Beruflich Dokumente
Kultur Dokumente
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.
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)
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
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)
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
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)
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)
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
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!)
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
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
Insets: endoscopy
Note that ECLs secrete lots of stuff: Gastrin, Histamine, Endorphins, Serotonin, cholecystokinin (CCK), somatostatin
7
Microscopic anatomy of stomach
Acid Secretion
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
8
Regulation of Gastric Acid Secretion
Molecular mechanisms
Vagal nerve:
Direct Ach action and
↑ GRP production (↑ gastrin release)
Gastrin:
Stimulates parietal cell directly
Gastrin receptors on ECL ↑ histamine activates parietal cell indirectly
Vasoactive intestinal peptide (VIP), secretin also inhibit parietal cell function
9
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!
* entry of gastric contents into duodenum also leads to inhibition of gastric acid secretion (via secretin release)
Gastric Emptying
Regulated by: neural enterogastric reflex and hormonal (enterogastrone) mechanisms
Inhibits gastric secretion / duodenal filling
10
Pathogenesis of PUD:
Causative: H. pylori, acid, NSAIDs / ASA, Pepsin
Protective: prostaglandins, mucous production, bicarb, mucosal blood flow
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
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
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)
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
Clinical Presentation
Diarrhea in 1/3 (damage prox. intestinal mucosa, inactivate pancreatic enzymes: hyperacidity, ↑ fluid load - ↑ secretions)
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
12
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
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
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)
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
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
16
Endoscopy (peroral) use pinch biopsy forceps to get small bowel mucosa
Allows for pathologic evaluation of mucosal disease
Villi absent
Celiac disease Crypts elongated (trying to ↑ SA)
Plasma cells, lymphocytes in lamina propria
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!
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)
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!
Definition of Diarrhea
Too much water lost in stool!
o Normal stool water: 130 mL / 24h
o Diarrhea: > 200mL / 24h (3SD > normal)
19
Segmental Distribution of Intestinal Na Transport Proteins
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
Colonic Na absorption
Intestinal Cl Secretion
same mechanism as lots of other places
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
Diarrheal Disease
Diarrhea: in some part of digestive tract, the balance shifts: absorption > secretion
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
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
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
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)
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)
Paradoxical diarrhea: Partial small bowel obstruction can present with watery diarrhea
↑ hydrostatic pressure proximal to obstruction diarrhea!
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)
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)?
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
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
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)
* 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
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
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
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!
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
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
starts in rectum, moves more proximally, colonic only anywhere in GI tract (rare upper GI), mostly colon / Ileum
Endoscopy
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?)
31
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
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!
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)
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
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
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)
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)
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!
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
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 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
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.
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
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)
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
Pathophysiology:
↑ T-lymphocytes, mast cells in lamina propria
Release of tryptase, histamine excite visceral sensory nerves
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 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!
42
Bile Pigment (Bilirubin)
Bilirubin is breakdown product of heme (from RBC)
Control of gallbladder
Concentration of bile
via active ion transport across tight gallbladder epithelium
Enterohepatic circulation
Compounds recirculate between liver intestine
43
Gallbladder Diseases (overview)
Cholelithiasis = stone(s) in GB
Cholecystitis = inflammation of GB
Choledocholithiasis = obstruction
Cholangitis = infection
Cholelithiasis
Cholesterol is major source of gallstones
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
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)
Treatment:
Correct ECV Emergent decompression
Give Abx (ERCP / percutaneous transhepatic cholangiogram)
Correct initial cause
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
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
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
Chronic Pancreatitis
Gradual fibrotic destruction of pancreatic tissue
Recurrent acute pancreatitis can lead to chronic pancreatitis (but could also have no Hx of AP)
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)
Pathogenesis
Most alcoholic
Idopathic or other (CF, hereditary pancreatitis, hypertriglyceridemia,
autoimmune, tropical) – see next few sections
Mechanisms
Calcification plugging of ducts ↓ blood flow
Direct toxic effects, fibrosis Cytotoxic lymphocytes
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)
TREATMENT: STEROIDS!
IMPORTANT: this is one you can actually treat!
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
Surgery:
nd
for pain + dilated duct (pancreaticojejunostomy) for pseudocyst repair (2 line)
for pain + nondilated duct (resection) for biliary stricture
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
Inheritability
Inheritance involved in 10-20% pts
“Familial pancreatic cancer”: pancreatic cancer in 2 relatives
53
Pancreatic Intraepithelial Neoplasia (PanINs)
Most pancreatic cancer evolves this way
Infiltrating adenocarcinoma:
ductal structures stain (L)
Propensity to invade nerve (middle) - painful
Invasion (R)
Incidentalomas
Prognostic dilemmas, ↑ $$$
↑ prevalence with age
E.g. pancreatic cystic neoplasms(above)
Volume matters
Pts do well (if doc & support staff experienced)
Need to refer to HIGH VOLUME CENTER (% mortality ↓↓↓)
If you have Fanconi/BRCA mutations (e.g. PALB), ↑ susceptibility of cancer to dsDNA strand breaking agents
Hope is important (pts need to recalibrate life; help them enjoy what’s left)
55
Pediatric GI
Dark-red to maroon blood in stool – probably upper GI tract (through acid) or means it’s been there for a while
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
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)
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.
PYLORIC STENOSIS
“olive” (small firm mass in mid-epigastric region is pathognomonic)
More common in males
Therapy:
Initially: correct fluid, electrolyte imbalances
Surgery is treatment of choice (pyloromyotomy) – open up thickened muscle
57
Liver Tests
Overview
Major roles of the liver (tests based on these)
Metabolism Storage
Detoxification Digestion (bile)
Bilirubin
Normal metabolism:
Hemoglobin / myoglobin broken down heme unit + Fe
Heme converted to indirect / unconjugated bilirubin
o transported with albumin
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
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 ↓ ↓
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!)
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!
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
Alcoholic hepatitis
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%)
Diagnosis:
• Ultrasound (bright liver) – see pic
• Liver biopsy: 15-20% show fibrosis or cirrhosis; hyaline bodies too
Disease Test(s)
Hemochromatosis Serum iron, % sat, ferritin (measure fasting iron)
Wilson’s disease Serum ceruloplasmin, urine copper
Porphyria cutanea tarda Urine uroporphyrin
α1-antitrypsin deficiency Phenotype (AAT)
Autoimmune hepatitis ANA (anti-nuclear antibodies)
Primary biliary cirrhosis AMA (anti-mitochondrial antibodies)
Viral hepatitis 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
Acetaminophen hepatotoxicity
Metabolized to N-acetyl-p-benzoquinone amine (active metabolite)
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
62
Hepatitis: Basics
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
Alkaline Phosphatase
Alk Phos = “sensor of bile flow”
Hepatocytes: make the components of bile
Alk phos: located on membrane along bile canaliculus
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
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
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)
Epidemiology
In USA: Acute Viral Hepatitis
Hepatitis A > B > C
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
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
Hepatitis A virus
The virus:
Picornavirus (RNA virus)
No envelope (bile stable)
Cytopathic (ruptures) pathogenesis
Capsid proteins elicit universal neutralizing antibody
(all one serotype)
Hepatitis B
#1 cause of liver cancer worldwide (2B infected)
Esp. in developing countries (↓ with vaccine)
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
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
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
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
Copper metabolism
1. Ingest copper
2. Absorbed in intestine
3. Portal circulation
4. To liver, metabolized
5. Most secreted with bile feces
In liver: normally
Uptake through a transporter (Ctr1) at
basolateral surface of hepatocyte
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
71
Diagnostic testing for Wilson Disease
Treatment
Chelation therapy get copper out! d-penicillamine, trientine, tetrathiomolybdate
Dietary therapy avoid copper-rich foods: liver, shellfish, chocolate, nuts, legumes
o Drinking water: old copper pipes (e.g. Baltimore)
Zinc acetate: uses same transporter in intestine; outcompetes copper for uptake
Liver transplant if severe (cures! Whole defect is in hepatocyte!)
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
72
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
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)
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
73
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!
Prognosis
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)
74
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
Summary: NAFLD
• The most common liver disease in the US
• Associated with obesity and metabolic syndrome
• Insulin resistance is the key component of pathogeneses
75
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)
5’ nucleotidase: liver-specific phosphatase (if AP↑, make sure it’s liver’s fault!)
U/S: Gallbladder w/ 4 stones U/S: dilated biliary tree CT: huge liver mass (arrow) MRCP: ERCP: stones &
biliary tree biliary tree
Diagnosis
Cholestatic pattern of ↑ liver enzymes (alk phos ± bili)
o ↑ IgM, ↑ cholesterol too
Positive AMA (presence of antibody, not titer is important)
Clinical Manifestations
FATIGUE is #1 3/4 pts, doesn’t correlate with disease stage
o 20% have concurrent hypothyroidism (exacerbates)
77
Other symptoms:
Portal hypertension can develop in non-cirrhotic dz too (obliteration of portal vessels)
Osteoporosis in 1/3 (4x RR) – women, too
Hyperlipidemia: HDL disproportionally elevated vs LDL (not atherosclerotic risk)
o Xanthomas can result! Fat under skin – see pic
Vitamin deficiency (↓ ADEK) in jaundiced pts; uncommon
Sicca syndrome (dry eyes/mouth)
Raynauds
Fibrosing alveolitis
Cutaneous calcinosis (see pic)
Management
Ursodeoxycholic acid is standard of care Other:
Naturally occurring bile acid, mechanism of action unclear Treat fat soluble vitamin (ADEK) deficiencies
Liver enzymes, itching improve Cholestyramine for itching
Liver transplant for decompensated cirrhosis
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”)
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
78
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?
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: anabolic steroids, celecoxib, tamoxifen, OCPs, senna
Cholestatic hepatitis: PCNs, INH, NSAIDs, macrolides, cascara, TZDs, kava
Cholangiolitis: TMP-SMX, phenytoin, carbamazipine
Vanishing bile duct syndrome: 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
79
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
Sarcoidosis: Noncaseating granulomas in liver can obstruct / obliterate small bile ducts looks like PSC
o Larger ducts are rarely involved; looks like PSC often
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)
80
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)
Biochemical Features
LFTs: injury mostly hepatocellular
o ↑ ALT (moderate / marked) with only minor elevation in alk phos
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
81
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)
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
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
82
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)
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!)
83
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)
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)
85
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
Symptoms:
1. Variceal hemorrhage
2. Ascites
3. Encephalopathy
4. Jaundice
(about 50% get one of these w/in 5 yrs)
Portal Hypertension
Portal vein: superior mesenteric vein + splenic vein (inferior mesenteric vein dumps into splenic vein)
provides 80% of liver’s blood supply
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
86
Type Post-sinusoidal Post-hepatic
Example Veno-Occlusive Disease Budd-Chiari Syndrome
Pic
Normal sinusoid
Cirrhotic sinusoid
NO Paradox:
NO would be good therapy in liver (dilate sinusoid)
but would be bad for splanchnic bed (↑ vasodilation)
87
Summary of Mechanisms of Portal Hypertension in Cirrhosis
↑ intrahepatic resistance ↑ portal venous inflow
Structural (fibrosis, regenerative nodules) Splanchnic vasodilation (↑ NO)
Active vasoconstriction (↓ NO, ↑ vasoconstrictors)
88
What predicts variceal hemorrhage?
Larger varicies are more likely to rupture
(better predictor than ↑ pressure)
↑ Variceal wall tension too
Specific therapy
Pharmacological: terlipressin, somatastatin /analogs, vaasopression / nitroglycerin
Endoscopic therapy: ligation, sclerotherapy
Shunt therapy: TIPS (if all else fails)
89
Prevention of re-bleeds
Lowest rates obtained with ligation + β-blockers
BAND & put on β-blocker
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)
90
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
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
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
91
Hepatic Encephalopathy
Pathophysiology
Normally
Ammonia from protein metabolism goes into liver via portal vein
Comes out as urea excreted
Clinical Presentation
Asterixis is hallmark sign
Perception of space is impaired
o E.g. number connection test , make a star with matchsticks
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
92
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
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
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!
“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)
93
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
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
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
94
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
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)
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)
95
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!
Lab Values
↑ Alk Phos in cholestasis
↑ AST, ALT in hepatocellular disease
↑ AST:ALT (> 2) is consistent with alcoholic hepatitis
↓ albumin if progressing to cirrhosis
Portal hypertension
Higher pressure in portal vein
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
96