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G31 Gastroenterology Toronto Xotes 2023

1. Assess hemodynamic stability

*

2. Resuscitate (IV fluids * blood transfusion)

I

3. Assess coagulation status ICBC.INR/PTT)

Always exclude upper Gl lesion before

localizing the site of the bleeding to the

lower Gl tract i

4. Determine site olbleeding

i

T

Massive bleeding'llemodynamically unstable?

Clinical suspicion of UGIB based on risk factors?

(increased possibility of UGI source)

Hemodynamically stable,no UGIB risk factors?

(decreased possibility of UGI source)

i

Colonoscopy only

(or flexible sigmoidoscopy)

Colonoscopy and OGD

I

•For SLOW bleeding (<05ml/min):radionucleotide Tc-99m-tagged RBC scan

•For RAPID bleeding(>0.5 ml/min): angiography ± embolization

Figure 11. Approach to hematochezia

Diverticular Bleeding

Etiology

• herniation ofdiverticula exposes vasa recta, increasing susceptibility to disruption

• bleeding most common from the right colon (thinner walled),although diverticula often develop

throughout colon

Clinical Features

• painless hematochezia, acute onset

• stool can range frombright red to dark maroon;gelatinous clots often mixed in

Management

• often resolves spontaneously

• if colonoscopy identifies source (rare),hemostatic therapy can be applied

• if ongoing,can consider embolization or surgery

Infectious Colitis

Etiology

• variety ofpathogens;often due to Campylobacter, Entamoeba histolytica. Salmonella, E. coli, Shigella

• consider travelhistory, food exposures

Clinical Features

• bloody diarrhea,fever, abdominal pain

Management

• stool cultures to determine pathogen and guide management

• see Acute Diarrhea, U 15

Colorectal Carcinoma SIS

• see General Surgerv and lhoracic Surgery,GS43

Colorectal Polyps

• see General Surgerv and lhoracic Surgerv. GS41

Familial Colon Cancer Syndromes

• see Genera!Surgerv and lhoracic Surgerv. GS42

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Benign Anorectal Disease

• see General Surgery and Thoracic Surgery, GS47

QuidsReference Diagnostic Tests for

Common Liver Conditions

Liver Disease Diagnostic Tests

Viral Hepatitis Ant. HAVIgM, HBsAg,

anti-HCV

Aitoamnune Hepatitis ANA.SMA, LKM,Ig Investigations of Hepatobiliary Disease levels

Ceruloplasmin, liver

biopsy

Iron saturation,

ferritin.HFE genetic

testing

1-antitrypsin levels,

liver biopsy

Careful medication

history,liver biopsy

U/S,metabolic

testing,liver biopsy

toon's Disease

A. Tests of Liver Function

Hereditary

Table 17. Liver Function Tests Hemochromatosis

Test What Do Levels Correlate

With?

Increased by Howto Interpret

nVAnbtrypsm

Deficiency

Druganduced liver

Prothrombin Time

(PTorlMR)

Hepatic protein synthesis

All coagulation factors exceptVIII VitaminK deficiency (due to

Hepatocellular dysfunction PT/INR will promptly correct if

vitamin K is administered,so

malnutrition,malabsorption,etc.) increased PTi'INR in absence

of vitamin K deficiency is a

reliable marker of hepatocellular

dysfunction

Rule out potential causes other

than hepatocellular dysfunction

k>MY

NAFUVNonalcoholic

Steatohepafitis

(HASH)

Serum Albumin Hepatic protein synthesis (and Hepatocellular dysfunction

other causes listed innext column) Malnutrition

Renal or fit losses

Significant inflammation

Malignancy

Hepatic excretion from hepatocyte liver dysfunction

tobiliary system

UU = wtkaxtea antibody;SMA = smoothmuxde

mttodf.LXM = hw-lidrey mkimonial-1antibody;

Serum Direct Bilirubin’ Conjugation is pteserved even

in end stage liver failure,thus

increased direct bilirubin indicates

liver dysfunction

DDx for Hepatomegaly

• Congestive (right heart failure.BuddChiari syndrome)

• Infiltrative

. Malignant (primary,secondary

lymphoproliferative.leukemia)

• Benign (fatty liver,cysts,

hemochromatosis,extramedullary

hematopoiesis,amyloid)

• Proliferative

• Infectious (viral,tuberculosis,

abscess,echinococcus)

• Inflammatory (granulomas (sarcoid),

histiocytosis X)

’Serum Bilirubin

‘

canaliculus breaXUowr product of hemoglobin:metabolized in the reticuloendothelial system ol liver,transported through biliary system,

excreted via gut

•direct bilirubin= conjugated;indirect bilirubin= unconjugated

B. Tests of Liver Injury

Table 18. Liver Enzyme Profile

Profile Liver Enzyme Notes

Change

Hepatocellular t AST ALT more specific to liver

AST from multiple sources (especiallymuscle)

Elevation of both highly suggestiveof liver injury

Mosl common cause of elevated AIT is fatty Ever

Cholestasis "stasis of bile flow

If AlP is elevated alone,rule out bone disease by fractionating AlP and/or checking GGT

If ALP elevation out of proportion to ALT,

'AST elevation,consider:

Obstruction olcommon bile duct (e.g.extraturmnal- pancreatic cancer,lymphoma:intraluminalstones, cholangiocarcinoma.sclerosing cholangitis,helminths)

Predominant risein hepatocellular enzyme possible in acute biliary obstruction secondary to a stone

due to the sudden impairment in bile flow and because ALP is an inducible enzyme which takes time

to rise

Destruction of microscopic ducts (e.g.PBC)

Bile acid transporter defects (e.g.drugs,intrahepatrccholestasis of pregnancy)

Infiltration of the liver (e.g.liver metastases.lymphoma,granulomas,amyloid)

•ALT

All clotting factors except factor VIII and

von Willebrand factor are exclusively

synthesized in the Irvet Factor VIII is

also produced in the endothelium.In

cirrhosis,risk of bleeding does not

correlate closely with elevations in INR/

PTT since so many of the proteins in the

coagulation cascade are affected

Cholestatic » AlP

» GGT

ALT >AST -most causes of hepatitis

AST >ALT =alcoholic liver disease

or other causes of hepatitis (ie.

non-alcoholic liver disease) that have

progressed to advanced cirrhosis

Acute Viral Hepatitis (General)

Definition

• viral hepatitis lasting <6 mo

Clinical Features

• most are subclinical

• flu-like prodrome may precede jaundice by I -2 wk

N/V. anorexia, headaches, fatigue, myalgia, low-grade fever, arthralgia, and urticaria (especially

HBV)

• only some progress to icteric (clinical jaundice) phase,lasting days to weeks

pale stools and dark urine 1-5 d prior to icteric phase

hepatomegaly and RUQ pain

splenomegaly and cervical lymphadenopathy (10-20°i

, of cases)

Serum Transaminases >1000 due to

• Viral hepatitis

• Drugs/ toxins

• Autoimmune hepatitis

• Hepatic ischemia

• Less often,common bile duct stone

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G33Gastroenterology Toronto Notes 2023

Investigations

• AST and ALT (>10-20x normal in hepatocellular necrosis)

• ALP minimally elevated

• viral serology, particularly lgM antibody directed to the virus

Treatment

• supportive (hydration, diet)

• usually resolves spontaneously, but if severe HBY infection, treatment with antiviral agent such as

tenofovir or entecavir can be considered;in acute hepatitis C, antiviral treatment should be considered

(see Hepatitis C Virus, G34)

• indicationsfor hospitalization:encephalopathy, coagulopathy,severe vomiting,hypoglycemia

Prognosis

• poor prognostic indicators: comorbidities, persistently high bilirubin (>340 mmol; 20 mg/dL),

increased 1NR, decreased albumin, hypoglycemia

Complications

• cholestasis (most commonly associated with HAV infection)

• hepatocellular necrosis: AST, ALT >10-20x normal, ALP and bilirubin minimally increased, increased

cholestasis

Alcoholic Hepatitis:history ot chronic

EtOH use (possibly with recent increased

consumption, although often patient

may have stopped drinking in the

days-weeks prior to presentation due to

symptoms).RUO abdominal pain.AST/

ALT >2.AST usually <300.low grade

fever,mikfiy elevated WBC

Major Sources of ALP

• Hepatobiliary tree

• Bone

• Placenta

• Intestine

DDx for Hepatitis

• Viral infection

• Alcohol

• Drugs

• Immune-mediated

• Toxins

Hepatitis A Virus

• RNA virus

• fecal-oral transmission; incubation period 4-6 wk

• diagnosed by elevated transaminases, positive anti-HAV lgM

• in children:characteristically asymptomatic

• in adults:fatigue, nausea, arthralgia,fever, jaundice, hepatomegaly

• can cause ALL and subsequent death (<l-5%)

• can relapse (rarely), but never becomes chronic

• treatment is supportive (no specific treatments available, disease is often self-limiting)

Without treatment.8-20% of those with

ongoing immunoactive chronic hepatitis

can develop cirrhosis within 5 yr. In

contrast those in the immune tolerant

phase (with extremely high HBV-DNA

levels) are at minimal risk for liver

fibrosis as they do not have immunemediated liver injury

Hepatitis B Virus

Table19. Hepatitis B Serology

HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc Liver Enzymes

Risk of HCC in HBV increases with

increasing age. which is likely a

surrogate for increasing liver fibrosis/

cirrhosis,and serum HBVDNA

Risk of HCC in HCV increases only after

cirrhosis develops

Acute HBV +

Chronic IHBe-Ag positive) HBV *

(generally highHBV- DHA)

Chronic (HBe-Ag negative) H8V

(generally low HBV- ONA)

BesohredInfection

lgM

IgG AIT.AST may or may not be

elevated

IgG All.AST may or may not be normal

t t IgG

lm~jriration

HCV (and HBV) treatment lowers the

risk of HCC

Symptoms

Anti-HBs

Risk Factors for Progression

• EtOH

• HIV coinfection

• Old age at diagnosis

Anb-HBc IgG

Anti-HBe

Anti-HBc lgM

7

~ T T T T I /f f r

2 3 45 6 12 24

Months after inoculation

Figure12.Time course of acute hepatitis B infection

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G34 Gastroenterology Toronto Notes 2023

Epidemiology

•4 phases of chronic hepatitis B: not all carriers will go through all 4 phases, but all carriers will have

positive HBsAg In acute hepatitis B.HDV coinfection

1. immune tolerance: extremely high HBV-DNA (>20000 lU/mL), HBeAg positive, but normal increasesseverity of hepatitis but does

not increase risk of progression to

chronic hepatitis.However in the conte xt

of chronic hepatitis B.superinfection

with HDV increases progression to

cirrhosis

ALT/AST;due to little immune control and minimal immune-mediated liver damage;

characteristic of perinatal infection (or‘incubation period’in adult with newly-acquired

HBV)

2. immune clearance (or immunoactive):HBV-DNA levels (>20000 lU/mL), HBeAg positive;

due to immune attack on the virus and immune-mediated liver damage;characterized by

progressive disease without treatment and increasing liver fibrosis (sometimes progressing to

cirrhosis and/or HCC);likely to benefit from treatment

3. inactive carrier (immune control):lower HBV-DNA (<2000 lU/mL), HBeAg negative,

Causes of Elevated Serum

anti-HBe positive, ALT/AST normal; due to immune control without immune-mediated liver Transaminases In Chronic Hepatitis B

damage;risk of reactivation to phase 2 (clinically resembles acute hepatitis B), especially with • Active hepatitis(either immune

immunosuppression e.g. corticosteroids or chemotherapy f

1

*? **Phase

'"

HBeAg-positive

4. HBeAg-negative chronic hepatitis(immune escape) (“core or precore mutant”):elevated hepatfths)

'

5

°

f HBeA9

'ne9atlve ac1lve

HBV-DNA (>2000 lU/mL),HBeAg negative because of pre-core or core promoter gene . Reactivation (e.g.due to

mutation, anti-HBe positive, ALT/AST high;characterized by progressive disease without immunosuppression)

treatment and increasing liver fibrosis (sometimes progressing to cirrhosis and/or HCC); • Hepatitis D

likely to benefit from treatment *

^

iJ^

J

^

rt,ylive,

'

E

,

0H'

Treatment

•counselling: 40% of men and 10% of women with perinatal infection without treatment will die from

HBV-related complications

• HCC screening with U/Sq6 mo, especially if high serum HBV-DNA levels, cirrhosis, men, (ages >40 in RlSy*

n(ts°

^^

to7hepah^

B!nfecti.dB

•contexts to consider pharmacological therapy:

1. HBeAg positive and HBV-DNA >20000 IU/mL and elevated ALT

2. HBeAg negative and HBV-DNA >2000 IU/mL and elevated ALT with or withoutstage >2

fibrosis on liver biopsy

3. to prevent flare when placed on immunosuppressive therapy such as prednisone,

chemotherapy, biologies,etc.

•treatment goal:reduce serum HBV-DNA to undetectable level

• prolonged immune-mediated damage leads to higher risk of liver fibrosis

•treatment options:tenofovir, entecavir, lamivudine (not preferred due to high rate of developing

resistance)

•vaccinate against HAV ifserology negative (to prevent further liver damage)

•follow blood and sexual precautions

•vaccinate household contacts

• Unprotected sexual intercourse

(especially if multiple partners)

• Needle sharing (e.g.injection drug

users)

• Travel to endemic regions

• Exposure to human blood,semen,

and other bodily fluids

Clinical Features of Hepatitis B

• Many patients are asymptomatic,

both in the acute and chronic phases

• Acute hepatitis can manifest as

jaundice, nausea,arthritis, or

constitutional symptoms

• Patients with chronic hepatitis

can be asymptomatic, experience

exacerbations, develop extrahepatic

complications(e.g.glomerular

disease), or develop cirrhosis

Hepatitis D Virus

• defective RNA virus requiring HBsAg for entry into hepatocyte, therefore infects only patients with

HBV; causes more aggressive disease than HBV alone

• coinfection: acquire HDV and HBV at the same time

• HDV can present as ALT and/or accelerate progression to cirrhosis

• treatment:low-dose interferon (20% response) and liver transplant for end-stage disease

Hepatitis C Virus

•RNA virus(7 genotypes; genotype 1 is most common in North America)

•blood-borne transmission;sexual transmission is “inefficient”

•major risk factor:injection drug use

•other risk factors:blood transfusion received before 1992 (or received in developing world),tattoos,

intranasal cocaine use

•acute hepatitis C occurs 2-6 mo after transmission

• symptoms mild and vague (fatigue, malaise, nausea) therefore not commonly diagnosed in acute

stage

almost 30% of cases of acute hepatitis C are cleared spontaneously without therapy

Diagnosis

•suspected on basis of elevated ALT/AST'

and positive serum anti-HCV

•diagnosis established by detectable HCV-RNA in serum

•normal hepatocellular enzymes does not rule out active disease or presence of advanced fibrosis

•abdominal U/S and transient elastography (TibroScan*) to assess the staging of the disease and the

degree of fibrosis

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Treatment

• blood-borne precautions; vaccinate for hepatitis A and B if serology negative; avoid HtOH

• clearest indication for treatment is in subgroups likely to develop clinically significant liver disease,

i.e. persistently elevated transaminases, liver biopsy showing moderate-advanced fibrosis/cirrhosis,

and at least moderately severe necrosis/inflammation

• now that a safe, effective cure is available, the risk/benefit ratio favours treating everyone with

chronic hepatitis G

• choice and duration of treatment depends mostly on whether patient is cirrhotic (and if so, whether

decompensated or not), prior treatment history, and possibly genotype (but less so with availability of

pan-genotypic therapies)

• direct acting antiviral ( DAA) tablets (Maviret*, a combination of glecaprevir and pibrentasvir, and

Epdusa’, a combination of velpatasvir and sofosbuvir) are the most commonly used

• other oral interferon-free regimens (for all genotypes) (e.g. sofosbuvir/ledipasvir, ombitasvir/

paritaprevir/ritonavir t dasabuvir, or elbasvir/grazoprevir, and sofosbuvir/velpatasvir) are also

available but used less frequently

• it is important to check for hepatitis B prior to therapy as direct acting antivirals may lead to

reactivation of hepatitis B

Prognosis

• 80% of acute hepatitis C cases become chronic (of these, 20% evolve to cirrhosis within 20 years of

exposure)

• risk of HCC increases if cirrhotic

• can cause cryoglobulinemia; associated with membranoproliferative glomerulonephritis, lymphoma

Table 20. Characteristics of the Viral Hepatitides

HAV HBV HCV HDV HEV CMV EBV Yellow Fever

Virus Family Caliciuridae

Genome

Envelope

Transmission

Picomotiridoe Hepadnavmdae Flamiridoe Delloviiidae Herpesviridoe Herpesviridoe Flavivirus

SNA DNA ENA RNA RNA DNA RNA RNA

No Yes Yes Yes No Yes Yes Yes

Fecal Vector (mosquito) -oral (en- Close contacts, Saliva- oral

most body

Asia,central fluids

America.India.

Fecal-oral Parenteral/sexual or

equivalent

Veitical

Parentcral/sexual Non parenteral

llianslusion.IV drug (close contact in endem- demic: Africa,

user, sexual (- HBV)) ic areas)

40% have no known Parenteral (blood

lisk factors products.IV drug user ) Pakistan)

- sexual transmission is

inefficient

6 wk 6 mo 3-6 d

Usually abrupt Usually insidious

Communicability 2-3 wkin lateincuba - HBsAg* state highly

lion to early clinical communicable

phase Increased during third

Aculc hepatitis in most trimester or early

adults.10% of children post partum

Chronicity None, although can

relapse

Anli-HAV (IgM)

Incubation

Onset

4 - 6 wk 3-13 wk

Usually abrupt

Communicable prior Infectious only in

to overt symptoms presence ofH8V (HBsAg

and throughout required for replication)

chronic illness

2-26 wk

Insidious

2-8 wk

Usually abrupt Variable

Unknown Variable -

dormant or

persistent

20- 60 d 30-50 d

Variable

Highly

communicable

during year after

primary infection

but nevercero

Usually abrupt

Variable,vector-dependent

5% adults,90% infants 80%,20% ol which 5%

develop cirrhosis

SeeTable 19,633 HCV- RNA

Anli-HCV (IgGi'IgM) Anti-HOV (IgGflgM)

Common;latent Common;latent Infection confers

lifelong immunity

Anti-HEV (IgGf Anti- CMV IlgMI Monospot; Anti-YF (IgM/IgG)

anti-EBV IgM/

IgG,EBV-DNA

quantitation

None

Serology HBsAq

IgM) gG)

Yf-VAX -,1dose

booster qTOyr

Vaccine Havrix - , 2 dosesq6

mo,combined with

Twinrix - at 0,7,

and 21d

Recombivax;

HBTM. No

ages11-15.2 doses

q6 mo

No No No No

General hygiene

Treat close contacts

(anti-HAV Ig)

Prophylaxis for highrisk groups

Prevention;HBVvaccine Prevention:no

and/or hepatitis B Ig vaccine

(HBIg) for needlestick. Rx:interferon

sexual contact,infants ribaviriniprotease

of infected mothers inhibitor; although

(HAV vaccine * HAV Ig) (unless already immune) all oral antiviral (IFNRx;oral antivirals vs. free) therapies now

interferon ifindications available are highly

efficacious

Prevention:HBVvaccine Prevention:gen- In high-risk Supportive

eral hygiene,no transplant treatment

vaccine patients:CMV post-infection

Ig and antivirals

(ganciclovir,

valgancidovir)

Management Prevention

Supportive

treatment post

infection

unless immune

met

0.10.3% 0.5 -2% 1% 2-20% coinfection with 1-2% overall.

H8V. 30% superinlection 10-20% in

Predisposes HBV carriers pregnancy

to mote severe hepatitis

and faster progression

to cirrhosis

Acute Mortality Rareinimmu- Rare

nocompctent

adults

20-60%in developing countries

Oncogenicity

Complications

No Yes Yes Yes No No Yes No

Can causeAIFand

subsequent death

(*TS%|

HCCsecondary to

cirrhosis,serum cirrhosis per yr,

sickness-like syndrome, cryoglobulinemia,

glomerulonephritis. 8 cell non- Hodgkin

cryoglobulinemia. lymphoma

polyarteritis nodosa,

porphyria cutanea tarda

HCC In 2-5% of Leukocylodastic

vasculitis,membranous third trimester

glomerulonephfopathy (10 -20% AIF)

Mild,except in 5% of newborns Associated

with multiple

handicaps

Immunocompromised

patients at risk in Western

ofCMV-induced world)

hepatitis,

retinitis,colitis,

esophagitis,

pneumonitis

Can cause c.

with Burkitt's a recurrent

lymphoma and toxic phase with

nasopharyngeal liver damage. Gl

carcinoma (rare bleeding,and

high

rates

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G36 Gastroenterology Toronto Notes 2023

Autoimmune Liver Disease

• diagnosis of exclusion:rule out viruses,drugs/EtOH, metabolic, or genetic causes

• can be severe:40% mortality at 6 mo without treatment

• extrahepatic manifestations

sicca, Raynaud’s, thyroiditis,Sjogren’s, arthralgias

hypergammaglobulinemia (particularly elevated IgG)

typical auto-antibodies: ANA and/or anti-smooth muscle antibody

infrequently may see anti-LKM elevation (liver kidney microtome), especially in children

• can have false positive viral serology (especially anti

-HCV)

biopsy - periportal (zone I) and interface inflammation and necrosis

• treatment: corticosteroids(80% respond) ± azathioprine (without this, most will relapse as

corticosteroids are withdrawn)

Drug-Induced Liver Disease

Table 21. Classification of Hepatotoxins

Predictable Idiosyncratic

trample

Dose-Dependence

latent Period

Host Factors

Acetaminophen, CCI4

Usual

Hours-days

Not important

Phenytoln. lNH

Unusual

Weeks-months

Very important

• many different patterns of liver injury'

(i.e. hepatocellular,cholestatic, mixed, granulomatous, ALE)

can be seen in drug-induced liver injury and thus this requires a high index ofsuspicion

• see: LiverTox for Information regarding drug-specific risks and patterns of hepatotoxicity (http://

livertox.nih.gov)

Specific Drugs

• acetaminophen

• metabolized by hepatic cytochrome P450 system

can cause ALE (transaminases >1000 U/L followed by jaundice and encephalopathy)

» requires 10-15 g in healthy individuals, 4-6 g in alcoholics/anticonvulsant users

mechanism:high acetaminophen dose saturates glucuronidation and sulfation elimination

pathways-» reactive metabolite (NAEQ1(n-acetyl-p-benzoquinone imine)) is formed -> covalently

bindsto hepatocyte membrane

presentation

first 24 h: nausea and vomiting (usually within 4-12 h of overdose)

24-48 h: asymptomatic, but ongoing hepatic necrosis resulting in increased transaminases

>48 h: continued hepatic necrosis possibly complicated with ALE or resolution

note: potential delay in presentation in sustained-release products

blood levels of acetaminophen correlate with the severity of hepatic injury, particularly if time of

ingestion known

therapy

gastric lavage/emesis (if <2 h after ingestion)

oral activated charcoal

N-acetylcysteine (NAC -Mucomyst') can be given PO or IV (most effective within 8-10 h of

ingestion, butshould be given regardless of time of ingestion)

- promotes hepatic glutathione regeneration

no recorded fatal outcomes if NAC given before increase in transaminases

NAC use should be determined by the Kumack-Matthew nomogram or if unclear, lime of

ingestion

• chlorpromazine: cholestasis in 1% after 4 wk; often with fever, rash, jaundice, pruritus, and

eosinophilia

• Isoniazid (lNH)

20% develop elevated transaminases but <1% develop clinically significant disease

susceptibility to injury increases with age

• Methotrexate (MIX)

causes fibrosis/cirrhosis;increased risk in the presence of obesity, DM, alcoholism (i.e.with

underlying risk for pre-existing fatty liver)

scarring develops withoutsymptoms or changes in liver enzymes, therefore biopsy may be needed

in long-term treatment

• amiodarone: can cause same histology and clinical outcome as alcoholic hepatitis

• others: azoles,statins, methyldopa, phenytoin, propylthiouracil (PTU), rifampin,sulfonamides,

tetracyclines

• herbs: chaparral, Chinese herbs (e.g. germander, comfrey, bush tea)

Hy’s Law:drug-induced hepatocellular

jaundice indicates a mortality of at

least10%

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G37 Gastroenterology Toronto Notes 2023

Wilson’s Disease

Definition

• autosomal recessive defect in copper elimination (gene ATP7B)

Etiology

• decreased biliary excretion of copper plus decreased incorporation of copper into ceruloplasmin

• worldwide incidence: I in 40000

Clinical Manifestations of Wilson's

Disease

ABCD

Astcrixis

Basal ganglia degeneration:suspect if

parkinsonian featuresin the young

Ceruloplasmin decreases

Cirrhosis

Corneal deposits(Kayser-Fleischer ring)

Copper

Dementia

Clinical Features

• liver: acute hepatitis, ALI;

, chronic active hepatitis, cirrhosis, low-risk of HQ.

'

• eyes: Kayser- Meischer rings (copper deposits in Descemet'

s membrane); more common in patients

with CNS involvement, present in only 50% of isolated liver involvement

• CNS:basal ganglia (wing (

lapping tremor, Parkinsonism), cerebellum (dysarthria,dysphagia,

incoordination, ataxia),cerebrum (psychosis, affective disorder)

• kidneys:i anconi’ssyndrome (proximal tubule transport defects) and stones

• blood:intravascular hemolysis;maybe initial presentation in fulminant hepatitis

• joints: arthritis, bone demineralization, calcifications

Investigations

• suspect if increased liver enzymes with clinical manifestations at young age (<40); especially

combination of liver disease with dystonia, psychiatric symptoms

• screening tests

1. reduced serum ceruloplasmin (<50% of normal)

2. Kayser-Pleischer rings (usually require slit-lamp examination)

3. increased urinary copper excretion (measure 24-hour urine copper)

• gold standard

1. increased copper on liver biopsy by quantitative assay

2. genetic analysis imperfect as many mutationsin ATP7B are possible

• first-degree relativesshould also be considered forscreening

Treatment

• 4 drugs available

1. penicillamine: chelates copper, but poorly tolerated

2. trientine: chelates copper

3. zinc:impairs copper excretion in stool and decreases copper absorption from gut. Often used

as maintenance therapy or in neurologic presentations

4. tetrathiomolybdate: preferred if neurological involvement

• hepatic presentations are best treated with a trientine + zinc combination

• liver transplant in severe cases of liver failure

Hemochromatosis

Definition

• excessive iron storage causing multiorgan system dysfunction (liver, in particular) with total body

iron stores increased to 20-40 g (normal 1 g)

Etiology

• primary (hereditary) hemochromatosis

• usually related to Hl-

'

E mutation (see Epidemiology below)

decreased hepcidin production resultsin increased G1absorption and tissue iron deposition

despite adequate iron stores

• secondary hemochromatosis

• parenteral iron overload (e.g. transfusions, hemodialysis, parenteral iron injections)

excessive oral iron intake (e.g. dietary iron overload)

• other liver diseases (e.g. EtOH, NAELl), viral hepatitis)

• iron-loading anemias(hemolytic,sideroblastic, aplastic, thalassemia major)

• ineffective erythropoiesis

Epidemiology

• classic hereditary hemochromatosis most common in Northern European descent

• primarily due to the recessive gene, HFE,which has a homozygous genetic prevalence of 1/400

• mainly caused by mutations in the HFE gene (e.g.C282Y/C282Y, C282Y/H63D)

C282Y/H63D only potentially causative as compound heterozygote

• rare non-HFE mutations also exist (e.g.ferroportin, hemojuvelin, hepcidin, aceruloplasminemia)

*

Hemochromatosis Clinical Features

ABCDH

Arthralgia

Bronze skin

Cardiomyopathy, cirrhosis of liver

Diabetes (pancreatic damage)

Hypogonadism (anterior pituitary

damage)

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G38Gastroenterology Toronto Notes 2023

Clinical Features

• usually presents with trivial elevation in serum transaminases although often picked up incidentally

when iron studies noted to be elevated

• liver:cirrhosis (less common nowadays due to earlier detection), HCC (200x increased risk)

• pancreas: DM, chronic pancreatitis

• skin:bronze or grey (due to melanin, not iron)

• heart:diastolic dysfunction and arrhythmias in early stages with dilated cardiomyopathy in later

stages

• pituitary: hypogonadotropic hypogonadism (impotence, decreased libido, amenorrhea)

• joints:arthralgia (any joint, but especially metacarpophalangeal joints), chondrocaldnosis

Investigations

• screening for individuals with clinical features and/or family history (25% chance of sibling having

the disease)

transferrin saturation (free l-

'

e

-

f

/total iron binding capacity (T'

lBC)) >45%

serum ferritin >400 ng/mL

HIE gene analysis: 90% of primary hemochromatosis involves C282Y allele, while H63D and

S65C alleles also commonly involved and screened

• MKI (often used instead of a liver biopsy)

non-invasive approach to assess iron overload

most sensitive and specific modality in the diagnosis of hemochromatosis

• serum ferritin >1000 ng/mL or symptoms of organ injury (c.g, elevated Lin'

s,symptoms of heart

failure)

• can be used to follow treatment by phlebotomies

• liver biopsy (generally used to detect cirrhosis or if potential for other causes of liver disease)

markers of advanced fibrosis:if any of the following are present at the time of diagnosis -> ages

>40, elevated liver enzymes, or ferritin >1000 ng/mL

considered if compound heterozygote and potential other cause of liver injury (e.g. NAl-

'

LD,

excess LtOH, hepatitis)

if C282Y/C282Y and no markers of advanced fibrosis, then biopsy generally not needed

• HCC screening if cirrhosis

Treatment

• phlebotomy: weekly or q2 wk then lifelong maintenance phlebotomies q2-6 mo, generally aiming for

ferritin of 50-100 ng/mL

• deferoxamine if phlebotomy contraindicated (e.g. cardiomyopathy, anemia)

• primary hemochromatosis responds well to phlebotomy

• secondary hemochromatosis usually requires chelation therapy (administration of agents that bind

and sequester iron, and then excreted)

Prognosis

• normal life expectancy if treated before the development of cirrhosis or DM

Ferritin may never normalize if other

causes of high ferritin present (e.g.fatty

liver from metabolic syndrome or EtOH)

Alcoholic Liver Disease

Definition

• spectrum of diseases, ranging from:

fatty liver (common amongst individuals with EtOH use disorder):reversible if EtOH stopped

• alcoholic hepatitis (35% of individuals with EtOH use disorder): usually reversible if EtOH

stopped

cirrhosis(10-15% of individuals with EtOH use disorder):potentially irreversible

Pathophysiology

• several mechanisms, poorly understood

• ethanol oxidation to acetaldehyde

reduces NAD+ to NADH; increased NADH decreases ATP supply to liver,impairing lipolysisso

fatty acids and triglycerides accumulate in liver

bindsto hepatocytes evoking an immune reaction

• EtOH increases gut permeability leading to increased bacterial translocation

• EtOH metabolism causes:

relative hypoxia in liver zone 111 (near central veins; poorly oxygenated) > zone 1 (around portal

tracts, where oxygenated blood enters)

necrosis and hepatic vein sclerosis

• histology of alcoholic hepatitis

ballooned (swollen) hepatocytes often containing Mallory bodies, characteristically surrounded

by neutrophils

• large fat globules

fibrosis:space of Disse and perivenular

Standard Drink Equivalent

1standard drink =14 g EtOH

-12 oz beer (5% alcohol)

-5oz wine (12-17%)

-3oz fortified wine (17-22%)

-1.5 oz liquor (40%)

Tip:percentage EtOH multiplied by oz in

1standard drink roughly equals 60

Biopsy + Histology of Alcoholic

Hepatitis (triad)

• Hepatocyte necrosis with

surrounding inflammation in zone ID

• Mallory bodies (intracellular

eosinophilic aggregates of

cytokeratins)

• Chicken-wire fibrosis (network

of intralobular connective tissue

surrounding cells and venules)

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G39 Gastroenterology Toronto Notes 2023

Clinical Features

• >2-3 standard drinks/d in females and >3-6 standard drinks/d in men for >10 yrleads to cirrhosis, but

only in about 10-20% of those who consume this amount daily on a continuous basis;cirrhosis risk

increases with amount of EtOH consumed above threshold

• clinical findings do not accurately predict type of liver involvement

• fatty liver

mildly tender hepatomegaly; jaundice rare

mildly increased transaminases <5x normal

• alcoholic hepatitis

variable severity: mild to fatal liver failure

mild:stops drinking because feels unwell, resumes when feeling better (if assessed,findings of

hepatitis, potentially mild jaundice, and mildly elevated 1NR)

severe:stops drinking but feels unwell, low grade fever, RUQ discomfort, increased WBC countmimics right lower lobe pneumonia and cholecystitis

Investigations

• blood tests are non-specific, but in general

AST:ALT >2:1 (both usually <300)

CBC:increased mean corpuscular volume (MCV), increased W BC often seen with alcoholic

hepatitis but not necessarily in other alcohol-related liver injury

increased GGT

Gl Complications of Alcohol Use

• Esophagus

t Mallory-Weiss tear

• Esophageal varices(secondary to

portal hypertension)

. Stomach

• Alcoholic gastritis

• Pancreas

• Acute pancreatitis

• Chronic pancreatitis

. Liver

• Alcoholic hepatitis

• Fatty liver

. Cirrhosis

• Hepatic encephalopathy

• Portal hypertension

• Ascites

. HCC

Treatment

• alcohol cessation (see Psychiatry. PS28)

• Alcoholics Anonymous (or similar programs), disulfiram, naltrexone, acamprosate

• multivitamin supplements (especially thiamine)

• caution with drugs metabolized by the liver

• prednisolone if severe alcoholic hepatitis based on Maddrey’s discriminant function or Model for EndStage Liver Disease (MELD) score as described in Prognosis

pentoxifylline less used since most definitive trial did not demonstrate efficacy

Prognosis

• Maddrey’

s discriminant function (based on PT and bilirubin) and MELD predict mortality and guide

treatment (consideration of corticosteroids for severe disease based on Maddrey <32 or MELD S21)

• bilirubin response at day 7 of corticosteroids (Lille model) also factors into prognosis and decision on

whether to continue full course of corticosteroids if started

• fatty liver:complete resolution with cessation of EtOH intake

• alcoholic hepatitis mortality

immediate:30%-60% in the first 6 mo ifsevere

. with continued EtOH: 70% in 5 yr

• with cessation: 30% in 5 yr

Non-Alcoholic Fatty Liver Disease

Definition

• spectrum of disorders characterized by macrovesicular hepatic steatosis,sometimes with

inflammation and/or fibrosis

• most common cause of liver disease in North America

Etiology

• pathogenesis not well elucidated; insulin resistance implicated as key mechanism, leading to hepatic

steatosis

• histological changes indistinguishable from those of alcoholic hepatitis despite negligible history of

EtOH consumption

Risk Factors

• component of the metabolic syndrome along with obesity,T2DM, HTN, hypertriglyceridemia

• other less common causes such as medications (e.g.tamoxifen, corticosteroids,MTX),Wilson’s, TPN,

rapid weight loss, and others

Clinical Features

• often asymptomatic

• may present with fatigue, malaise, and vague RUQ discomfort

Investigations

• elevated serum AST, ALT ± ALP; AST/ALT <1

• presents as echogenic liver texture on U/S

• non-invasive testing of fibrosis: E1B4, NAFLD fibrosisscore, PibroTest", EibroScan*

• liver biopsy cannot distinguish fatty liver from alcoholic vs. non-alcoholic, but considered when

investigating alternative etiologies or assessing for level of fibrosis

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Treatment

• mainstay is gradual weight loss(0.5-1 kg/wk) as rapid weight loss can worsen liver disease

ideally, aim to lose at least 7-10% of body weight

• evidence for the use of pharmacologic agentssuch as pioglitazone and liraglutide, but potential

benefits must be balanced with associated adverse effects (e.g. weight gain and CHI-

'

with pioglitazone)

• some evidence for vitamin E (800 IU daily) if there is hepatic inflammation in non-diabetic, noncirrhotic patients

• some evidence for benefits of coffee drinking (3cups/d) and vitamin D

• consideration for bariatric surgery

Prognosis

• main causes of death, particularly in non-cirrhotic group, are cardiovascular disease and malignancy

• better prognosis than alcoholic hepatitis

» <25% progress to cirrhosis over a 7-10 yr period

• risk of progression increases if inflammation or scarring occurs alongside fat infiltration (nonalcoholic steatohepatitis)

• other clinical indicators of unfavourable prognosis: obesity,T2DM,age, metabolic syndrome, higher

levels of fibrosis

Acute Liver Failure (formerly Fulminant Hepatic Failure)

Definition

• severe decline in liver function characterized by coagulation abnormality (INK >1.5) and

encephalopathy

• in setting of previously normal liver

• rapid (<26 wk duration)

Etiology

• drugs (especially acetaminophen), hepatitis B (measure anti

-HBc, IgM fraction because sometimes

HBV- DNA and even HBsAg rapidly become negative), hepatitis A, hepatitisC (rare), ischemic,

idiopathic

Treatment

• correct hypoglycemia,monitor level of consciousness, prevent G1bleed with PP1, monitor for infection

and multiorgan failure (usually requires ICU)

• consider liver biopsy before INK becomes too high

• chief value of biopsy is to exclude chronic disease, less helpful for prognosis

• liver transplant ( King'

s College criteria can be used as prognostic indicator): consider early, especially

if time from jaundice to encephalopathy >7 d (e.g. not extremely rapid), ages <10 or >40, cause is drug

or unknown, bilirubin >300 pmol/L, INK >3.5, creatinine >200 prnol/L

Figure13. Progression of liver

dysfunction based on liver function

tests-the “W"

Cirrhosis

Definition

• liver damage characterized by diffuse distortion of the basic architecture with fibrosis and formation

of regenerative nodules

• biopsy gold standard for diagnosis

• compensated cirrhosis = absence of complications, can last for 10-20 yr with almost normal life

expectancy

• decompensated cirrhosis = development of complications such as ascites (most common), variceal

bleeding, encephalopathy

Etiology

• fatly liver (alcoholic or NAI'

LD)

• chronic viral hepatitis(B, B+D, C; not A or E)

• autoimmune hepatitis

• drugs (e.g. chronic MTX or amiodarone use)

• hereditary hemochromatosis

• PBC

• chronic hepatic congestion

cardiac cirrhosis(chronic right heart failure, constrictive pericarditis)

hepatic vein thrombosis (Budd-Chiari)

• cryptogenic (i.e. no identifiable cause, although many of these patients may represent “burnt-out nonalcoholic steatohepatitis(NASH)")

• rare:Wilson’s disease,Gaucher’

s disease,al-antitrypsin deficiency

MELD-Na (Model for End-Stage Liver

Disease)

• Predicts 3 mo survival and used to

stratify patients on transplant list

• Based on creatinine, INR,total

bilirubin,and serum sodium

concentration

MELD 3.0

• Updated score that Includes new

variablessuch asfemale sex and

serum albumin

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Investigations

• definitive diagnosis is histologic (liver biopsy)

• other tests may be suggestive

blood work

fall in platelet count <150 is the earliest finding

in late stages of cirrhosis, rise in 1NR, fall in albumin,rise in bilirubin

elevated bilirubin is usually seen in more advanced disease or in the setting of a concurrent

insult

in very advanced cirrhosis (pre-terminal event), may also see hypoglycemia but this is more

often a feature seen in severe AL1-

• I

'

ibroTestcombination of various clinical and biochemical markers that can predict degree of

fibrosis

imaging

U/S is the primary imaging modality but only finds advanced cirrhosis

CT to look for varices, nodular liver texture,splenomegaly, ascites

transient elastography (TibroScan*): noil

-invasive tool using elastography for measuring liver

compliance (variable availability)

- rapidly replacing liver biopsy to determine extent of liver fibrosis and make the

diagnosis of cirrhosis

• gastroscopy:varices or portal hypertensive gastropathy

Treatment

• treat underlying disorder

• decrease insults(e.g. EtOH cessation, hepatotoxic drugs, immunize for hepatitis A and B if nonimmunc)

• follow patient for complications (esophageal varices, ascites, HCC)

• prognosis:Child-Pugh Score and MELD score

• liver transplantation for end-stage disease;use MELD score (e.g.MELD >15)

Cirrhosis Complications

VARICES

Varices

Ascitcs/Anemia

Renal laiturc (HRS)

Infection

Coagulopathy

Encephalopathy

Sepsis

Table 22. Child-Pugh Score and Interpretation

Classification 1 2 3

Serum bilirubin (|iinol/L)

Serum albumin (g/L)

04 34- 51 >51

>35 28-35 <28

INR <1.7 1.7-2.3

Controllable

>2.3

Presence of ascites Absent Refractory

Encephalopathy Absent Minimal Severe

Inlerprelalion

Points Class tile Expectancy

15-50 yr

Candidate for transplant

1-3 mo

Perioperative Mortality

5-6 A 10%

7-9 8 30%

10-15 C 82% Usual causes of death in cirrhosis:renal

failure (hepatorenal syndrome),sepsis,

Cl bleed,or HCC

Score:5-6 (Child's A|. 7-9(Child’sB).10-15 (Child's C|

'Note:Child's classificationis rarely usedlor shunting(TIPS or other surgical shunts),but is stillusefulto quantitate the severityof cirrhosis

Complications

• hematologic changes in cirrhosis

pancytopenia from hypersplenism:plateletsfirst, then YVBC, then hemoglobin

decreased clotting factors resulting in elevated INR

relationship of INR to bleeding tendency is controversial;some patients may be hypocoagulable,

others may be hypercoagulable

• variceal bleeds

1/2 of patients with cirrhosis have gastroesophageal varices and 1/3of these develop hemorrhage

with an overall mortality of >30%

HVPG >10 mmHg is the strongest predictor of variceal development

treatment: resuscitation,antibiotic prophylaxis, vasoactive drugs (e.g.octreotide IV) combined

with endoscopic band ligation orsclerotherapy, TIPS

• renal failure in cirrhosis

classifications

pre-renal (usually due to overdiuresis)

acute tubular necrosis

HRS

Hepatorenal Syndrome vs. Pre-Renal

Failure - Difficult to Differentiate

• Similar blood and urine findings

. Urine sodium:very low in

hepatorenal: low in pre-renal

• IV fluid challenge: giving volume

expanders improves pre-renalfailure,

but not HRS

Hepatopulmonary Syndrome

Clinical Triad

• Liver disease

• Increased alveolar-arterial gradient

while breathing room air

• Evidence for intrapulmonary vascular

abnormalities

- type 1:sudden and acute renal failure (rapid doubling of creatinine over 2 wk)

n

- type II:gradual increase in creatinine with worsening liver function (creatinine

doubling over years)

HRS can occur at any time in severe liver disease, especially after:

- overdiuresis or dehydration,such as diarrhea, vomiting, etc.

- Gi bleed

- sepsis

L

Fibrosis

o

may regress and disappear if +

cause of liver injury is treated or resolves

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G42 Gastroenterology Toronto Notes 2023

treatment for HRS (generally unsuccessful at improving long-term survival)

- for type I HRS:octreotide + midodrine t albumin (increases renal blood flow by

increasing systemic vascular resistance)

- definitive treatment isliver transplant

•hepatopulmonary syndrome

majority of cases due to cirrhosis, though may be due to other chronic liver diseases,such as noncirrhotic portal HTN

thought to arise from:

ventilation-perfusion mismatch (intrapulmonary shunting and limitation of oxygen diffusion)

failure of damaged liver to clear circulating pulmonary vasodilators and/or increased

production of vasodilators by liver

• clinical features

* hyperdynamic circulation with cardiac output >7 L/min at rest and decreased pulmonary +

systemic resistance (intrapulmonary shunting)

• dyspnea, platypnea (increase in dyspnea in upright position, improved by recumbency), and

orthodeoxia (desaturation in the upright position, improved by recumbency)

diagnosis via contrast-enhanced echocardiography:inject air bubbles into peripheral vein; air

bubbles appear in left ventricle after third heartbeat (normal = no air bubbles;in ventricular

septal defect, air bubblesseen <3heart beats)

only proven treatment is liver transplantation

Ellects of Portal Hypertension

.Esophageal varices

•Gastric varix -> melena

•

Splenomegaly

•Caput medusa,umbilical henna

•

Ascites

•Hemorrhoids

Ellects of Liver Failure

Encephalopathy(coma)

Xanthelasma

Scleral icterus,

jaundice

Fetor hepaticus

Spider angioma

Gynecomastia

Muscle wasting

Bleeding tendency(bruising)

r k

I

Loss of sexualhair,testicular atrophy i

Ankle edema

Palmar erythema

Dupuytren's contracture,asterixis anemia

v

Leuckonychia,Terry s nails,clubbing

7

j

I

/

I

C3

- J

Figure 14. Clinicalfeatures of liver disease

Hepatocellular Carcinoma

• see General Suruerv and '

thoracic Suruerv, GS53

Liver Transplantation

• see General Surgery and Thoracic Surgery, GS54

Portal Hypertension s

Definition

• pressure gradient between hepatic vein pressure and wedged hepatic vein pressure (corrected

sinusoidal pressure) >5 mmHg

Pathophysiology

• 3sites of increased resistance (remember pressure

= flow x resistance)

• pre-sinusoidal (e.g. portal vein thrombosis,schistosomiasis,sarcoidosis)

sinusoidal (e.g.cirrhosis, alcoholic hepatitis)

• post-sinusoidal (e.g.right-sided heart failure, hepatic vein thrombosis, veno-oedusive disease,

constrictive pericarditis)

Complications

• G1 bleeding from varices in esophagus, less commonly in stomach, even less frequently from portal

hypertensive gastropathy

• ascites

• hepatic encephalopathy

• thrombocytopenia

• renal dysfunction

• sepsis

• arterial hypoxemia

Portal Hypertension

Signs

• Esophageal varices

• Melena

• Splenomegaly

• Ascites

• Hemorrhoids

Management

• (3-blockers

. Nitrates

• Shunts(e.g.TIPS)

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Treatment

• non-selective (3-blockers (propranolol, nadolol, carvedilol) decrease risk of bleeding from varices;

PKEDESCI trial (Lancet 2019;393:1597-1608) showed that non-selective (3-blockers in cirrhotic patients

with portal hypertension lowers risk of decompensation (particularly ascites)

• TIPS:to decrease portal venous pressure

radiologically inserted stent between portal and hepatic vein via transjugular vein catheterization

and percutaneous puncture of portal vein

can be used to stop acute bleeding or prevent rebleeding or treat ascites

complications: hepatic encephalopathy, deterioration of hepatic function

• contraindicated with severe liver dysfunction, uncontrolled hepatic encephalopathy, and

congestive heart failure

• most commonly used as a “bridge" to liver transplant

Hepatic Encephalopathy s

Definition

• spectrum of potentially reversible neuropsychiatric syndromes secondary to hepatic insufficiency

and/or portosystemic shunting, diagnosed after ruling out other causesfor symptoms (e.g.structural/

metabolic)

Pathophysiology

• portosystemic shunt around hepatocytes and decreased hepatocellular function increase level of

systemic toxins (believed to be ammonia from gut, mercaptans,fatty acids, amino acids) which go to

tne brain

Precipitating

*

Factors for Hepatic

Encephalopathy

HEPATICS

Hemorrhage in Gl tract/Hypokalemia

Excess dietary protein

Paracentesis

Alkalosis/Anemia

Trauma

Infection

Colon surgery

Sedatives

Precipitating Factors

• nitrogen load (Gl bleed, protein load from food intake, renal failure, constipation)

• drugs(narcotics,CNS depressants)

• electrolyte disturbance (hypokalemia, alkalosis, hypoxia,hypovolemia)

• infection (SBP)

• deterioration in hepatic function or superimposed liver disease

• spontaneous portosystemic shunts (e.g.splenorenal shunts) or intentional portosystemic shunts (e.g.

TIPS)

A Randomized. Double-Blind. Controlled Trial

Comparing BHaximin plus Lactulose with

lactulose Alone in Treatment of Overt Hepatic

Encephalopathy

American j Ustioenterol 2013:103:1498 U63

Study: Prospettnre double- blinded Kl.

Purpose:Efficacy and safety ol illenmin plus

lactulose n.lactulose alone lor treatment of

overt HE.

Results:Of trie patients.48(76%) in group A

0actulose plusrifaximin 1200 mg/d. ir63|compared

with 29 (S0.n|in group B (lactulose plus placebo.

irST|bad complete reversal olHE (P'

0.004)

Th ere was a significant decrease in mortality alter

treatment until lactulose plus ilfaumin vs.lactulose

plus placebo (23JHvs.49.1V P«0.05).Ihere were

significantly more deaths m group B because olsepsis

(group A vs.group B:7:17, P'0.01),whereasthere

were as differences because ol Gl Weed (groupAvs.

group B:4:4,

^

nonsignificant (NS)|and HRS (group A

us.group B:4:7.P-HS), Patients in the lactulose plus

rilasmin group had shoitor hospitalstay (5.8

-34 vs.

8Je4.Sd.MI.001l.

Conclusion: Combination ol lactulose plus idaiimin

is moceeffettive than lactulose alone in the treatment

ol overt HE.

Stages

A. minimal hepatic encephalopathy (diagnosed with specialized cognitive testing)

B. overt hepatic encephalopathy (stages 1 to IV)

I:apathy, restlessness, reversal of sleep-wake cycle,slowed intellect, Impaired computational

abilities, impaired handwriting

II:asterixis, lethargy, drowsiness, disorientation

111:stupor (reusable),hyperactive reflexes,extensor plantar response (positive Babinski sign)

IV:coma (response to painfulstimuli only)

Investigations

• clinical diagnosis:supported by laboratory findings and exclusion of other neuropsychiatric diseases

• rule out:

non-liver-related neuropsychiatric disease in a patient with liver problems (e.g. EtOH withdrawal

or intoxication,sedatives,subdural hematoma, metabolic encephalopathy)

» causes of metabolic encephalopathy (e.g.renal failure, respiratory failure,severe hyponatremia,

hypoglycemia)

• characteristic EEG findings:diffuse (non-focal), slow, high amplitude waves

• scrum ammonia levels increased, but not often necessary to measure in routine clinical use

Treatment

• treat underlying precipitating factors

• decrease generation of nitrogenous compounds

routine protein restriction is no longer recommended given patients generally have concurrent

malnutrition and muscle wasting; however, vegetable protein (as opposed to animal protein) may

help reduce risk of encephalopathy

lactulose or lactitol: titrated to achieve 2-3 soft stools/d

prevents diffusion of NHJ (ammonia) from the colon into blood by lowering pH and forming

non-diffusible NHt +(ammonium)

serves as a substrate for incorporation of ammonia by bacteria, promotes growth in bowel

lumen of bacteria which produce minimal ammonia

also acts as a laxative to eliminate nitrogen-producing bacteria from colon

• oral rifaximin for both acute treatment and maintenance therapy has high level evidence for efficacy

• best acute treatment in patients who cannot take medication orally is lactulose or lactitol enemas

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Ascites

Definition

• accumulation of excess fluid in the peritoneal cavity

Etiology

Table 23. Serum-Ascites Albumin Gradient in the Evaluation of Ascites

Serum [Alb]

- Ascitic [Alb] >11 g/L (1.1g/dl)

Portal Hypertension Related

Serum [Alb]

- Ascitic [Alb] <11 g/L (1.1g/dL)

Non-Portal Hypertension Related

Cirrhosis/severe hepatitis

Chronic hepatic congestion (rightheart failure,Budd-Chiari)

Massive liver metastases

Peritoneal carcinomatosis

PeritonealIB

Pancreatic disease

Serositis

Nephrotic syndrome*

Portal vein thrombosis

Idiopathic portal fibrosis

'In nephrotic syndrome:decreased serum (Alb) to begin with, Iherelorc gradient not helpful

Pathophysiology

• key factor in pathogenesis is increased sodium (and water) retention by the kidney for reasons not

fully understood. Theories include:

underfill hypothesis

overfill hypothesis

peripheral arterial vasodilation theory (most popular):as portal hypertension developsin

cirrhosis, production oflocal mediators such as nitric oxide leadsto splanchnic arterial

vasodilation, ultimately pulling blood away from the systemic circulation and resulting in

reduced effective arterial volume, which causes compensatory sodium and fluid retention by the

kidneys (i.e. circulatory volume is increased, as per the overfill hypothesis, but effective volume is

decreased as per the underfill hypothesis)

Underfill Hypothesis

Firststep in ascitesformation is

increased portal pressure and low

oncotic pressure (e.g. low serum

albumin) driving water out of the

splanchnic portal circulation into

abdominal cavity:the resulting

decreased circulating volume causes

secondary sodium retention by the

kidney

Overfill Hypothesis

Cirrhosis directly causesincreased

sodium retention by the kidney in the

absence of hypovolemia and ascites

arisessecondarily

Diagnosis

• abdominal U/S

• physical exam (clinically detectable when >500 mL)

• bulging flanks,flank dullness,shifting dullness,fluid-wave test positive

most sensitive symptom: ankle swelling

Investigations

• diagnostic paracentesis

1st aliquot: cell count and differential

2nd aliquot: chemistry (especially albumin, but also total protein; amylase if pancreatitis;TG and

chylomicrons if turbid and suspect chylous

» 3rd aliquot:C&S,Gram stain

4th aliquot:cytology (usually positive in peritoneal carcinomatosis)

Treatment

• diuretic-sensitive ascites

Na ’

restriction (daily sodium intake <2 g)

no need for fluid restriction unless significant hyponatremia (e.g. Na * <120-125 mmol/L)

» diuretics:spironolactone,furosemide

aim for weight loss 0.5-1 kg/d, more if concomitant peripheral edema (which is mobilized quicker

than ascitic fluid);overly rapid weight loss increases risk of renal failure

if target weight loss is not achieved and there are no complications, increase dose to achieve target

while monitoring for complications

• refractory ascites(diuretics are inadequate or not tolerated)

• therapeutic paracentesis with IV albumin

TIPS in an appropriate patient (no contraindications) with potential transplant-free survival

advantage

liver transplantation should be considered in every case,since development of ascites in patients

with cirrhosis is associated with a high 2 yr mortality

Complication: Primary/Spontaneous Bacterial Peritonitis

• primary/SBP

complicates ascites, but does not cause it (occurs in 10% of cirrhotic ascites); higher risk in

patients with G1bleed

1/3of patients are asymptomatic,thus do not hesitate to do a diagnostic paracentesis in ascites

even if no clinical indication of infection

fever, chills, abdominal pain,ileus, hypotension, worsening encephalopathy, acute kidney injury

• Gram-negatives compose 70% of pathogens: H.coli (most common), Streptococcus, Klebsiella

Serum Ascites Albumin Gradient

(SAAG) r

serum albumin - ascites

albumin

. >11 g/l portal HTN

. ascitic fluid total protein >25g/L,

suggests cardiac portal hypertension

. ascitic fluid total protein <25

g/L,suggests cirrhosis portal

hypertension

. <11 g/L unrelated to portal HTN

ascites)

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Cil5 Gastroenterology Toronto Notes 2023

• diagnosis

absolute neutrophil count in peritoneal fluid >0.25xl09 cells/L (250 cells/mm 3)

Gram stain positive in only 10-50% of patients

• culture positive in <80% of patients (not needed for diagnosis)

• prophylaxis: consider in patients with:

• cirrhotic with Cil bleed: ceftriaxone IV daily or norfloxacin BID x 7 d

• previous episode of SBP: long-term prophylaxis with daily norfloxacin or TMP-SMX

• treatment

IV ABx (cefotaxime 2 g IV' q8h or ceftriaxone 2 g IV daily is the treatment of choice for 5 d;

modify if response inadequate or culture shows resistant organisms)

IV albumin (1.5 g/kg at time of diagnosis and 1 g/kg on day 3) decreases mortality by lowering

risk of acute renal failure

Biliary Tract s

Jaundice

•see table 2, G5 and I

'

igurcs 15 «m/ 16

Definition

•yellowing of the skin,sclera, and/or mucous membranes due to abnormal deposition of pigmented

bilirubin

Signs and Symptoms

•dark urine, pale stools:suggests that bilirubin elevation isfrom direct fraction

•pruritus:suggests chronic disease, cholestasis

•abdominal pain:suggests biliary tract obstruction from stone or pancreatic/biliary tumour

(obstructive jaundice)

•painless jaundice in the elderly:think of pancreatic cancer

•kernicterus: rarely seen in adults due to maturation of blood brain barrier

Investigations

•blood work:CBC,bilirubin (direct and total), liver enzymes(AST,ALT, ALP,GGT),liver function tests

(1NR/PT, PTT, albumin), ± amvlase/lipase

• U/S or CT for evidence of bile duct obstruction (e.g. bile duct dilation)

•more detailed evaluation of bile duct ± surrounding structureslike pancreas:

MRCP: non-invasive

• KUS:sensitive for stones and pancreatic tumours

ERCP:invasive, most accurate, allows for therapeutic intervention

PTC:if ERCP fails (endoscopic access not possible)

Jaundice (Tserum bilirubin)

RBC destruction

(rcticuloondolliclial system)

I

Hb Globin

I

Heme

I

Conversion

I

Bilirubin (unconiugatcdl

h

Fractionate bilirubin Primarily Alb uncon|i»gated Primarily conjugated I

r Bilirubin-Alb

I

Hemolysis

Gilbert'

ssyndrome

Hepatobiliary disease

Abdominal ultrasound LIVER

Glucuronyl transferase

conjugates bilirubin

1

Bile duct normal Bile duct dilated f 4'

15-20%

reabsorbed Hepatocellular disease Bile duct obstruebon

Biliary excretion via I into duodenum onterohopatic

circulation Visualize bile duct 1'

Virus

Autoimmune

Hemochromatosis

Wilson'

s disease, etc.

Intestinal flora I

y

Urobilinogen Endoscopic bile duct

decompression not likely

to be necessary

Endoscopic bile duct

decompression likely

to be necessary 1

70-85%

I 4

Stcrcobilmogcn 10% excreted

via urine

Magnetic resonance I

cholangiopancreatography IMRCPI

Endoscopic retrograde

cholangiopancreatography (ERCP! Sto r i

L J

Figure 15. Approach to jaundice Figure 16. Production and excretion

of bilirubin

+

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G16 Gastroenterology Toronto Notes 2023

Gilbert’s Syndrome

Definition

• hereditary hyperbilirubinemia due to a deficiency of glucuronyl transferase characterized by repeat

episodes of mild asymptomatic jaundice

Etiology/Epidemiology

• some patients have decreased hepatobiliary uptake

• affects 7% of population,especially males

• autosomal dominant, 70% due to a mutation in the UGT gene

Clinical Features

• presents in teens-20s, often an incidental finding

• only manifestation is intermittent jaundice with increased serum unconjugated bilirubin developing

most characteristically while fasting, or at times of acute illness; no other clinical implications

Treatment

• none indicated (entirely benign)

Gilbert'sSyndrome vs.Crigler-Najjar

Syndrome

Gilbert’sSyndrome:mild decrease in

glucuronyltransferase activity

Crigler-Najjar Syndrome:complete

deficiency of glucuronyltransferase

Primary Sclerosing Cholangitis

Definition

• inflammation, fibrosis, and stricturing of biliary tree (intra- and/or extrahepatic bile ducts) from

scarring

Etiology

• primary/idiopathic (most common)

• associated with 1BD, more commonly UC, in up to 70-80% of patients (usually male) with PSC

• secondary (less common)

long-term choledocholithiasis

cholangiocarcinoma

surgical/traumatic injury (iatrogenic)

contiguous inflammatory process

• post-ERCP

associated with H1V/A1DS (“HIV cholangiopathy")

lgG4-related disease

critical illness

Signs and Symptoms

• often insidious, may present with fatigue and pruritus

• may present with signs of episodic bacterial cholangitissecondary to biliary obstruction

• may present with jaundice, hepatomegaly,splenomegaly, excoriationssecondary to pruritus

Investigations

• increased ALP ( hallmark), less often increased bilirubin

• mildly increased AST, usually <300 U/L

• p-ANCA (30-80%), elevated lg\l (40-50%)

• MRCP and ERCP shows narrowing and dilatations of bile ducts that may result in “beading," both

intrahepatic and extrahepatic bile ducts

• if intrahepatic narrowing only, do anti-mitochondrial antibody to rule out PBC

• consider livery biopsy ifsuspecting small duct variant

Complications

• repeated bouts of cholangitis may lead to complete biliary obstruction with resultant secondary

biliary cirrhosis and hepatic failure

• increased incidence of cholangiocarcinoma (10-15%): difficult to diagnose and treat

• increased incidence of colon cancer in those with concurrent 1BD

Treatment

• image bile duct (MRCP) at least annually for early detection of cholangiocarcinoma (controversial)

• endoscopic sphincterotomy, biliary stent in selected cases of dominant common bile duct stricture

• ABx for cholangitis

• suppurative cholangitis requires emergency drainage of pus in common bile duct

• liver transplantation appears to be the best treatment for advanced sclerosing cholangitis (>90% 1 yr

survival; mean follow-up time from diagnosis to need for transplant is 10 yr)

• ursodiol: previously recommended, but studiessuggest that it increases mortality if taken in high

doses

n

L J