidly than ALT
 Pyridoxal-5’-phosphate deficiency – causes ↑ AST vs ALT

Alkaline Phosphatase
Causes of ↑ alkaline phosphatase (note: not specific for liver dz!)
 Intrahepatic cholestasis
 Extrahepatic biliary obstruction
 Space-occupying lesion in liver (neoplasm, granuloma)
 Bone disease (e.g. Paget’s disease)

rd
Pregnancy (3 trimester – placental alk phos!)

Why is alk phos ↑ in cholestasis?

 Synthesized in hepatocyte, usually excreted into bile
 If bile blocked, more goes to bloodstream
 Also ↑ synthesis (upregulation) in obstruction (can’t do it if
hepatocyte damaged

5’-nucleotidase
 Phosphatase specific for liver; not present in bone/placenta/intestine
 Use: to establish that alk phos elevation is due to liver problems
o Unexplained ↑ alk-phos: get a 5’-nucleotidease

Gamma-glutamyl transpeptidase
 Similar use to 5’ nucleotidase but not as specific; the lecturer wasn’t a fan of it.

59
 Prothrombin time or INR Serum albumin
PT / INR elevated in: Serum albumin ↓ with:
 Vitamin K deficiency  ↓ synthesis (liver)
 ↓ synthesis of factors I,II,V,VII,X  Malnutrition too
(e.g if liver compromised) Need to feed patient if albumin is low!

Poor prognosis if > 5sec above control Hypergammaglobulinemia

Ig ↑ in…
Treatment
IgG Chronic liver disease
 Give vitamin K IgA Alcoholic liver disease
 Consider liver transplant IgM Primary biliary cirrhosis

Cholestasis
Cholestasis: decreased bile flow
Diagnosis:
Physiological Morphological Clinical Lab
Stagnation of bilirubin  Jaundice  ↑ bilirubin
↓ bile flow  ↑ alk phos
in bile canaliculi, hepatocytes  Pruritis  ↑ bile acids

Intrahepatic cholestasis
Etiology: most liver diseases! Hepatitis, biliary cirrhosis, drug-induced, etc.
 Sepsis-associated cholestasis is a big one

Extrahepatic cholestasis / biliary obstruction

Causes: Choledocholithiasis, bile duct narrowing, pancreatic cancer (head of pancreas)
Diagnosis: U/S initially, ERCP / PCT / MRCP to image bile ducts, liver biopsy

Liver tests in cholestasis

Enzymes:
 ↑ serum bilirubin; direct fraction > 20% total
 ↑ alk phos (5’-nucleotidase, gamma-glutamyl transpeptidase too)
 Minimal or no elevation of serum aminotransferases

Primary biliary cirrhosis

Epidemiology: 30-65 yo, primarily women (95%), 1/10k

Symptoms: fatigue, pruritis, xanthoma
Lab tests: AMA (antimictochondrial antibodies) in 90-95%
Treatment: cholestyramine (pruritis), calcium + vit D + bisphosphonates (osteoporosis), urosdeoxycholic acid
liver transplant if needed

Alcoholic hepatitis

Increased susceptibility to alcoholic hepatitis:

 Females (smaller, less body water, metabolize faster – more acetaldehyde)
 Heterozygous for deficient aldehyde dehydrogenase (flushing!)
 Nutritional factors (undernourished or overnourished)

60
 Non-alcoholic steatohepatitis
Epidemiology: Very common these days (↑ obesity): 1.2-8.0 % of referrals
 mostly women (65-80%), 41-60 yo
 many have obesity (80%), DM type II (50-75%), hyperlipidemia (20-80%)

NOTE: ALT > AST (differentiates from alcoholic hepatitis)

Other lab values:

• ↑ Aminotransferases: 2-3X>normal
• ↑ Alkaline phosphatase (50%)
• ↑ iron and ferritin common
• Bilirubin and albumin usually normal

Diagnosis:
• Ultrasound (bright liver) – see pic
• Liver biopsy: 15-20% show fibrosis or cirrhosis; hyaline bodies too

Inherited Liver Diseases

Disease
Hemochromatosis
Wilson’s disease
Porphyria cutanea tarda
α1-antitrypsin deficiency
Autoimmune hepatitis
Primary biliary cirrhosis
Viral hepatitis
Test(s)
Serum iron, % sat, ferritin (measure fasting iron)
Serum ceruloplasmin, urine copper
Urine uroporphyrin
Phenotype (AAT)
ANA (anti-nuclear antibodies)
AMA (anti-mitochondrial antibodies)
Viral markers

Hemochromatosis
Iron storage disease with widespread tissue injury
 Autosomal recessive; associated with HLA-A mutation (short arm of chromosome 6) – homo- or hetero-zygous

Clinical features:
 Manifestations of chronic liver disease  Skin pigmentation  Hypogonadism
 Carbohydrate intolerance  Cardiac arrhythmias / failure  Arthropathy (pseudogout)

Labs: ↑ serum iron (> 170 μg/dL), ↑ % transferring sat (>55%), ↑ serum ferritin (> 300 ng/mL)
 Can do liver bx or hemochromatosis genotype too

Treatment
 Phlebotomy to remove iron; chelating agents (not as good)

Wilson’s disease
Copper accumulation in liver / brain
 Autosomal recessive, women > men

Presentation: acutely (hemolysis) or as chronic liver disease

 Can see Kayser-Fleisher ring (copper in cornea) in eye in 50%

Labs: ↓ serum ceruloplasmin, ↑ liver / urine copper

Treatment: chelating agents
61
Porphyria cutanea tarda
Deficiency of uroporphyrinogen decarboxylase (5th enzyme in heme biosynthesis

Presentation: Cutaneous photosensitivity (pic),

 Complications: Portal inflammation, cirrhosis, hepatocellular cancer

Labs: ↑ hepatic iron, ↑ urinary uroporphyrin, anti-HCV Ab often

Acetaminophen hepatotoxicity
Metabolized to N-acetyl-p-benzoquinone amine (active metabolite)

Toxicity is dose related (>15g in 80% cases)

 Blood level > 300μg/mL @ 4h is severe
 6-25% fatality rate

Course
Day 1 anorexia, nausea, vomiting
Day 2 abatement of sx
Day 3-5 overt hepatitis (↑ PT, hypoglycemia, jaundice)

Treatment: give N-acetyl cystine during 1st 16h and can prevent all these symptoms
 Supportive therapy, liver transplantation if needed

Autoimmune hepatitis

Epidemiology: Female>M, 5-200/million

Presentation: acute onset in 40%, cirrhosis @ presentation in 25%, extrahepatic manifestations common
Symptoms: Abdominal pain / tenderness, hepatomegaly (50%), amenorrhea / acne, fatigue, anorexia, intermittent fever,
arthralgias, arthritis, polymyalgia, skin rash
Prognosis: 50% 5 yr survival w/o rx
Treatment: Prednisone (good result – need to dx this one!)

Lab features: ↑ aminotransferases, hypergammaglobulinemia, autoantibodies (ANA > 1:80)

Biopsy: Periportal hepatitis, focal liver cell necrosis, lymphoplasmacytic infiltrates

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 Hepatitis: Basics

Blood supply to the liver

The only organ that uses venous blood (70-80% supply)
 In: Portal vein, hepatic artery, bile duct
 Out: Hepatic vein to IVC
 Note: bile ducts use hepatic arterial supply
(compromise hepatic artery  bile duct damage!)
Same structure preserved microscopically
 In: Portal triad: vein, artery, bile duct
 Blood flows through sinusoid
 Out: central vein HV

Transaminases (liver enzymes)

Hepatic enzymes that catalyze the transfer of amino groups to form hepatic metabolites of pyruvate (ALT) and oxaloacetate (AST)

Alanine aminotransferase (ALT) Aspartate aminotransferase (AST)

Specificity to liver
In hepatocyte cytoplasm
In hepatocyte mitochondria
Variation (zone 3-zone 1)
Half-life
More specific to liver Less specific: in muscle (↑ in seizure, MI, etc.)
LOTS (ALT predominates in cytoplasm) Less but still present
Most AST in mitochondria (80%)
Doesn’t change ↑ AST in zone 3 cells
Longer Shorter (AST↓ more rapidly)

Aspartate aminotransferase (AST)

 Remember: Most AST in mitochondria (80%), ↑ AST in zone 3 cells
 So ↑ AST (AST > ALT) if
o mitochondria damaged
o zone 3 cells affected

Both released from hepatocytes during cellular injury

 “Normal” liver enzymes: what’s in the blood reflects what’s in the hepatocytes (so ALT > AST)
 Injury (hepatitis): ALT, AST leak out, ↑ serum ALT and AST (ALT > AST, but both ↑)

Characteristic Patterns of Liver Enzymes

Ischemia / acetaminophen toxicity: Rapid, high spike

 Viral / other drugs: usually have slower rise
 Good for figuring out etiology

Alcoholic Hepatitis
 AST:ALT > 2:1
 AST rarely higher than 350 – if so, look for another cause
63
 Basics of Hepatitis
Hepatitis = liver inflammation
 Doesn’t imply contagious
 High AST / ALT don’t tell you “how sick the liver is” or “how bad the hepatitis is”
o Don’t correlate with outcome, Just tell you that something’s wrong

Zones of the Liver Lobule

Zone 1: closest to portal triad
Zone 3: closest to central vein

Cells near central vein (zone 3) have

 Less oxygen (more susceptible to ischemic injury)
 Less ALT (AST levels are the same)

Alkaline Phosphatase
Alk Phos = “sensor of bile flow”
 Hepatocytes: make the components of bile
 Alk phos: located on membrane along bile canaliculus

 If you block bile flow (cholestasis, mass)

o ↑ production of alk phosphatase
o Leaks out into blood (can’t go into bile!)

Bile acids also ↑ in blood when bile flow blocked (can’t go into bile!)

Bilirubin
Byproduct of heme degradation
 glucoronidated (conjugated) by hepatocyte to make it water soluble

Getting bilirubin from blood into hepatocyte is “free” – no energy required

 So if hepatocyte damaged, will keep importing & conjugating bilirubin

Conjugated bilirubin is really concentrated in bile,

so it “costs energy” to pump bilirubin into canaliculus against the gradient

 When hepatocyte is damaged: can’t excrete in bile (not enough energy)

 Direct bilirubin goes back into blood!  Direct hyperbilirubinemia!

Hepatocellular vs Cholestatic Liver Disease

Predominantly Hepatocellular Predominantly Cholestatic
 ↑ Aminotransferases (AST / ALT)  ↑ alkaline phosphatase
 ↑ GGT / 5’-NT / bile acids
(hepatocytes messed up) (bile flow is the problem)
Can have ↑ bilirubin in both

Cholestasis: disorder of cholepoesis & bile secretion, as well as stoppage of bile flow in intra/extrahepatic bile ducts
 Clinically: ↑ bile acids / enzymatic markers of cholestasis (mainly alk phos, confirm hepatic with GGT/5’NT)

↑ Bilirubin:
 in hepatocelluar problems (hepatocytes don’t have energy to pump it out)
64
  in cholestasis (not removing bile  ↑ gradient)

Jaundice
Jaundice is both a symptom and a disorder of bilirubin metabolism

DDx of jaundice by Lab Tests:

Hemolysis Liver dysfunction Biliary disease
Total bili ↑ ↑↑ ↑
Indirect bili ↑↑ ↑ No Δ
Direct (conj) bili No Δ ↑↑ ↑
Alk phos No Δ No Δ or ↑ ↑↑

Hepatitis: Acute vs Chronic

Acute Chronic
lasts < 6 months lasts > 6 months
recent / sudden persistent over time / years

Cases
1. 22yo med student: AST = 200 (ULN 35), ALT = 90 (ULN 35), alk phos 130 (ULN 110)
a. Hepatitis, even if bilirubin 2.0 (worse)
b. Was out partying all night: does that make sense? Yes: AST:ALT > 2 = alcoholic hepatitis

2. 46yo M with pneumonia, hypotensive yesterday with SBP 40 mm Hg, BP 100/55, h/o Tylenol 2 tabs qd x 5d, No EtOH or
past h/o liver disease. AST 5500, ALT 3000, bilirubin 6.3, alk phos 720
a. Not enough Tylenol to be the cause (but could be if Hx of EtOH intake)
b. Severe hepatitis due to ischemia: maintain BP/perfusion, expect to resolve quickly

3. 40 yo F with RUQ abd. pain; afebrile & icteric. Suspect gallstones / choledocholithiasis with dilated intrahepatic bile ducts
a. Bilirubin will be ↑ & mostly direct, Alk phos ≫> AST / ALT, Cholestatic disorder
b. Indirect hyperbilirubinemia will not be predominant; she does not have a hepatitis disorder

65
 Viral Hepatitis
Hepatitis: inflammation in the liver; see also the ID/Micro lecture (similar content)

Remember: Hepatitis doesn’t just mean Hepatitis Viruses!

Non-infectious causes of hepatitis:
• Alcohol use • Halothane • Other medications
• Acetaminophen • Isoniazid • Shock or acute obstruction

Non-viral causes of hepatitis:

 Pneumococcal pneumonia  Tuberculosis  Syphilis
 Leptospirosis  Histoplasmosis
 Sepsis  Ricketsial infections

Viral causes: CMV, EBV, HIV, adenovirus, Hepatitis viruses

Epidemiology
In USA: Acute Viral Hepatitis
 Hepatitis A > B > C

Before 1970: 1:3 chance of getting hepatitis from blood transfusion

 After 1970: stopped paying donors (drug users sell blood!)
 Other improvements: HCV tests, anti-HIV tests, ALT testing, etc. – now risk basically zero

Typical Course of Hepatitis

1. Exposure
2. Incubation (asymptomatic)
3. Prodrome (malaise, etc)
4. Symptoms & Jaundice (usually tested here)
5. Symptoms resolve, convalescence
6. Persistence for some of them

Exposure HAV & HEV HBV & HDV HCV

Transmission: (insert charts)
Fecal-oral +4 0 0
Hep A / B are fecal/oral
Sexual +1 +4 +1
Hep B is the big sexual transmission one
Blood +1 +4 +4
Hep C is blood contact mainly
Perinatal +1 +4 +2

Incubation: overlap (cant’ tell which one based on timing) HAV+HEV HBV+HDV HCV
Incubation (weeks) 2-6 6-24 6-300
Jaundice: HAV/HBV more likely to cause; HCV more rarely
% Jaundice 30-70 20-40 15-25
Persistence: inversely proportional to severity of symptoms
% Persist 0 5 80
 (↑ persistence in HCV but no jaundice)

Lab tests
 Transaminases: ↑ ALT, AST > 10x normal
 IgM antibody
 Neutralizing antibodies (= recovery)
 Viral particles (= ongoing infection) – protein & nucleic acid

66
 Prevention & Treatment

Vaccines for HAV and HBV

Medical treatment: HAV HBV+HDV HCV HEV

HAV: None, prevent secondary cases IG Pooled Specific No ?
HBV: Pegylated interferon alpha, or nucleoside/tide analogues Vaccine Yes HBV (not HDV) No No
HCV: Pegylated interferon alpha and ribavirin

Hepatitis A virus
The virus:
 Picornavirus (RNA virus)
 No envelope (bile stable)
 Cytopathic (ruptures) pathogenesis
 Capsid proteins elicit universal neutralizing antibody
(all one serotype)

Fecal-oral transmission; rarely blood (would have to be viremic)

 Endemic virus, esp. in developing nations

Presentation: Jaundice is common,

 essentially no chronic disease

Diagnosis: IgM anti-HAV (acutely)

Treatment: rest
Prevention: pre/post-exposure (vaccine)

Hepatitis B
#1 cause of liver cancer worldwide (2B infected)
 Esp. in developing countries (↓ with vaccine)

Transmission: many ways to get hep B (why it’s so prevalent)

 Vertical transmission (mother-child) common in developing countries
 Sex, blood / body fluids, transfusion, transplants, etc.

Why so transmissible?
 makes TONS of virus and extra surface antigens (serum packed)
 environmentally stable (can hang out on tables, equipment, etc).

The Virus:
 Pararetrovirus (DNA with RNA intermediate)
 4 genes (C,P,S,X), 5 proteins, lots of overlapping reading frames
o efficient but constrain evolution (vaccine!)
o Drugs: may cause immune escape
(target protein  virus mutates  change overlapping surface antigens  immune system loses response)
 Oncogenic (X-protein may play role)
 Can integrate into human genome, but not pathogenic (dead end)

67
Life cycle:
 Replication: entry  uncoating  genome incompletely closed (opened from circle) to be imported to nucleus
o Completly Closed Circular DNA (cccDNA): genome closed & repaired inside nucleus
 Makes a bunch of transcript for viral replication
 Can be INTEGRATED into host genome (stable, reservoir) – hard to eliminate
 Patients probably don’t totally clear virus (latent)
Older than 5 5 or younger
Natural history: Wide range: Sicker, but more likely to clear Less sick, but less likely to clear
 Mild infection (asx) • 30% to 50% clinically ill (jaundice) • <10% clinically ill (jaundice)
 Severe chronic liver disease  • 2% to 10% chronically infected • 30% to 90% chronically infected
o Fibrosis, subsequent cirrhosis
o Liver failure, hepatocellular carcinoma, death

Serology of HBV
Acute HBV infection with recovery Chronic hepatitis

HBsAg goes away before 6 months HBsAg and HBeAg present for ≥ 6 mo
Marker What is it? What does it mean?
 Marker of infectivity
HBsAg Surface antigen
 Acute or chronic HBV infection currently present
Anti-HBs Ab against HBs  Past exposures or previous immunization
 Total antibody against core antigen (IgG + IgM)
Total
Anti-core antigen  Could be acute, chronic, or resolved
anti-HBc
 Indicates exposure to HBV
IgM
IgM vs core Ag  Recent infection with HBV (< 6 mo)
anti-HBc
 Active viral replication, indicates active disease
 ↑HBeAg = ↑ risk progressive liver dz
HBeAg Hepatitis B e Ag
 Generally not seen w/o HBsAg
 Absence ≠ no viral replication
 Viral load (not shown above) – ongoing viral rep
HBV DNA PCR of HBV DNA  ↑ in acute and chronic infection
 Sustained loss = resolution of viral rep  resolution of liver dz
 Resolving disease
Anti-HBe Antibody to HBeAg
 Seroconversion to anti-HBe  viral suppression, ↓ infectivity, ↑ Pgx
ALT Liver enzyme  Liver function
DNA test is a good one to rely on; Normal ALT with surface antigen = healthy carrier

Treatment: Prevention:
 Interferon-α – can control infection (durable!)  Pre-exposure (vaccine)
 Lamivudine, tenofovir, etc. – can’t eradicate  Post-exposure (HB IG up to 1 week post-exposure + vaccine)
68
Lab Tests for HBV: For Reference
Acute Past exposure Past Chronic Chronic Healthy
Marker
Hep B (immunity) immunization Hep B Precore* Carrier

HBsAg + + + +
Anti-HBs + +
Total
anti-HBc + + + + +
IgM
anti-HBc +
HBeAg + +
HBV DNA + +/- +/-

Anti-HBe +/- + +
ALT ↑ normal normal ↑ ↑ normal
*Precore mutant: mutation  stop codon; doesn’t make HBeAg

Hepatitis D
NEEDS HBV: Hepatitis B (HBsAg) coat with δ antigen genome inside (D = “dependency issues”)
 Tests: for RNA, but not easy to get

Hepatitis C
Epidemiology:
 Big in US (most common cause of liver failure that requires transplant), lots in Baltimore
o Associated with: low SES, IDU, sexual practices
 Worldwide epidemic; big in Egypt

TONS OF VARIABILITY (way more than HIV) – really really hard to make vaccine
 Becomes progressively diverse after infection (innumerable variants – quasispecies)

Clinical implications of virology: Persistent, resistant to treatment, vaccine hard to develop, antivirals in development

Transmission
 Percutaneous blood exposures: IDU, rare blood transfusion, needlesticks
 Sexual transmission: unknown role of intercourse? Maybe ↑ in MSM
 Household, nonsexual: perinatal
 Nosocomial: developing vs. developed world

Natural History (Thick arrows = more frequent)

 Exposure usually results in chronicity;
o most remain stable, can progress to cirrhosis
 Most who get cirrhosis can compensate
o some develop end-stage liver dz (ESLD)
Screening:
 anti-HCV EIA (essentially an ELISA)
 HCV RNA if Treatment of HCV
o acute infection – needle stick / jaundice  Pegylated interferon-α & ribavirin
o high index of suspicion and EIA negative  No vaccine
 Can do post-exposure prophylaxis
69
 Hepatitis E
 Overall: similar to Hep A
 Incubation: average 40 days, range 15-60
 Illness severity ↑ with age

PREGNANCY is a big risk factor, can be FATAL

 (CFR 1-3% overall, 15-25% in pregnancy!)

Course: acute, ↑ ALT spike early

Epidemiology
 Most outbreaks associated with fecally contaminated drinking water
o Pig farmers have ↑ risk (zoonotic?)
 Minimal person-to-person transmission; secondary attack rare
• U.S. cases: usually hx of travel to HEV-endemic areas

Diagnosis: Consider it if non A-D hepatitis (esp in pregnancy!

 IgM for acute, IgG for chronic

Summary

5 hepatotropic viruses
TRANSMISSION COURSE KEY FEATURE
HAV Fecal/oral Self-limited No envelope = bile stability
HBV Surface antigen in vaccine
HCV Blood/sex/etc Chronic Viral diversity
HDV Needs HBV
HEV Fecal/oral Self-limited Fatal in pregnant women

 Viral particles: ongoing infection

 Anti-viral Abs: IgMs are recent

70
 Inherited and Metabolic Liver Disease
Infants Adults
 Mostly α-1 antitrypsin deficiency  Mostly hemochromatosis
 Wilson, others too  Wilson’s, others too

Wilson Disease
Autosomal recessive disorder that affects hepatocyte functions in the transmembrane transport of copper

Gene: ATP7B (a.k.a. “WND”) – encodes metal transporting P-type ATPase

Copper metabolism
1. Ingest copper
2. Absorbed in intestine
3. Portal circulation
4. To liver, metabolized
5. Most secreted with bile  feces

Ceruloplasmin: carrier protein - carries copper in various parts of the body

In liver: normally
 Uptake through a transporter (Ctr1) at
basolateral surface of hepatocyte

 Binds to metallochaperones : deliver to specific

pathway, protect against intracellular chelation

 Incorporated into ceruloplasmin

 Excreted to bile by ATP7b at trans-golgi network

Wilson disease
 Mutate ATP7b  copper accumulates in
hepatocytes
o Lots of mutations have been identified
 Oxidative damage (metal!)  cell death
 Copper: leaks into plasma, accumulates in other tissues

Epidemiology
 Autosomal recessive; 1/30k (1:100 are heterozygous carriers), equivalent in all ethnic groups
 200+ mutations, little correlation between phenotype & mutation
o (same mutations  vastly different presentations)

Clinical Presentation
Disease of the liver that can affect other organs when copper comes in
 Eyes: Kayser-Fleischer rings
o Deposition of copper in cornea (need to do slit lamp exam)
o Present in 50-60% of patients (95% of those with neuro/psych Sx)
o Can also see in cholestatic disorders
 Brain: neuropsychiatric disorders
 Heart: cardiomyopathy
 Bones: osteoporosis & arthropathy

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Diagnostic testing for Wilson Disease

Test Rationale Results Notes

Not too specific:
 Copper carrying protein ↓  Varies with age (normal 20-35 mg/dL)
Serum
 Mainly made in liver  ↑ with acute inflammation, hyperestrogenemia
ceruloplasmin
 WD: not getting Cu out of TGN  ↓ in severe renal / enteric protein loss, cirrhosis,
aceroplasminemia
 Look @ non-ceruloplasmin bound Cu ↑ Lack of specificity:
Serum copper (packaging not happening!) > 25 μg/dL  ↑ in acute hepatitis, chronic cholestasis,
 24 h urine copper < 15 is nL heterozygotes, copper poisoning
Best biochemical evidence
Hepatic
 Sampling error: from inhomogenous Cu
parenchymal  Look at copper in hepatocytes ↑ distribution (late stage WD)
copper
 ↑ in copper toxicosis syndromes too
most pts compound heterozygotes
Genetic > 200  Hard (too many mutations)
 H1069Q (50% Northern European pts)
studies mutations  Used in pedigree analysis
 A778L in 30% Asian pts

Treatment
 Chelation therapy
 Dietary therapy
 Zinc acetate:
 Liver transplant
get copper out! d-penicillamine, trientine, tetrathiomolybdate
avoid copper-rich foods: liver, shellfish, chocolate, nuts, legumes
o Drinking water: old copper pipes (e.g. Baltimore)
uses same transporter in intestine; outcompetes copper for uptake
if severe (cures! Whole defect is in hepatocyte!)

Summary: Wilson Disease

• Autosomal recessive disorder; defect of ATP7B • Treatment with chelator, zinc and liver
• Variable presentations transplant
• Multiple diagnostic tests, use in combo

Hereditary Hemochromatosis
Autosomal recessive disorder that relates to excessive iron deposition in tissues, especially in liver

Gene: HFE (↑ intestinal iron absorption, iron utilization); other mutations in iron metabolism pathway can be involved

Iron Homeostasis
1. Ingest iron (big excess – most recycled)
2. Absorption is highly regulated (don’t want too much, very little absorbed)
a. Iron taken up by transporter
b. Bound to ferritin in enterocyte
c. Exported across basement membrane to plasma
3. Used in erythropoesis, etc.  recycled

Remember: lose very little iron / day (skin shedding, etc)

 exception = menstruation

How is absorption regulated?

 Crypt-programming & hepcidin models

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Crypt-programming model
Undifferentiated duodenal crypt cells (not exposed to dietary Fe):
1. Take up Fe from bloodstream (via transferrin receptor with help of HFE!)
2. Accumulate intracellular pool of Fe
3. These crypt cells eventual differentiate into absorptive villous enterocytes
4. Daughter cells are “programmed” according to Fe pool in parent cell
a. If sufficient intracellular pool (blood Fe OK): small absorptive capacity for Fe
b. If insufficient intracellular pool (blood Fe ↓): large absorptaive capacity for Fe

In hemochromatosis: iron uptake into enterocytes messed up (HFE mutated!)

 Crypt cell ends up with low iron (can’t get iron in!)
 Low iron in cell  “thinks” that there’s low body iron
 differentiates into high absorptive capacity daughter villous enterocytes 
 ↑ iron uptake is end result!

Hepcidin model
Rate of iron influx into plasma depends primarily on hepcidin in this model
 If plasma Fe high: ↑ hepcidin synthesis  ↓ release of iron (enterocytes / Mϕ)
 If plasma Fe low: ↓ hepcidin synthesis  ↑ release of iron
 Idea: HFE involved somehow? Unknown? Somehow ↓ hepcidin  ↑ release

Epidemiology of hemochromatosis
 Most common, identified genetic disorder in Caucasian population (1:200): HFE mutations
o C282Y/C282Y homozygous (90% pts with hemochromatosis)
o C282Y/H63D heterozygous (3-5% hemochromatosis)

Clinical presentation of hemochromatosis

 Classic: Cirrhosis, bronze skin, diabetes (iron in pancreas) (now rare –early diagnosis)
 Cardiomyopathy, dysrhythmias (deposition in heart)
 Fatigue, malaise, arthralgia, hepatomegaly

Diagnosis of hemochromatosis
Need to differentiate from 2° iron overload (sickle cell / hemolysis / etc)
 ↑ AST / ALT (if liver compromised)
 ↑ transferrin saturation, ↑ ferritin, ↑ liver iron-index (measurements of iron in blood)

FHx / suspicion  blood test  HFE gene testing  liver biopsy (iron stain)
Treatment of hemochromatosis
 Phlebotomy (every week or biweekly – 250 mg Fe / 500 mL blood!)
o Target ferritin: < 50 ng/mL; transferrin sat < 50%
 Maintain ferritin (25-50 ng/mL) with maintenance phlebotomy
 Avoid vitamin C (reduce impact of rapid iron mobilization, which ↑ risk of cardiac dysrhythmia)
Survival ↑ if you get iron depletion done in 18 months!

Summary: hemochromatosis
• Autosomal recessive disorder; HFE mutation • Serum iron study and genotyping
– C282Y/ C282Y or C282Y/H63D • Phlebotomy for treatment
• Variable clinical presentation

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 α1-antitrypsin deficiency
Autosomal codominant inheritance
Gene: α1-antitrypsin: inhibitor of proteolytic enzyme (elastase)
 75 different protease inhibitor alleles have been identified
 Z-variant: single AA substitution  abnormal folding of
protein in hepatic secretory organelles

Pathogenesis
Different in lung vs liver!

Lung disease: Can’t secrete  proteolytic balance shifts

 ↑ protease activity  panacinar emphysema

Liver disease: Accumulation of misfolded protein causes cell death

Path / Lab Findings

Pathology: see PAS-positive AAT inclusions stuck in liver (can’t excrete)
Serology: small peak of α1-antitrypsin disappears!

Prognosis

Risk of lung disease: e.g. panacinar emphysema - varies with genotype

 ↑↑ for ZZ or null
 Correlates with AAT level (AAT↓  ↑ protease imbalance  ↑ COPD risk)

Risk for liver disease: also varies with genotype

 ↑ in ZZ, not null
 Correlates with misfolding of proteins (AAT misfolds in ZZ, just absent in null)

Diagnosis:
 most diagnosed in childhood
 Clinical presentation, biochemical studies (AAT in blood), liver Bx (see above), phenotyping (protein electrophoresis)
Treatment
 Family screening  Surveillance for hepatocellular carcinoma
 AAT infusion  Transplant if needed
 Treat complications / therapy for lung disease (liver transplant cures disease)

Summary: α1-antitrypsin deficiency

• Autosomal codominant • Pathogenesis differs in the lung and the liver
• Many variances • Liver transplant cures the disease

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 Non-Alcoholic Fatty Liver Disease (NAFLD)
Epidemiology: related to obesity / insulin resistance (↑)
 may soon replace HCV as #1 cause of cirrhosis needing transplant!

Progression
1. Steatosis: fat accumulating in liver
2. Steatohepatitis: fat + inflammation & death of hepatocytes
3. Cirrhosis

Insulin Insulin resistance

In normal patients, insulin release facilitates… Central component of metabolic syndrome
 ↑ fat storage  ↑ fatty acid deposition in liver cells
 ↑ lipolysis  ↑ lipogenesis

Summary: NAFLD
• The most common liver disease in the US
• Associated with obesity and metabolic syndrome
• Insulin resistance is the key component of pathogeneses

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 Cholestatic Liver Disease
Key Concepts
Cholestasis - any liver disorder characterized by impaired bile flow.
Lab findings
↑ serum alkaline phosphatase +/- bilirubin the hallmark of cholestasis
↑ GGT or 5’nucleotidase: to confirm liver-specific disease
ALT/AST Typically only mildly abnormal

Cholestasis can lead to: acute and/or chronic liver disease, cirrhosis, and hepatobiliary cancers

Pathophysiology
Bile flow: depends on multiple structural / functional components within hepatocytes & cholangiocytes
 Intrahepatic (hepatocytes) & extrahepatic (obstruction) are main categories of cholestasis

Etiology:
 Genetic or acquired defects of determinants of bile formation
 Obstruction / inflammation / destruction of cholangiocytes or hepatocytes

Bile production
 Small bile ducts (lined by hepatocytes) 
larger bile ducts; (lined with cholangiocytes)

 Bile starts to be formed by hepatocytes,

composition modified by cholangiocytes

 Small bile ducts  common bile duct  duodenum

Clinical Presentation of CLD

 Icterus, jaundice, other PE findings / features of cirrhosis

 Pruritis, RUQ pain, fevers/chills (infectious)

o Charcot’s triad, Raynaud’s pentad if acute cholangitis

 Fat-soluble vitamin deficiencies (ADEK)

A Night blindness
D Osteomalacia
E Neuropathy / rash (rare)
K Coagulopathy
Lab Tests
Alkaline phosphatase
 Made by biliary epithelium / hepatocytes, intestines, placenta, bone
 Liver disease: retained bile salts  ↑ AP synthesis, then it spills out into bloodstream

5’ nucleotidase: liver-specific phosphatase (if AP↑, make sure it’s liver’s fault!)

Gamma-gluamyltranspeptidase (GGT): liver-specific enzyme; use like 5’-NT

 ↑ with drugs that induce microsomal enzymes (EtOH / dilantin) too – not just cholestasis!

Bilirubin: ↑ direct (conjugated) bili in obstruction or intrahepatic cholestasis

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 Imaging
ULTRASOUND is ALWAYS THE FIRST TEST for ↑ alk phos with itching!

Good for Dx of… Notes

Ultrasound dilated biliary tree, gallstones.
CT Scan masses that may cause biliary obstruction NEED CONTRAST
MRI masses that may cause biliary obstruction.
MRCP strictures/obstruction MRI that specifically looks at the bile ducts.
Invasive procedure
ERCP Can see bile ducts; also possible intervention.
allows visualization of bile ducts by fluoroscopy,

U/S: Gallbladder w/ 4 stones U/S: dilated biliary tree CT: huge liver mass (arrow) MRCP: ERCP: stones &
biliary tree biliary tree

DDx of Cholestatic Liver Disease

Intrahepatic Extrahepatic
 Primary Biliary Cirrhosis OBSTRUCTION (almost always)
 Primary Sclerosing Cholangitis  Gallstones
 Drug-induced  Malignant
 “Overlap” syndromes  Infection
 Systemic diseases, incl. sepsis  Primary sclerosing cholangitis
 Rare causes

Primary Biliary Cirrhosis (PBC)

Autoimmune destruction of small intrahepatic bile ducts  inflammation, sclerosis

 Genetics / environment; Females>M (9:1)

 AMA: Anti-mitochondrial antibody (90-95% of pts, <1% normal controls: pretty specific / sensitive)

Diagnosis
 Cholestatic pattern of ↑ liver enzymes (alk phos ± bili)
o ↑ IgM, ↑ cholesterol too
 Positive AMA (presence of antibody, not titer is important)

Histology: non-suppurative cholangitis if you do a biopsy

 Inflammation / necrosis around bile ducts (“florid duct lesion”)
 Bile duct dropout (ductopenia), ductular proliferation, granuloma

Clinical Manifestations
 FATIGUE is #1 3/4 pts, doesn’t correlate with disease stage
o 20% have concurrent hypothyroidism (exacerbates)

 Itching (20-70%) Worse with night, fabric/heat, pregnancy

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Other symptoms:
 Portal hypertension
 Osteoporosis
 Hyperlipidemia:
 Vitamin deficiency
 Sicca syndrome
 Raynauds
 Fibrosing alveolitis
 Cutaneous calcinosis (see pic)
can develop in non-cirrhotic dz too (obliteration of portal vessels)
in 1/3 (4x RR) – women, too
HDL disproportionally elevated vs LDL (not atherosclerotic risk)
o Xanthomas can result! Fat under skin – see pic
(↓ ADEK) in jaundiced pts; uncommon
(dry eyes/mouth)

Management
Ursodeoxycholic acid is standard of care
 Naturally occurring bile acid, mechanism of action unclear
 Liver enzymes, itching improve
Other:
 Treat fat soluble vitamin (ADEK) deficiencies
 Cholestyramine for itching
 Liver transplant for decompensated cirrhosis

Primary Sclerosing Cholangitis (PSC)

Chronic, idiopathic, cholestatic liver disease leading to:
 progressive inflammation, fibrosis, and stricturing of intra- and extra-hepatic bile ducts

Epidemiology: 1/160k in US, 75% are MEN, majority Caucasians, typically present ≈ 40 years old
 70-80% have co-existent ulcerative colitis (like “UC of the bile duct”)

Pathogenesis: genetic & immunologic associations (HLA haplotypes)

Histology: Lymphocytic bile duct infiltration & scarring

 “onion skin” around bile duct

Clinical features
Symptoms Enzymes: cholestatic pattern
 Young men with diarrhea, bloody stools, jaundice  ↑ Alk phos (> 1000), ↑ bilirubin ↑
 Fatigue & itching  AST & ALT near normal – cholestatic enzymes

Diagnosis
 Imaging studies (U/S, MRCP / ERCP)
 Colonoscopy (look for IBD)
 Liver biopsy sometimes; exclude other disease
 Autoantibodies not usually used clinically

ERCP:
 scope down into duodenal ampulla
 end of scope has camera & some ports
 Nets to remove stones, stents to keep it open

ERCP in PSC:
 like ulcerative colitis, bile ducts have scarring & stricture
 “beads on a string” – bile behind the strictures

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Management
 Dilate / stent strictures with ERCP (percutaneous drains are alternative)
 Screen: cholangiocarcinoma / colorectal cancer in pts with UC
o Pts with both UC + PSC are at ↑↑ risk for these cancers
o Ca19-9 (tumor marker), imaging
 Liver transplant if serious but 15% recurrence rate
 High dose ursodeoxycholic acid?

REMEMBER: PBC vs PSCPBC

PBC = primary biliary cirrhosis PSC = primary sclerosing cholangitis
 Middle aged women with jaundice & itching  Young men with jaundice & diarrhea

Drug-induced Cholestasis
Meds / herbal supplements can cause acute / chronic cholestatic syndromes
 Range: from acute reversible cholestasis to chronic irreversible destruction of bile ducts; History is key

Clinical Presentation
 Majority are acute / resolve spontaneously after removal of drug
o (key to dx – temporal relationship & resolution after withdrawal)
 Jaundice, fatigue, pruritis, anorexia
 Rash / eosinophilia are possible

Pathophysiology
Variety of mechanisms of liver injury
 Interfere with uptake / transport / secretion of bile salts
 Toxic accumulations of drugs / metabolites
 Immune-mediated hypersensitivity reactions (see rash!)

Examples:
 Bland cholestasis:
 Cholestatic hepatitis:
 Cholangiolitis:
 Vanishing bile duct syndrome:
anabolic steroids, celecoxib, tamoxifen, OCPs, senna
PCNs, INH, NSAIDs, macrolides, cascara, TZDs, kava
TMP-SMX, phenytoin, carbamazipine
Chlorpromazine, tetracyclines, TPN, PCNs, macrolides, comfrey, azoles

Treatment
 Removal of suspected medication is KEY  Liver transplant if needed
 Cholestyramine (itching)  PATIENCE: can take weeks/months for liver
 ?ursodeoxycholic acid enzymes to return to normal

Overlap syndromes
 Have features of both autoimmune hepatitis and PBC or PSC

Rare causes of cholestasis, inserted for genes-to-society compliance:

 Alagille syndrome-AD JAG1 mutation, intrahepatic cholestasis, heart, eye, vertebral defects and characteristic facies.
 Progressive Familial Intrahepatic Cholestasis (PFIC, Byler’s disease)- AR leads to cirrhosis by age 10-15. Mutation of FIC-1 in type 1.
 Benign Recurrent Intrahepatic Cholestasis (BRIC)- intermittent attacks of jaundice and itching, but no permanent liver damage

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 Cholestatic variants of viral hepatitis
Essentially all hepatitis viruses (ABCE, CMV, EBV) can have cholestatic presentations
 HBV / HCV: severe cholestatic liver disease in immuncompromised hosts (Fibrosing Cholestatic Hepatitis)
o Not uncommon after organ transplants (≈ 10% liver transplants for HCV)

Systemic disease
Sepsis
 Extrahepatic bacterial / fungal infection: bacterial LPS impairs bile acid transport
 Treatment: treat underlying infection

Others
 Hepatic congestion: chronic right-sided heart failure can look predominantly cholestatic
o Hepatojugular reflex (press on RUQ, see JVP↑) & elevated indirect bilirubin are key to distinguish

 Paraneoplastic (Stauffer’s syndrome) in absence of hepatic metastases / obstruction

 Sarcoidosis: Noncaseating granulomas in liver can obstruct / obliterate small bile ducts  looks like PSC
o Larger ducts are rarely involved; looks like PSC often

 HIV/AIDs Cholangiopathy: consequence of underlying opportunistic infection

o CD4 < 100, with CMV / cryptosporidial infection
o Cholangiogram: see strictures, dilatations, papillary stenosis
o Treatment: HAART!

Extrahepatic Cholestasis (Biliary obstruction)

A GI EMERGENCY! Can cause rapidly progressive, life-threatening infection (ascending cholangitis)

Etiology:
Signs / Sx: KNOW THESE
 Choledocolithiasis
Charcot’s Triad Reynold’s Pentad
 PSC
1. Fever/rigors 1. Fever/rigors
 Infectious (worms!): strongyloides, ascaris, etc.
2. Jaundice 2. Jaundice
 Malignant
3. RUQ pain 3. RUQ pain
o Cholangiocarcinoma
o Pancreatic carcinoma (@ head of pancreas; “painless jaundice”)
4. Hypotension
o Lymphoma 5. Mental status changes

Treatment:
EMERGENT DECOMPRESSION of biliary tree + supportive care
 Fluid resuscitation
 Antibiotics (cover anaerobes & gram negs)

Approach to the patient with cholestasis

1. Suspect if ↑ alk phos
2. Confirm liver origin with GGT / 5’-NT
3. Do U/S
a. Mass: CT/MRI/Bx
b. Dilated ducts: MCRP/ERCP/PTC
c. Normal ducts: check AMA
i. If AMA normal: Bx liver

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 Autoimmune Hepatitis, Alcoholic Liver Dz, and Non-Alcoholic Fatty Liver
Autoimmune Hepatitis
First described by Waldenstrom, 1950; initially thought to be “lupoid hepatitis”; corticosteroids (general immune suppression) in 1970s

Epidemiology
 Uncommon disorder (2/10k)
 Associated with other immune disorders (e.g. thyroiditis)
 Women > Men (3.6:1)

Multiple presentations:
Asymptomatic Indolent disorder Acute disorder
jaundice, marked ↑ ALT 
Just ↑ ALT fatigue, malaise, arthralgias
occasionally acute liver failure

Histology
 Interface hepatitis
o inflammation at portal tract / lobule interface
o Lymphs / plasma cells (making IgGs)

 Bridging necrosis / fibrosis = more severe disease

Biochemical Features
 LFTs: injury mostly hepatocellular
o ↑ ALT (moderate / marked) with only minor elevation in alk phos

 ↑ Globulin fraction (usually more than 2x; γ-globulin > 1.1x)

 Autoantibodies must be present

o usually ANA, SMA(smooth muscle actin), LKM-1, SLA/LP
o none are specific for AIH (but need for Dx)

 Associated with HLA DR3 and DR4 – genetic component?

Subtypes of Autoimmune Hepatitis
Type 1 Type 2 Type 3
ANA , SMA, anti-actin
Anti-LKM1 Anti-SLA/LP
HLA DR3/4
Uncommon in US (kids from other countries) Very similar to type 1
More common in US
Associated with HCV Propensity to relapse after steroid discontinuation

Diagnosis of AIH
 Need to exclude chronic viral hepatitis (no viral markers!)
 Combination of criteria: hyperglobulinemia, antibodies (above), hepatitis on liver Bx, no viral markers

Role of Chronic HCV?

Non-organ-specific Ab occur in 25% of HCV pts (SMA/ANA most common)
 SMA not directed to actin
 Anti-LKM1 found in 10%
o Directed against CYP2D6  HCV with AIH features may require
o Often have worsening of ALT with INF immunosuppressive treatment‼
o 14x ↑ risk thyroiditis

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Therapy
Immunosuppressive therapy
 ↑ survival in severe AIH; risk-benefit ratio for milder disease is less certain
 Post-menopausal women, those with cirrhosis respond equally well

Response:
 ↓ AST, ALT to < 2x ULN, bili / γ-globulin normalize, interface hepatitis disappears (65% @ 18mo, 80% @ 3 yrs)
o Without treatment, patients get cirrhosis / complications
 Continue steroids for 1-2 yrs, then taper over 6-12 wks (continue other immunosuppression)

Summary: Autoimmune Hepatitis

 Need to recognize (significant morbidity / mortality)
 Most can be tapered off steroids, but only a minority of pts can be tapered off of all immunosuppression
 HCV pts with features of AIH may need immunosuppression

Alcoholic Liver Disease

3 major conditions: and overlap!
 Cirrhosis
 EtOH hepatitis
 Fatty liver

Small minority of heavy drinkers get liver disease!

 1 beer = 14 g of alcohol / day
 Risk starts to go up around 2-3 drinks / day (≈ 30 g)

Risk factors:
 Daily quantity of alcohol consumed  Presence of HCV infection
 Duration of heavy consumption  Genetic predisposition (twin studies)
 Nutritional factors, both obesity and malnutrition  Female gender

Clinical Features: inflammatory condition

 Jaundice  Abdominal pain  Fever
 Nausea and anorexia  Hepatomegaly

Lab features:
 Leukocytosis (inflammatory)
 ↑ AST & ALT (but mild: < 400 IU/mL), with high AST:ALT ratio
 Prolonged prothrombin time
 ↑ bilirubin (mostly conjugated)

Assessing severity
 Spontaneous encephalopathy is single worst clinical prognostic factor
 Ascites = ↑ severity

Discriminant function: can use to assess severity

4.6 × (PTpatient − PTlab control ) + total bili (mg/dL) > 93

 If > 93: 30 day mortality of 45-50% - bad!

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Pathogenesis
After heavy drinking…
 Ethanol oxidized to acetaldehyde (alcohol dehydrogenase) NAD+  NADPH in the process
 Acetaldehyde oxidized to acetate (aldehyde dehydrogenase) NAD+  NADPH in the process
 ↑ NADPH/NAD ratio  favors hepatic synthesis of FAs and triacylgylcerol
o Those processes use NADPH  NAD (so favored by ↑ NADPH!)

Molecular mechanisms
 Heavy alcohol ingestion  ↑ CYP450 2E1 and NADPH oxidase
o Acetaldehyde is highly reactive
o Enzyme induction, low GSH stores  development of oxidant stress in liver
 Alcohol  innate immune system  pro-inflammatory cytokines (TNF-α, IL-6)
o These cytokines induce NFκB and TGF-β (stimulate fibrogenesis)

Treatment
Concepts
 Eliminate offending agent
 Alter pathophysiology by addressing mechanism of injury / repair
 Target selected subgroup based on response (not too sick but could benefit from treatment)

Treatment: Most clinical improvement in 1st 6-12 months

 Abstinence is mainstay (few long-term studies on impact)
o 5 yr mortality: 45% if continue to drink, 13% if abstain

 Corticosteroids in those with most severe forms

o Rationale: anti-inflammatory, anti-fibrotic, predominantly ↓ TNF / ↓ IL6
o Benefit, esp. 30 days, but goes away @ 2 yrs (pts start drinking again)

Summary of alcoholic liver disease

 Only a minority of heavy drinkers develop serious alcoholic liver damage (15-25%)
 Alcoholic hepatitis is an inflammatory disorder characterized by jaundice, anorexia and abdominal pain
 There is a complex metabolic and cytokine-mediated interaction between different cell types leading to liver injury
 Abstinence is the cornerstone of therapy, but corticosteroids may be helpful in the most severe cases of alcoholic hepatitis

Non-Alcoholic Fatty Liver Disease / NASH

Non-alcoholic Fatty Liver Disease (NAFLD)
Most common cause of abnormal liver enzymes / chronic liver dz in USA (Hep C #1 for transplant)
 Fatty infiltration can be associated with inflammation and/or fibrosis

Risk Factors: associated with…

 Obesity  ↑ visceral fat accumulation
 Type 2 DM  Dyslipidemia (low HDL, ↑ TGs)

 Abdominal obesity (↑ waist/hip ratio) is a big one

o Different kind of fat – associated with insulin resistance, ↑ TG, ↓ HDL, HTN, etc.

 Metabolic syndrome: associated with NAFLD but interaction (cause / effect?) not well understood
o Related to insulin resistance?
Imaging:
 Normally liver = spleen for density on CT
 NAFLD/NASH: see liver < spleen (fat!)

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Pathogenesis (uncertain): Insulin resistance is key!
Normally, in fed state In NAFLD with insulin resistance
Insulin’s actions (↑ insulin release after meal) Hyperinsulinemia: ↑ insulin (resistant  try to compensate)

1.↓ lipolysis in adipose tissue 1. ↑ lipolysis (insulin resistance in adipose tissue) 

2.↑ glycolysis & FA synthesis (↑ with ↑ NADPH) 2. ↑ uptake of FFA by liver cells
3. ↑ accumulation of TGs in liver 3. ↑ synthesis of FA in liver
(insulin resistance doesn’t apply to liver & ↑insulinemia)
 End result: liver overwhelmed

Natural History of NAFLD:

 Can stay as just steatosis (NAFLD alone)
 Can also progress to NASH (see below) in a few patients
 In HCV pts, progression is much more likely

NASH: Non-alcoholic steatohepatitis

In setting of NAFLD, something leads to fibrotic changes

Risk factors for development of NASH (inflammatory changes)

 Age > 45  Diabetes Mellitus
 BMI > 30  AST / ALT ratio > 1

Prognosis of NAFLD / NASH

 When you go from fat only (NAFLD) to fat + inflammation (NASH), ↑ risk for bad stuff happening (↑ mortality!)
o ↑ risk of CVD & malignancy (top 2 causes of death, liver = #3)

Pathogenesis: Multiple “hits” probably involved: something pushes pt over the top
 adipocytokines, insulin resistance, oxidative stress / apoptosis, lipotoxicity / ER stress, etc. play a role
 Normally: balance between pro- and anti-inflammatory cytokines in liver
o Cytokine balance shifts to inflammation  necrosis, fibrosis (NASH)

1st hit obesity, DM, insulin resistance  hepatic steatosis (NAFLD)

2nd hit ↑ endotoxin levels, peroxisomal FA oxidation, FA toxicity
Result lipid peroxidation, production of byproducts 
 Cytokine balance  proinflammatory

Lab features of NASH

 ↑ AST & ALT (like alcoholic, chronic so mild ↑)
o ALT > AST in majority (vs. alcoholic etiology!)
 ↑ TGs, ↓ HDL, ↑ insulin
 Hyperglobulinemia, hypoalbuminemia, long PT are unusual
 Occasionally ↑ uric acid, ferritin, autoimmune markers
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Treatment of NAFLD
Correct insulin resistance Treat based on mechanisms of cell injury
 Diet / exercise  Anti-oxidants
 Metformin  Anti-cytokine therapy
 Thiazolidinediones  Anti-fibrotic therapy

AFLD / NAFLD: Multiple Risk Factors are Key

Big-time boozers ↑ risk, even if normal BMI
Fat heavy drinkers* ↑↑↑ risk
HCV + heavy drinking ↑↑↑ risk
*Heavy drinkers more likely to be obese too!
*RR for obesity = 2.5x!
NAFLD / NASH: summary
 Most frequent cause of abnormal LFTs
 Potentially serious outcomes in 10-15%
 Insulin resistance is a key factor in more advanced forms of NAFLD (NASH)
 Gradual weight loss is adequate treatment for those pts with steatosis without NASH
 Treatment of more advanced disease will probably require correction of insulin resistance or other approaches directed
toward mechanism of cell injury

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 Portal Hypertension & Cirrhosis
Teaching points from introductory cases
 ↑ direct bili alone doesn’t tell you if it’s bile duct obstruction or hepatocellular
 Prothrombin time is best to tell you severity of acute liver disease (short half-life of clotting factors)
o “do I have to hospitalize this guy or not?”
 After acute liver disease resolves, scar tissue in liver can remain:
o Normal liver enzymes, but ascites, spider veins, etc.

Cirrhosis: Overview
 End stage of any chronic liver disease
 Histology: regenerative nodules surrounded by fibrous tissue

Natural history:

Compensated = no symptoms,
decompensated = symptoms

Decompensation  ↓↓median survival

Symptoms:
1. Variceal hemorrhage
2. Ascites
3. Encephalopathy
4. Jaundice
(about 50% get one of these w/in 5 yrs)

Complications result from portal hypertension or liver insufficiency

Portal Hypertension
Portal vein: superior mesenteric vein + splenic vein (inferior mesenteric vein dumps into splenic vein)
 provides 80% of liver’s blood supply

Causes of Portal Hypertension

 Cirrhosis is most common cause of portal hypertension
 Site of increased resistance in cirrhosis is sinusoidal
 Other causes classified according to site of increased resistance

Type Pre-hepatic Pre-sinusoidal Sinusoidal

Example Portal or splenic vein thrombosis Schistosomiasis Cirrhosis

Pic

Thrombus (e.g. from infection post- Schistosome eggs block things up Cirrhosis: #1 for portal hypertension
Notes
delivery in umbilical vein) (see in Middle East) in USA; scarring/nodules in sinusoids

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 Type Post-sinusoidal Post-hepatic
Example Veno-Occlusive Disease Budd-Chiari Syndrome

Pic

Obliteration of hepatic venules  ↑ Hepatic vein thrombosis = BC; post-

Notes
pressure throughout liver, portal v. hepatic portal hypertension in RHF too

Portal Hypertension from Cirrhosis: Pathogenesis

↑ intrahepatic resistance is initial mechanism leading to portal hypertension
 Splenomegaly & enlargement of portosystemic collaterals ( varices) can result

Normal sinusoid

 Space of Disse between hepatocyte & sinusoid

 Fenestrated capillaries (let large molecules out to be metabolized)
 Stellate cell: normally just stores vitamin A

 NO: normally plays role in dilating sinusoid

Cirrhotic sinusoid

 Activation of stellate cell  starts to secrete collagen

 Collagen deposition  nodules  cirrhosis
o Sinusoids contract
o Defenestration: Fenestrations clogged up, ↑ resistance

 ↓NO , ↑vasoconstrictors (adds to problem)

Key point: ↑ intrahepatic resistance is not only

 structural (sinusoidal fibrosis, regenerative nodules) but also
 functional (active vasoconstriction)

Portal hypertension can result from :

 ↑ resistance to portal flow Pressure = Resistance × Flow
 ↑ portal venous flow

Splanchnic vasodilation in portal hypertension (from ↑ NO)

 Perpetuates portal hypertension (↑ portal blood flow)

NO Paradox:
 NO would be good therapy in liver (dilate sinusoid)
 but would be bad for splanchnic bed (↑ vasodilation)

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 Summary of Mechanisms of Portal Hypertension in Cirrhosis
↑ intrahepatic resistance ↑ portal venous inflow
 Structural (fibrosis, regenerative nodules)  Splanchnic vasodilation (↑ NO)
 Active vasoconstriction (↓ NO, ↑ vasoconstrictors)

Complications of Portal Hypertension

Splenomegaly  Thrombocytopenia
Spleen gets larger (↑ pressure), removes more platelets (thrombocytopenia  pancytopenia)

Varices & Variceal Hemorrhage

Splanchnic vasodilation  ↑ portal venous inflow, variceal growth

↑ portal pressure  flow into collaterals

 most importantly in distal esophagus
 Increase in size progressively
 Worse liver dz = ↑ risk of varices,

Variceal hemorrhage is #1 cause of death in cirrhosis

 Don’t actually die from bleed itself these days, but starts downward spiral

Takes about 12 mm Hg pressure to form varices

 All people who have varices have 12 mm Hg,
but not all people with > 12 mm Hg pressure have varices!
 (some people can have high pressure, but still reserve collaterals to take advantage of)

Measurement of portal pressure: HPVG

 Can’t just measure pressure directly (can’t cath) – percutaneous, transjugular are
hard, have complications
 Hepatic venous pressure gradient is the safest / most reproducible method

Hepatic Venous Pressure Gradient (HPVG)

 Cath into jugular  hepatic vein  wedge  measure WHVP
o wedge hepatic vein pressure (WHVP) ≈ sinusoidal pressure

 Deflate balloon, pull back a bit  measure FHVP

o free hepatic vein pressure (FHVP) ≈ IVC pressure

 HVPG = WHVP – FHVP (normally ≈ 3-5 mmHg)

o ≈ gradient between sinusoid & IVC
o FHVP helps correct for ↑ extravascular, intraabdominal pressure
o reflects portal vein pressure

HVPG in various types of portal hypertension

WHVP FHVP HVPG Why?
Pre-hepatic nL nL nL you’re measuring sinusoidal pressure, which doesn’t really change
Pre-sinusoidal nL nL nL (blockage is downstream)
Good for cirrhosis: sinusoidal pressure is ↑
Sinusoidal ↑ nL ↑  (fibrosis, defenestration, sinusoidal constriction)
Post-sinusoidal ↑ nL ↑ ↑ sinusoidal pressure
Post- HF ↑ ↑ nL sinusoidal pressure is ↑, but so is IVC pressure – so no ↑ gradient!
hepatic Budd-Chiari - - - Thrombus in hepatic vein – can’t cath!

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What predicts variceal hemorrhage?
 Larger varicies are more likely to rupture
(better predictor than ↑ pressure)
 ↑ Variceal wall tension too

 Red signs & “Child B/C” (staging criteria)

Therapies for Varices

 Vasoconstrictors
 Venodilators
 Combo
 Endoscopy
 TIPS / shunt surgery

Vasoconstrictors: try to ↓ portal flow

 Use non-selective beta blockers: ↓ CO and constrict splanchnic bed
 Octreotide, vasopressin (for acute bleeding, IV)

Vasodilators: modest effect; try to dilate

 Trying to ↓ systemic pressure, ↓ resistance in liver

Endoscopic variceal band ligation:

 Put a rubber band around it!
 Used to control bleeding varices that don’t respond to octreotide

TIPS: Transjugular intrahepatic Portosystemic Shunt

 Attempt to ↓ resistance to portal flow: shunt through liver!
 Procedure:
o Thread catheter through jugular vein to hepatic vein
o Put shunt through liver to portal vein
o Blood can flow portal vein  hepatic vein, pressure ↓ immediately
 Note that liver isn’t getting that blood now! Bypassing! (side effects)

Treatment Strategies for Varicies

Prevention of 1st hemorrhage
 Non-selective β-blockers are pretty good at preventing 1st variceal hemorrhage
o Adding nitrates (venodilators) doesn’t help too much
 Banding doesn’t have any advantage in survival vs β-blockers
o β-blockers are preferred (easier) unless very large varices (then band them!)

Treatment of acute variceal hemorrhage

General management:
 IV access and fluid resuscitation
 DO NOT OVERTRANSFUSE: get to adequate circulating volume, Hb ≈ 8 g/dL
o Too much blood  ↑ risk for re-bleed

Specific therapy
 Pharmacological: terlipressin, somatastatin /analogs, vaasopression / nitroglycerin
 Endoscopic therapy: ligation, sclerotherapy
 Shunt therapy: TIPS (if all else fails)

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Prevention of re-bleeds
 Lowest rates obtained with ligation + β-blockers
 BAND & put on β-blocker

Ascites & Hepatorenal Syndrome

Cirrhosis is most common cause of ascites
 Other causes: Peritoneal malignancy, heart failure, peritoneal tuberculosis, pancreatic causes, Budd-Chiari, nephrogenic

Pathogenesis: high pressure in two vascular beds

 Liver sinusoidal pressure ↑ and splanchnic vessel pressure ↑

 Ascites fluid is coming from sinusoidal pressure, not splanchnic pressure

o Portal vein obstruction doesn’t lead to ascites (not splanchnic bed)
o Budd-chiari: occlude hepatic vein  ascites w/o splanchnic bed pressure ↑

 Need HVPG > 12 mm Hg to develop ascites

o Get ↓ urinary sodium excretion (vasodilation  kidney senses low effective perfusion pressure)

SAAG & Ascites Protein

How to tell where ascites is coming from?

Serum-ascites albumin gradient (SAAG)

 correlates with sinusoidal pressure gradient

 SAAG > 1.1 g/dL = sinusoidal pressure > 12 mm Hg

o Means liver is cause of ascites

 Peritoneum could be making too much (cancer / TB) –

but would have ↓ SAAG

Ascites protein < 2.5 means sinusoids affected

 In Heart Failure: lots of protein in ascites

o still have fenestrations in sinusoids
o proteins can get out
o Ascites protein > 2.5

 In Cirrhosis: “capillarized” sinuosids

o collagen clogging fenestrations
o can’t get protein into ascites fluid (low ascites protein)
o Ascites protein < 2.5

Treatment of ascites

Sodium restriction
 2g per day (just enough that they can eat normal food)
 Fluid restriction not necessary unless hyponatremic
 Goal: negative sodium balance
 Careful: people with sodium restriction tend to stop eating (bad)

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Diuretics:
 Spironolactone is #1: really high aldosterone levels in these pts Diuretic goals for ascites
o If you just use Lasix proximally, will reabsorb distally
 Shoot for 1kg in 1 wk, 2kg/wk afterwards
st

 Furosemide if inadequate weight loss or hyperkalemia

 Decrease if > 0.5kg/day
 Side effects: from diuretic: Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia

Refractory ascites (10% cirrhotic pts)

Diuretic-intractable ascites (80%) therapeutic doses of diuretics can’t be achieved (complications)
Diuretic-resistant ascites (20%) no response to maximal diuretic therapy
Refractory = worse survival than pts with diuretic-responsive ascites

Treatment of refractory ascites

 large volume paracentesis (take the fluid off! – but comes back in a week)
 TIPS: ↓ portal pressure, stops formation of ascites
o ↓ ascites recurrence but ↑ RISK OF ENCEPHALOPATHY (stuff not cleared by liver  brain)
o No survival difference

Spontaneous bacterial peritonitis

 ascites can get infected; most common serious infection in people with cirrhosis & ascites

Pathogenesis of SBP: ↓ immune system, ↑ bacteria

 Normally: largest component of RES in liver (Kupffer cells) – protects itself, systemic circulation
o Lots of bacteria in portal vein with every bowel movement, but all taken out by Kupffer cells

 Cirrhosis: fluid goes around the liver (bacteria can get to systemic circulation)  transient bacteremia
o Ascites can get colonized too (pressure pushes bacteria in)
o ↓ complement too (liver compromised!)

Symptoms of SBP
 1/3 have no symptoms at all‼
o Look for PMNs > 250 & empirically treat for spontaneous bacterial peritonitis if ↑ PMNs
o Cover aerobic gram negative rods
 Symptoms when present: Fever, jaundice, abdominal pain, confusion, abdominal tenderness, hypotension

Hepatorenal Syndrome
Basically:
 Cirrhosis  ↓ arteriolar resistance (vasodilating)
 Kidneys see↓ effective arterial blood volume
 RAAS, epinephrine, ADH activated
 renal vasoconstriction  hepatorenal syndrome

Creatinine tells us which pts to consider for renal transplant

 If in renal failure, only therapy is liver transplant!

Treatment of HRS
 VASOCONSTRICTORS + ALBUMIN
o Vasopressin analogues (terlipressin, ornipresin), octreotide + midodrine, noradrenaline
o Albumin: stays intravascularly; helps keep fluid there too
o Helps: HRS improves in ≈ 60%, low recurrence – but still > 50% mortality in 1 mo
 TIPS or liver transplant if severe

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 Hepatic Encephalopathy
Pathophysiology
Normally
 Ammonia from protein metabolism goes into liver via portal vein
 Comes out as urea  excreted

If blood bypasses liver or liver doesn’t metabolize ammonia

 ↑ ammonia to brain
 Acts on GABA-BD receptors in brain

Grade hepatic encephalopathy (1-4) when pt comes to hospital

 1 = confusion, 2 = drowsiness, 3 = somnolence, 4= coma

Clinical Presentation
 Asterixis is hallmark sign
 Perception of space is impaired
o E.g. number connection test , make a star with matchsticks

 Reversal in day/night sleep patterns

o DON’T GIVE SLEEPING PILLS TO CIRRHOTICS
 unless you’re sure there’s no encephalopathy
 (bad – acts on benzo receptors!)
EEG: can see triphasic waves, diffuse slowing

Precipitants of hepatic encephalopathy

Cause Notes Cause Notes
Excess protein e.g. hamburgers ↓ serum K, plasma volume  azotemia
 NH3 +H  NH4
+ +
GI bleeding most common reason –
Diuretics  Alkalosis: shift equilibrium to right,
not perfusing liver!
Sedatives / hypnotics benzo receptor! NH3 is freely permeable (more into brain!)
TIPS (bypassing liver) Infections

Treatment
↑ ammonia fixation in liver ↓ ammonia production in gut
 Ornithine bcka’s  Lactulose
 Benzoate  Antibiotics
 Shunt occlusion / reduction (if TIPS is cause)  Adjust dietary proteins
Lactulose: get rid of ammonia
 Lactulose  lactic acid in bowel, acidify lumen (trap ammonia as NH4+ in lumen)
 Gives you diarrhea too (more ammonia in frequent stools)
Summary: Natural History of Cirrhosis

Note that all the treatments talked about today

have been palliative (not fixing underlying liver
disease)

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 Liver Transplant
For scoring systems: don’t memorize details; just what goes into them & trends
Regeneration
 Mature hepatocytes can regenerate / proliferate
 If chronically injured (stress, DNA damage), can’t regenerate
o Smart: liver doesn’t want these damaged cells to make new liver!
o Bad in severe liver damage, etc – can’t regenerate

History:
 1967 – 1st successful liver transplant (kidney, pancreas/liver 1st)

Current status
 > 15k pts on waiting list currently; 93k liver transplants have been performed (3,745 living donor transplants)
 Expensive: ≈ 400k

Survival: Good! > 70% @ 5 yrs!

Patient Selection: Indication, timing, appropriate candidate?

Indications
 Non-cholestatic cirrhosis is #1!
 neoplasms, metabolic dz, acute hepatic necrosis, cholestatic dz, more too

Hepatocellular carcinoma
 ↑ risk of cancer over time – survey for cancer.
 Transplant if you think you can avoid recurrence

Milan criteria: OK for transplant in HCC if…

 single lesion < 5 cm  no vascular invasion / extrahepatic mets
 ≤ 3 lesions, largest ≤ 3 cm  Tumor markers: ELSD & AFP > 500

Timing
 Acute liver failure (see below)
 ESLD (end-stage liver disease) – need to get a transplant!
 “Prioritization” (e.g. HCC) – given 22 points on MELD!

Acute liver failure

 transplant (but pts taking liver away from others – immediate indication)
 Acute onset of hepatic encephalopathy & coagulopathy (↑ PT) within 8 wks of jaundice
 2k/yr in US; 300-350 emergent liver transplants / yr (most can recover on own)

“Status 1” for liver transplant (life expectancy < 7d: transplant immediately!)
 Encephalopathy within 8 wks of 1 “liver symptom
st

 No pre-existing liver dz
 In ICU and: vent dependent, renal replacement therapy, INR > 2
 (Or: acute Wilson’s disease)

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 King’s college criteria
for acute liver failure – who won’t survive w/o liver transplant?
 Good positive predictive value, bad negative predictive value: If no transplant
 Will die if fit criteria, could die if don’t fit criteria
Acetaminophen-related Non-acetaminophen related
PT > 100 sec, or any 3 of:
pH < 7.3, or all 3 of:  NANB, Drug
 PT > 100 s  Jaundice  encephalopathy in > 7 days
 Cr > 3.5 mg/dL  PT > 50 sec
 Grade 3 hepatic encephalopathy  Age extremes (< 10 or > 40)
 Bilirubin > 17.4 mg/dL

Who gets a liver?

 When to refer a patient with cirrhosis for transplant evaluation?
 Sickest First! (but how to predict outcome?
 “Child-Pugh Classification”
Chronic Liver disease / cirrhosis
 MELD
Acute liver failure  King’s college criteria (see above)
Note: all 3 models (King’s College, CPT, MELD) DON’T CONTAIN AST or ALT!

Child-Turcotte-Pugh (CTP) Scoring system

 Assess 1-3 points for: encephalopathy, ascities, bili (adjust for PBC / PSC / etc), albumin, PT or INR,
o A: 5-6 (compensated cirrhosis)
o B: 7-9
o C: >10 (sick / decompensated)
 Lets you know chance of surviving surgery (transplant Childs “C” first)
 Drawbacks: subjective parameters (ascites), some parameters treatable, etc.

MELD score
 Accurately predicts short-term survival (6 mo) for cirrhosis
 Derived from Bilirubin, PT or INR, creatinine
o Lowest score (= healthiest) =6
o Highest score (= worst) = 40
o Transplant sickest first (highest MELD); Here (in this region) most patients transplanted with MELD around 20-25

 Use a calculator (complicated)

 For HCC: given 22 MELD points to start with, ↑ with every extension
o Need to prioritize (higher mortality risk even with preserved liver function  invading, etc)

Contraindications
Medical Social / Psychosocial
 Medically significant cardiopulmonary dz  Active EtOH and/or drug abuse
(won’t survive surgery) – very rigorous surgery  History of medical non-compliant
 Extra-hepatic malignancy (mets)  Inadequate social support
 Active untreated sepsis
 Extensive mesenteric / portal vein thrombosis

Relative contraindications:
 Advanced age (> 69 yo); Worse outcome in old pts if major comorbidities
 HIV (CD4 < 100 and/or ↑ VL)
 BMI > 40

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Pre-transplant evaluation
 Hx / PE  Creatanine clearance
 Labs to confirm etiology / severity; ABO typing  Serology (HBV/HCV/EBV/CMV/EBV/HIV)
 Cardiopulmonary assessment (echo, PFT,s tress test,  3D-CT to determine hepatic vascular anatomy, screen for HCC
etc); cath if positive stress test
o NOT a contraindication if you can correct CAD
with angioplasty / bypass & good LV function

Organ allocation
1. Acute liver failure has highest priority
2. Then MELD determines priority in cirrhosis
3. Waiting time used to break ties if pts have same MELD

Regional allocation: Nation  Region  OPO (organ procurement organization)

 Algorithm: Local status 1s > regional status 1s > local MELDs > regional MELDs > national status 1s > all others

How to expand the donor pool?

 Extended criteria (eg donor after cardiac death – DCD) – not as good; no flow to liver (biliary complications)
 Split liver transplantation size matters! Big donors can be used (e.g. one big adult  small adult + child)
 Living donor liver transplant (LDLT)

Living donor liver transplant: LDLT

Technically difficult
Overall complication (35%), mostly biliary / infectious
 Catastrophic complication ≈ 0.5%
 Mortality up to 0.5% for donors!

Donor: usually an ABO compatible close relative, preferably < 60 yo (preferably < 50)
 donor must be extremely healthy, recipient can’t be extremely sick (MELD ≈ 15-20)

Immunosuppression after Liver Transplantation

 Liver is more immune-friendly than kidney; but still need immunosuppression

Complications
Immediate Late
 PNF (primary non-functioning)  Chronic
 Surgical (HAT = hepatic artery thrombosis, biliary leak / rejection
stricture)  Recurrent
 Acute cellular rejection disease
 Drug toxicity
 Infections (50% bacterial > 20% fungal > 10% viral)

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 Liver Review
Just some key points – most covered elsewhere
Bile ducts get their blood primarily from hepatic artery supply
 Damage hepatic artery  damage bile ducts!

You need sufficient hepatic function to have…

1. Albumin synthesis These are
2. Coagulation factors exclusively done
3. Bilirubin conjugation by hepatocytes!

Lab Values
↑ Alk Phos in cholestasis
↑ AST, ALT in hepatocellular disease
 ↑ AST:ALT (> 2) is consistent with alcoholic hepatitis
↓ albumin if progressing to cirrhosis

Ascites / physical exam

(these findings are 100% sensitive)
 Vascular spiders
 Palmar erythema
 Abdominal wall collaterals (caput medusa)

Portal hypertension
Higher pressure in portal vein

 Spleen gets larger (splenomegaly)

o More platelets removed (thrombocytopenia!)

 Varicies develop (↑ flow through collaterals)

Cirrhosis
1. Portal HTN + vasodilation  splanchnic vasodilation

2. ↓ effective circulation
o Blood not in effective circulation anymore (sitting in splachnic bed)
o May have ↑ total volume, but ↓ effective arterial blood volume

3. Neurohumoral systems activated

o Na retention  ascites
o Renal vasoconstriction  HRS
o H2O retention  HypoNa

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