Curs-5-Mai 2015 - Ficat Si Pancreas - Final de Prezentat-Recovered)

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Liver
Motion and Activity

The position of the liver in the body is not
static.
moves up and down with the diaphragm and
rotates during respiration.
rotates backward when an individual lies down in
the supine position.
The upper surface of the liver can move upward from
1 cm to 10 cm when full expiration follows deep
inspiration.
The Anatomy of the Liver
LIVER Histology
lobules >> roughly
hexagonal structures
consisting of
hepatocytes. Radiate
outward from a central
vein.
At each of the six
corners of a lobule is a
portal triad
( p.arteriole,p.venule &
bile duct)
Between the
hepatocytes are the
liver sinusoids.
Figure 24.20 Liver Histology
Figure 24.20a,
b
Normal Liver - Microscopy
Liver Functions:
Metabolism Carbohydrate, Fat &
Protein
Secretory bile, Bile acids, salts &
pigments
Excretory Bilirubin, drugs, toxins
Synthesis Albumin, coagulation
factors
Storage Vitamins, carbohydrates etc.
Detoxification toxins, ammonia, etc.
Hepatic Physiology
Liver:
Largest solid organ in the body

Performs over 500 chemical processes
Produces over 160 different proteins
Makes clotting factors for the blood
Stores & releases sugar as glycogen
Metabolizes, detoxifies, synthesizes
Hepatic Physiology
1- homeostasis;
5-Detoxification
toxins, ammonia, etc
glycogenolysis &
Catabolism of hormones
gluconeogenesis
and other serum proteins
Chronic Liver
Disease
4-Synthesis:
- Albumin
- Coagulation factor
3-Secretory
bile, Bile acids, salts & pigments
Bile excretion
1-Storage:
- Glycogen
- Iron
- Cu, Iron, vitamins
-2-Metabolism Carbohydrate, Fat & Protein
There are eight liver segments.

Segment 4 is sometimes divided into segment 4a and 4b according to Bismuth.
The numbering of the segments is in a clockwise manner (figure).
Segment 1 (caudate lobe) is located posteriorly. It is not visible on a frontal
view.
1-SYNTHETIC FUNCTIONS
production and release of circulating factors critical to the

coagulation cascade
the single most sensitive tests of liver function are measures of

coagulation functionInternational Normalized Ratio (INR) and
factor VII and factor V levels.
synthesizes a wide variety of plasma proteins, the most

important of which is albumin.
variety of acute-phase proteins and cytokines that have important

interactions with a variety of inflammatory, infectious, and
regulatory processes.
2-Metabolism
Carbohydrate Metabolism
critical storage site of glycogen and is essential to the maintenance of
systemic glucose homeostasis through a complex process involving broad
interactions with lipid metabolism.
The liver also metabolizes lactate, and the Cori cycle is important in
maintaining peripheral glucose availability in the setting of anaerobic
metabolism.
Lipid Metabolism
modulator of lipid metabolism, critical role in the synthesis of lipoproteins,
triglycerides, gluconeogenesis from fatty acids, and cholesterol metabolism.
cholesterol is synthesized in the liver and is used most importantly for bile
salt synthesis.
Bilirubin Metabolism
Bilirubin circulates bound to albumin in the blood.
It is actively taken up by hepatocytes, where it is glucuronidated and actively
secreted into bile.
Benign disorders of bilirubin metabolism include:
conjugated (direct) hyperbilirubinemia.
Dubin-Johnson and Rotor's syndrome, which produce conjugated (direct)
hyperbilirubinemia.
Unconjugated hyperbilirubinemia is seen in Crigler-Najjar type II and Gilbert's
3-Bile and the Enterohepatic

Circulation
Bile is a mixed micelle composed of bile

1- acids and pigments, 2-phospholipids and cholesterol, 3-proteins, and
electrolytes.
The volume of bile secreted in an adult ranges from 500 to 1000 mL/24 h.
Electrolyte composition of bile is similar to plasma, intravenous volume
replacement of a high-volume biliary fistula output can be made milliliter for
milliliter with lactated Ringer's solution.
Role of the distal ileum in the reabsorption of bile salts became clear when
patients undergoing resection of the ileum for Crohn's ileitis developed
malabsorption and steatorrhea.
It was also noted that such patients had lower serum cholesterol levels,
ultimately found to be a result of increased hepatic metabolism of
cholesterol to bile acids to replace the bile acids not absorbed and recirculated.
Traditional LFTs (Liver Functional Test)
Traditional LFTs (Liver Functional

Test)
ALT: alanine aminotransferase (SGPT)
AST: aspartate aminotransferase (SGOT)
Alkaline Phosphatase & Bilirubin
Traditional LFTs
ALT: GPT
Found primarily in hepatocytes
Released when cells are hurt or destroyed
Normal levels depend on the reference range which
actually differs lab to lab
Considered normal between 5-40 U/L
Probably should be half of this (5-20?)
Traditional LFTs
AST:GOT
Found in many sources, including liver, heart,
muscle, intestine, pancreas
Not very specific for liver disease
Often follows ALT to a degree
Elevated 2 or 3:1 (vs. ALT) in alcoholics
Normal range: 8-20 U/L
Traditional LFTs
Alkaline Phosphatase:
Found in liver (especially biliary tract), bones,
intestines, & placenta
Fractionated or isoenzymes to source
Liver AP rises with obstruction or infiltrative
diseases (i.e., stones or tumors)
Normal range: 20-70 U/L
Traditional LFTs
Bilirubin: two primary sources
Indirect (unconjugated): old red cells, removed by the
spleen, sent to the liver
Direct (or conjugated) Liver adds glucuronic acid,
making these cells water soluble for excretion; now
called direct (or conjugated)
Normal range: less than 0.8 mg/Dl
Total bilirubin includes both direct and indirect types
Patterns of Abnormal
Elevations in ALT & AST only: suggests cellular
injury
Elevations in Alk Phos & Bilirubin: suggests
cholestasis or obstruction
Mixed pattern: ALT, AST, AP & Bili: probably the most
common scenario
LIVER DISEASE
Viral Hepatitides
Viral Hepatitides
Hepatitis A, B, C, D, E, G
Cytomeglovirus (CMV)
Herpes Virus (HSV)
Chronic Hepatitis
Chronic Hepatitis
Overview
Progression to cirrhosis over 20 years2

18% to 26% in liver clinic series
1% to 10% in community cohort series
Leading cause of chronic liver disease, cirrhosis, HCC, and
liver transplantation (40%)4
CLD Aetiology
Surgical Sieve
Viral
Autoimmune - Autoimmune hepatitis, PBC, PSC
Genetic - Wilsons, Haemochromatosis, Alpha 1
antitrypsin deficiency
Toxic / Drugs alcoholic, paracetamol
Non-alcoholic fatty liver (DM / metabolic syndrome,
pregnancy, idiopathic)
Differential Diagnoses
1-(Decompensated) Alcoholic liver disease

2-Viral liver disease
3-Autoimmune liver disease, Wilsons, HH etc
4-Hepatocellular Carcinoma
5-Pancreatic Cancer
6-Cryptogenic Liver Cirrhosis
What further history would be needed?

What signs would you look for on examination?
How would you investigate this

patient?
Bedside
Observations, BM, fluid balance, weight
Blood tests
LFTs (pre/post) (including albumin), INR
FBC, U&Es, CRP
Liver screen: autoantibodies, alpha-1 antitrypsin,
caeruloplasmin, serum copper, ferritin, viral hepatitis
serology
Imaging
US abdomen + portal vein doppler
CXR, CT, MRI, MRCP
Special tests
Ascitic tap, OGD (oesophageal varices), liver biopsy
Chronic HCV Infection

Natural History
Exposure
(Acute Phase)
15-45%
Resolved
Primary Point
of Intervention
55-85%
Chronic
5%-25% over 20-30 years
75-95%
Stable
Cirrhosis5%/yr decompensation
2-8%/yr HCC
Liver Decompensation
Hepatocellular Carcinoma
Poynard T. Lancet. 1997 349:825-832.
Mathurin P. Hepatology. 1998 27:868-872.
Benhamou J. Hepatology. 1999 30:1054.
Treatment
Goals
Viral eradication
Prevention of
disease progression
Treatment
Endpoints
Sustained loss of
HCV RNA in serum
(3-6 mos post-Tx)
Normalization of
liver enzymes
Improved liver
histology
Improved quality of
life
What is your management plan?

Conservative
Alcohol abstinence, optimise nutrition, low salt diet, fluid
restriction
Medical
Vitamin B supplementation (IV/PO), chlordiazepoxide
Diuretics
Paracentesis (give albumin)
NG feeding
Antibiotics (? SBP)
Steroids + albumin (N.B. avoid NaCl)
Lactulose (in hepatic encephalopathy)
Surgical
Liver transplantation
Recommended Treatment 2008

Chronic Hepatitis C
Peginterferon + Ribavirin Therapy
AASLD Practice Guidelines
Drug doses
PEG-IFN -2b (Peg-Intron) 1.5 g/kg weekly +
ribavirin 800 mg (G2/3),1000-1200 mg (G1) daily
PEG-IFN -2a (Pegasys) 180 g weekly +
ribavirin 800 mg (G2/3),1000-1200 mg (G1) daily
Treatment duration
For genotype 1, 48 weeks superior to 24 weeks
For genotypes 2/3, 48 weeks = 24 weeks
Strader DB, et al. Hepatology. 2004;39:1147-1171.
Autoimmune Hepatitis
What is autoimmune hepatitis?
Autoimmune hepatitis is a disease in which the

bodys own immune system attacks the liver and
causes it to become inflamed. The disease is
chronic, meaning it lasts many years. If
untreated, it can lead to cirrhosis and liver
failure.
Autoantibodies against hepatocytes

Young/middle age, mainly women
Presentation: jaundice, RUQ pain, systemic symptoms
May be associated with other autoimmune conditions
Investigations
- Type 1: anti-smooth muscle antibodies (80%), anti-nuclear
antibodies (10%)
- Type 2 (children): anti-liver/kidney microsomal type 1
antibodies
- Liver biopsy
Rx: immunosuppressant's (steroids, azathioprine),
transplant
How is autoimmune hepatitis

diagnosed?
Autoimmune hepatitis often occurs suddenly. Initially, you may feel like
you have a mild case of the flu. As PE does not often offer the examiner
much information to confirm a diagnosis of autoimmune hepatitis, your
doctor will need to useblood tests and a liver biopsy
antinuclear antibody (ANA),

smooth muscle antibody (SMA),
Liver/kidney microsomal antibody (LKM-1)
and anti-mitochondrial antibody (AMA)
are all of use, as is finding an increased Immunoglobulin G level.
However, the
In complex cases a scoring system can be used to help determine if a

patient has autoimmune hepatitis, which combines clinical and laboratory
diagnosis of autoimmune hepatitis always

requires a liver biopsy.
What causes autoimmune

hepatitis?
Your immune system normally attacks bacteria,
viruses and other invading organisms. It is not
supposed to attack your own cells; if it does, the
response is called autoimmunity.
In autoimmune hepatitis, your immune system
attacks your liver cells, causing long-term
inflammation and liver damage.
Scientists dont know why the body attacks itself in
this way, although heredity and prior infections may
play a role.
What are the symptoms and

complications of autoimmune
hepatitis?
Often, the symptoms of autoimmune hepatitis are minor.
When symptoms do occur, the most common are
fatigue
abdominal discomfort
aching joints
jaundice
enlarged liver
nausea
Liver biopsy histology at initial presentation showing peri-portal

lymphocytic infiltration and extensive peri-portal fibrosis.
How is autoimmune hepatitis

treated?
The goal of treatment is to stop the bodys attack on itself by
suppressing the immune system.
prednisone,,
azathioprine (Imuran)
Treatment starts with a high dose of prednisone. When

symptoms improve, the dosage is lowered and azathioprine
may be added.In most cases, autoimmune hepatitis can be
controlled but not cured. That is why most patients will need
to stay on the medicine for years, and sometimes for life.
long-term use of steroid can cause serious side effects

including diabetes, osteoporosis, high blood pressure,
glaucoma, weight gain and decreased resistance to infection.
Conventional Treatment
Regimens
Primary Biliary Cirrhosi

Primary Sclerosing Cholangitis
PBC and PSC

Primary Biliary Cirrhosis
Chronic granulomatous inflammation of interlobular bile
ducts
Autoimmune: anti-mitochrondrial antibody (98%)
Associated with other autoimmune conditions
F:M 9:1, 50 y/o
Inflammation, fibrosis and strictures (beading)
of intra and extra-hepatic bile ducts
? Autoimmune: ANCA (80%)
Associated with IBD
20-30% develop cholangiocarcinoma
Wilsons & 1AT Deficiency

Wilsons Disease
AR defect in copper transporting ATPase
Copper accumulates in liver + CNS +
Kayser-Fleischer rings
Rx: penicillamine, transplant
Alpha-1 Antitrypsin Deficiency
AR deficiency of 1AT
Serine protease inhibitor produced by liver
Emphysema + liver damage + HCC
Hereditory Haemochromatosis
Defect in HFE causes increased
intestinal iron absorption
Iron accumulates in liver, joints
(arthralgia), pancreas (bronze
diabetes), heart (dilated
cardiomyopathy), pituitary
(hypogonadism), adrenals, skin
Ix: LFTs, serum ferritin, iron,
transferrin saturation, TIBC, HFE
genotyping, glucose, x-ray joints,
liver biopsy (Perls stain), MRI liver,
ECG, Echo
Rx: venesection, low iron diet, treat
diabetes, heart failure etc. Genetic
screen relatives.
Histopathology Congenital
hemocromatosis
CIRROSIS OF THE LIVER
Description
A chronic, progressive disease of the liver
Extensive parenchymal cell

degeneration
Destruction of parenchymal
cells
Definition - Cirrhosis
End stage of chronic
hepatitis
conversion of normal
architecture to
abnormal nodules
nodular regeneration
fibrosis
Cirrhotic Liver
.
,
Liver cirrhosis
Description
Regenerative process is
disorganized
, resulting in abnormal blood vessel
and bile duct relationships from
fibrosis
Description
Normal lobular structure distorted by
fibrotic connective tissue
Lobules are irregular in size and
shape with impaired vascular flow
Insidious, prolonged course
Etiology and Pathophysiology

Cell necrosis occurs
Destroyed liver cells are
replaced by scar tissue
Normal architecture becomes
nodular

Four types of cirrhosis:
1-Alcoholic (Laennecs) cirrhosis
2-Postnecrotic cirrhosis
3-Biliary cirrhosis
4-Cardiac cirrhosis
1-Alcoholic (Laennecs)
Cirrhosis
Associated with alcohol abuse
Preceded by a theoretically
reversible fatty infiltration of the liver
cells
Widespread scar formation
2-Postnecrotic Cirrhosis
Complication of toxic or viral hepatitis
Accounts for 20% of the cases of
cirrhosis
Broad bands of scar tissue form
within the liver
3-Biliary Cirrhosis
Associated with chronic biliary
obstruction and infection
Accounts for 15% of all cases of
cirrhosis
4-Cardiac Cirrhosis
Results from longstanding severe
right-sided heart failure
Histopathology
Histopathology
Histopathology
Morphologic Classification
1-Micronodular cirrhosis
Nodules less than 3 mm in diameter
Believed to be caused by alcohol,
hemochromatosis, cholestatic causes
of cirrhosis, and hepatic venous outflow
obstruction
2-Macronodular cirrhosis
Diagnostic Studies
Liver function tests

Liver biopsy
Liver scan
Liver ultrasound
Which method: blood sample or

liver stiffness?
Hepascore
Fibrotest
Fibrometer
Liver stiffness
(FibroScan)
Liver stiffness
Portal fibrosis
Cholestasis
Sinusoidal
fibrosis
Centrolobular
fibrosis
Stiffness
Steatosis?
Portal blood
flow
Inflammation
70
Signs of CLD
Manifestations of Liver Cirrhosis
Clinical Manifestations
Early Manifestations
Abdominal pain
Fever
Lassitude (laziness)
Weight loss
Enlarged liver or spleen
Late Manifestations
Two causative mechanisms
Hepatocellular failure
Portal hypertension
Jaundice
Intermittent jaundice is characteristic
of biliary cirrhosis
Late stages of cirrhosis the patient
will usually be jaundiced
..
.
Jaundice or Scleral Icterus
Jaundice
Occurs because of insufficient
conjugation of bilirubin by the liver
cells, and local obstruction of biliary
ducts by scarring and regenerating
tissue
Skin
Spider angiomas (telangiectasia,
spider nevi)
Palmar erythema
Endocrine Disturbances
Steroid hormones of the adrenal
cortex (aldosterone), testes, and
ovaries are metabolized and
inactivated by the normal liver
Alteration in hair distribution
Decreased amount of pubic hair
Axillary and pectoral alopecia
Hematologic Disorders
Bleeding tendencies as a result
of decreased production of
hepatic clotting factors (II, VII, IX,
and X)
Anemia, leukopenia, and
thrombocytopenia are believed
to be result of hypersplenism
Peripheral Neuropathy
Dietary deficiencies of thiamine, folic
acid, and vitamin B12
Spider Angiomata
Spider Nevi
Nail Clubbing
Dupuytren's Contracture
Ascites
Ascites
.
.
Ascites
The most successful therapeutic regimen
is the combination of single morning oral
doses of Spironolactone and Furosemide,
beginning with 100 mg and 40 mg
Two major concerns with diuretic therapy
for cirrhotic ascites:
Overly rapid removal of fluid
Progressive electrolyte imbalance
Complications
Major Complications of Cirrhosis

Jaundice
Portal hypertension
Variceal bleeding
Ascites
Spontaneous bacterial peritonitis
Hepatorenal syndrome
Hepatic encephalopathy
CIRROSIS OF THE LIVER

Complications
1-Portal hypertension and esophageal varices

2-Peripheral edema and ascites
3-Hepatic encephalopathy
4-Hepatorenal syndrome
acute renal failure coupled with advanced
hepatic disease (due to cirrhosis or less often
metastatic tumor or severe alcoholic hepatitis)
characterized by:
Oliguria
benign urine sediment
very low rate of sodium excretion
progressive rise in the plasma creatinine
concentration
Hepatorenal Syndrome
Reduction in GFR often clinically
masked
Prognosis is poor unless hepatic
function improves
Nephrotoxic agents and
overdiuresis can precipitate HRS
Hepatopulmonary syndrome
Liver disease
Increased alveolar-arterial gradient while
breathing room air
Evidence for intrapulmonary vascular
abnormalities, referred to as intrapulmonary
vascular dilatations (IPVDs)
Hepatic Hydrothorax
Pleural effusion in a patient with cirrhosis and
no evidence of underlying cardiopulmonary
disease
Movement of ascitic fluid into the pleural
space through defects in the diaphragm, and
is usually right-sided
Diagnosis -pleural fluid analysis
reveals a transudative fluid
serum to fluid albumin gradient greater than 1.1
Hepatic hydrothorax
Confirmatory study:
Scintigraphic studies demonstrate tracer in the chest cavity
after injection into the peritoneal cavity
Treatment options:
diuretic therapy
periodic thoracentesis
TIPS
Portopulmonary HTN
Refers to the presence of pulmonary hypertension
in the coexistent portal hypertension
Prevalence in cirrhotic patients is approximately 2
percent
Diagnosis:
Suggested by echocardiography
Confirmed by right heart catheterization
Hepatic Encephalopathy
Spectrum of potentially reversible neuropsychiatric
abnormalities seen in patients with liver dysfunction
Diurnal sleep pattern pertubation

Asterixis
Hyperactive deep tendon reflexes
Transient decerebrate posturing
Complications
Peripheral Edema and Ascites

Ascites:
- Intraperitoneal accumulation of
watery fluid containing small
amounts of protein
Onset usually insidious
GI disturbances:
Anorexia
Dyspepsia
Flatulence
N-V, change in bowel habits
Complications
Portal Hypertension
Primary mechanism is the increased resistance
to blood flow through the liver
Portal Hypertension
Esophagea
l
Varices
Caput
medusae
(dilated abd.
veins)
Arteriovenous
shunting
Hypersplenism
Moderate anemia
Neutropenia
Thrombocytopeni
a
Hemorrhoids
Marked ascites
Complications
Portal Hypertension
Characterized by:
Increased venous pressure in
portal circulation
Splenomegaly
Esophageal varices
Systemic hypertension
Portal Hypertension
Normal pressure ranges from 7 to 10 mm Hg.
In portal hypertension, pressure exceeds 10 mm Hg, averaging

around 20 mm Hg and occasionally rising as high as 5060
mm Hg.
In extrahepatic portal vein thrombosis (without liver disease),

collaterals in the diaphragm and in the hepatocolic,
hepatoduodenal, and gastrohepatic ligaments transport blood
into the liver around the occluded vein (hepatopetal).
In cirrhosis, collateral vessels circumvent the liver and deliver

portal blood directly into the systemic circulation
(hepatofugal); these collaterals give rise to esophageal and
gastric varices.
Portal Hypertension
Isolated thrombosis of the splenic vein causes

localized splenic venous hypertension and gives rise to
large collaterals from spleen to gastric fundus.
From there, the blood returns to the main portal system
through the coronary vein.
In this condition, gastric varices are often present without
esophageal varices.
spontaneous bleeding is relatively uncommon except
from those at the gastroesophageal junction; spontaneous
bleeding from gastric varices can sometimes occur.
Compared with adjacent areas of the esophagus and
stomach, the gastroesophageal junction is especially rich
in submucosal veins, which expand disproportionately in
patients with portal hypertension.
The cause of variceal bleeding is most probably
rupture due to sudden increases in hydrostatic
pressure.
Complications
Portal Hypertension
Splenomegaly
Back pressure caused by portal hypertension chronic
passive congestion as a result of increased pressure in
the splenic vein
Complications
Portal Hypertension
Esophageal Varices
Increased blood flow through the
portal system results in dilation
and enlargement of the plexus
veins of the esophagus and
produces varices
Collaborative Care
Esophageal Varices
Endoscopic sclerotherapy or ligation
Balloon tamponade
Surgical shunting procedures (e.g., portacaval
shunt, TIPS)
Treatment of esophageal varices

Active bleeding
Central line & pulmonary artery pressures
Blood transfusions & fresh frozen plasma for
clotting factors
Somatostatin or Vasopressin constrict gut vessels
Nitroglycerin- to counter negative affects of
vasopressin
Airway/trach
Later prevention of re-bleeding
Beta-blockers
Long-acting nitrates
Soft food, chew well, avoid intra-abdominal pressure
Protonix (pantoprazole)
Rapid Endoscopy!
Sclerotherapy:
A sclerosant
solution
(ethanolamine oleate
or sodium tetradecyl
sulphate) is injected
into the bleeding
varix or the overlying
submucosa
Complications can
include fever,
dysphagia and chest
pain, ulceration,
stricture, and (rarely)
Band ligation:
Band ligation is
achieved by a
banding device
attached to the tip
of the endoscope
Balloon Tube Tamponade:
Complications
Portal Hypertension
Internal Hemorrhoids
Occurs because of the dilation of the
mesenteric veins and rectal veins
Complications
Portal Hypertension
Caput Medusae
Collateral circulation involves
the superficial veins of the
abdominal wall leading to the
development of dilated veins
around the umbilicus
Complications

Ascites:
amounts of protein
Complications

Factors involved in the pathogenesis of ascites:
- Hypoalbuminemia
Levels of aldosterone
Portal hypertension
Drug Therapy
There is no specific drug

therapy for cirrhosis
Drugs are used to treat
symptoms and complications of
advanced liver disease
Collaborative Care
Ascites
High carbohydrate, low
protein, low Na+ diet
Diuretics
Paracentesis
Paracentesis
To treat respiratory distress
Pt will loose 10-30 grams of
protein
Pt in sitting position
Empty bladder first
Post--watch for
hypotension, bleeding,
shock & infection
Peritoneovenous Shunt
Portosystemic Shunts
Complications
Liver damage causes blood to
enter systemic circulation
without liver detoxification
Complications
Main pathogenic toxin is NH3
although other etiological factors
have been identified
Frequently a terminal complication
Collaborative Care
Goal: reduce NH3 formation
Protein restriction (0-40g/day)
Sterilization of GI tract with antibiotics (e.g., neomycin)
lactulose (Cephulac) traps NH 3 in gut
levodopa
Cholestatic
Liver Disease

Differential diagnosis
Sarcoidosis
Granulamatous hepatitis
Hepatitis C
Drug induced hepatitis
PSC
Alcoholic liver disease
Idiopathic adult onset ductopenia
Autoimmune hepatitis
Features of PBC
Clinical Features
Sicca syndrome 50%
Thyroid disease 15%
Arthritis 10%
Less Common <5%
Raynauds
Breast cancer
Scleroderma
Renal stones
Laboratory
features
AMA positive (95%)
OR
ANA positive
ASMA positive
Elevated cholesterol
Elevated IgM level
Histologic Staging of PBC
CholangioCarcinoma:
Liver biopsy in a patient with a large, right lobe hepatic mass. Only a small area of the
slide contains hepatocytes. The remainder of the biopsy reveals an infiltrating
cholangiocarcinoma.
neoplasm typical of
The abnormal
adenocarcinoma-like proliferation of tubo-ductular structures, largely seen in the
upper left hand corner of the photograph, may be impossible to differentiate from
Image courtesy Dr. Chris Pappas
metastatic adenocarcinoma.
CholangioCarcinoma:
Epidemiology
Malignant bile duct cancer arising from
epithelial cells of the intra/extrahepatic bile
ducts
Rarebut lethal
3% of all GI malignancies
Increases with age (50-70 years old)
Molecular Pathogenesis
Malignant transformation incompletely
understood
Molecular defects involving oncogenes and tumor
suppressor genes
70-80% overexpress p53
Mutations in oncogenes K-ras, c-myc, c-neu, c-erB-2
Overexpression of MET, hepatocyte growth factor,
common feature
Share molecular features of hepatocellular carcinoma
Treatment
Surgical
Intrahepatic cholangiocarcinoma
Hepatic resection
61 patients: 60% 3 year survival
30 patients: 86/63/22% survival
Perihilar cholangiocarcinoma:
20-40% potentially resectable
Aggressive resection of bile duct, liver resection, and
caudate lobectomy

(PSC)
.
Primary Sclerosing Cholangitis (PSC)
Associated with ulcerative colitis (UC)

Incidence of colitis 90%
30% of CC diagnosed in UC and PSC
Annual incidence 1.5/year
Lifetime risk of 10-15%
Autopsy studies: 30% CC
More difficult to diagnose in PSC
1/3 cases of CC made within 2 years of
diagnosis
.
Primary Sclerosing Cholangitis (PSC)
Smokers and former smokers had

higher rates of cancer
Alcohol consumption
Role of CEA, CA-19-9, CA-50, and
CA-242 of limited value
Risk Factors
Parasitic infections
Hepatolithiasis
Toxic exposures: Thorotrast (20-30
years), auto/rubber/wood-finishing
Li-Fraumeni syndrome
Biliary Papillomatosis
Budd-Chiari syndrome
Mechanism Hepatic vein outflow obstruction:

hepatic vein thrombosis (Budd-Chiari syndrome)
o Original description: fatal acute thrombosis
o Expanded definition: acute, subacute, or chronic
occlusions of hepatic vein
o Signs/symptoms: hepatomegaly, pain, ascites
o Causes (most frequent to less frequent)
o Polycythemia vera (myeloproliferative diseases)
o Pregnancy or post-partum state
o Oral contraceptives
o Paroxysmal nocturnal hemoglobinuria
o Cancers, especially hepatocellular carcinoma
o Idiopathic (10%, presumably undiagnosed
thrombogenic disorder)
Budd-Chiari syndrome: pathology
Severe centrilobular congestion & necrosis; degree of

necrosis depends on degree of hepatic outflow occlusion
Budd-Chiari syndrome: treatment

o Address underlying cause; high mortality
without treatment
o Acute interventions:
o Surgical creation of portal-systemic shunt (portal vein to
systemic circulation), which allows reverse flow through
portal vein, but hepatic artery inflow preserved to prevent
infarction
o Angiographic thrombectomy and/or dilation of hepatic vein
LIVER TUMORS
Benign liver tumors
Basic workup
Differentiate between primary hepatic malignancy
vs. metastatic disease vs. benign
Hepatic abscess
Pyogenic
Amebic
Fungal
Echinococcal
Pyogenic abscess
80% of liver abscesses are pyogenic
Incidence is 8-22 per 100,000
Cholangitis is the most common cause of liver
abscesses
Patient usually present with variable constitutional
symptoms
US, CT, and MRI are all sensitive modalities for
identifying an abscess, however they do not
differentiate between pyogenic and amebic
Pyogenic abscess
Table 1 -- Pyogenic Liver Abscess Microbiology
Gram-negative
Aerobes
Escherichia coli
Common (10%)
Klebsiella
Gram-positive
Anaerobes
Aerobes
Staphylococcus
aureus
Enterococcus spp. Bacteroides spp.
Viridans
streptococci
Pseudomonas
Proteus
Uncommon (1%
10%)
Enterobacter
Citrobacter
Serratia
Fusobacterium
-hemolytic
streptococci
Anaerobic
streptococci
Clostridium
Lactobacilli
Pyogenic abscess
Treated with antibiotics and percutaneous drainage
Open surgical drainage is reserved for patients with
concurrent gastrointestinal disease processes that
require surgery or those patients who have failed
percutaneous drainage.
Pyogenic abscess
Almost uniformly fatal if left untreated.
Mortality rates 10-20%
Higher success rates with antibiotics and drainage vs.
antibiotics and simple aspiration
Pyogenic abscess
.
Fungal abscess
Fungal liver abscesses are being recognized with
increased frequency and currently account for
approximately 10% of hepatic abscesses
Candida albicans and other Candida species are
found in approximately 80% of cases
Fungal liver abscesses are usually multiple and
usually occur in immunocompromised patients.
Fungal abscess
Fungal liver abscesses are treated with systemic
antifungal therapy and drainage of the abscess cavity
or cavities by simple aspiration, percutaneous
drainage, or open surgical drainage
Amphotericin B is the first-line drug of choice for
systemic antifungal therapy because of its broad
fungal efficacy
Voriconazole or Caspofungin may be used to treat
patients who are not responding to Amphotericin B or
who have aggressive infections caused by other
fungal species
Echinococcal disease
Echinococcus is a flat tapeworm
Human infestation occurs with consumption of
contaminated vegetables or through contact with
infected animals or soil
E. granulosus forms cysts that are constituted by an
external acellular layer and an inner cellular germinal
layer that produces the brood capsules containing
protoscolicies, hydatid sand, or daughter cysts
The outer acellular layer is usually 2 to 5 mm thick
and is composed of fibroblasts that produce a
capsule of fibrous connective tissue called the
pericyst. The pericyst is calcified in approximately half
of patients.
The symptoms associated with hepatic E. granulosus
can vary considerably
specific enzyme-linked immunosorbent assay
(ELISA) and hydatid antigen immunobinding assays
yield a sensitivity and specificity up to 95% and 90%,
respectively
.
Chemotherapy with benzimidazole compounds
(mebendazole and albendazole) is the medical
treatment of choice
More recently, praziquantel, a synthetic isoquinolinepyrazine derivative, has been used in combination
with albendazole
with medical treatment alone, only 30% of patients
can expect clinical and radiographic resolution.
Medical treatment therefore should be used primarily
in conjunction with percutaneous drainage or surgery
For uncomplicated hydatid disease, morbidity and
mortality have been reported to be in the range of
20% and 1%,
the long-term results of PAIR and surgery for hepatic
hydatid cysts are excellent. Most series report
recurrence rates less than 10%.
Benign Hepatic Masses

The differential diagnosis of the benign solid hepatic
mass includes hepatic adenoma, focal nodular
hyperplasia (FNH), focal fatty infiltration, cavernous
hemangioma, and other rare neoplasms (e.g.,
mesenchymal hamartoma and teratoma)
Benign hepatic lesions are common, with an
estimated incidence of 7% to 9%, and in one autopsy
series, up to 20% of the population
Simple Cysts
Simple cysts are solitary more than 50% of the time
and asymptomatic more than 90% of the time.
Size can range up to 20 cm, although most are less
than 5 cm
Asymptomatic simple cysts less than 8 cm require no
intervention but should be observed
Simple Cysts
.
Simple Cysts
Any symptoms are usually related to mass effect,
causing pain in the right upper quadrant and
occasionally early satiety. Rarely, intracystic
hemorrhage and infection may develop
patients with symptomatic cysts (>5 cm) should
undergo laparoscopic or open cyst unroofing.
Complex cysts
If multiple simple cysts are seen, consider polycystic
liver disease
This is an inherited condition (autosomal dominant),
often found in association with renal cysts
the majority of patients with polycystic liver disease
remain asymptomatic with preserved liver function
and do not require surgical intervention
Complex cysts
.
Complex cysts
Biliary cystadenomas are uncommon, slow-growing
complex cysts measuring up to 20 cm in size. They
are benign but have malignant potential to transform
into cystadenocarcinoma and thus should be
surgically removed whenever recognized
The diagnosis is made by the presence of
mesenchymal tissue
Complex cysts
Radiologically, internal septations are almost always
seen in cystadenomas on contrast-enhanced CT or
MRI. Cystadenomas have irregular borders and a
thick stromal layer, and calcifications and mural
nodules can occasionally be seen in the walls
Complex cysts
.
Hemangioma
Autopsy series report prevalances from 0.5% to as
high as 20.0%. The female-to-male ratio is between
5:1 and 6:1. Hemangioma is usually found between
the ages of 30 and 70 years
tumors arise from the endothelial lining of blood
vessels as vascular ectasias and have been
associated with high estrogen states including
puberty, pregnancy, oral contraceptive use, and
androgen treatment
Hemangioma
Most tumors are less than 5 cm and asymptomatic
Contrast-enhanced CT with delayed venous
examination will demonstrate peripheral nodular
enhancement and progressive centripetal fill-in
Hemangioma
.
Hemangioma
Hemangiomas almost never require surgical
resection after the diagnosis is secure because most
lesions are asymptomatic, and risk of spontaneous
rupture is extremely small.
For symptomatic lesions, simple enucleation is
recommended because it preserves the maximal
amount of functional liver
Focal nodular hyperplasia (FNH)

Focal nodular hyperplasia (FNH) is the second
most common benign solid hepatic tumor (behind
hemangioma), comprising 8% of all primary hepatic
tumors.
Prevalence of FNH is estimated to be 3% of the
general population, predominantly in women in their
third to fifth decades.
The female-to-male ratio is between 6:1 and 8:1
Focal nodular hyperplasia- FNH

FNH consists of benign-appearing hepatocytes with
cords of fibrous septae radiating from a central
scar, which comprises biliary structures of
hepatocellular origin
Most patients present with an asymptomatic, solitary
tumor of less than 5 cm near the hepatic surface.
Only 10% of patients have clinical symptoms
Focal nodular hyperplasia -FNH

On contrast-enhanced multiphasic CT imaging,
lesions are usually homogenous and isoattenuating
to liver parenchyma before contrast injection. Lesions
are bright, hypervascular with hypodense central
scarring on arterial phase examination. If present,
radiating hypodense fibrous bands and septa that
arise from the scar are characteristic findings

.

Nuclear medicine imaging can sometimes be helpful
to distinguish FNH from hepatic adenoma
because sulfa-colloid is taken up by Kupffer cells
(present in FNH), which are usually absent in
adenoma

Treatment strategy is heavily influenced by the
certainty of diagnosis. In asymptomatic patients with
a clear diagnosis, no further treatment is
necessary, and the patient may be observed. In
equivocal cases in which all imaging modalities fail to
establish a firm diagnosis, biopsy is warranted for
histologic examination
Hepatic adenoma
Hepatic adenoma (HA) is a rare hepatic tumor that
occurs predominantly in women aged 20 to 40 years,
with a female-to-male ratio of at least 4:1 and
reportedly as high as 11:1.
It has a strong association with oral contraceptive
use, with an incidence of 3 to 4 in 100,000 oral
contraceptive users versus 1 in 100,000 nonusers
Hepatic adenoma
HAs are mostly solitary (70%80%), well
circumscribed, round, and unencapsulated. A
pseudocapsule is often present
Larger HA tumors (>5 cm) can be associated with
right upper-quadrant pain, fullness, or discomfort.
Because of its hypervascular nature and lack of a
capsule, HA carries a moderate to high risk of
spontaneous rupture, associated with increasing size
(>5 cm). When rupture occurs, it is intratumoral in
one third of cases and intraperitoneal in two thirds of
cases.
Hepatic adenoma
On CT, adenomas often appear heterogeneous
because of their mixed components of fat,
hemorrhage, and necrosis. On portal venous
examination or delayed images, they may appear
isodense. HAs are contrast enhancing because of
their rich vascular supply and often show peripheral
enhancement with centripetal progression, indicating
the presence of large subcapsular feeding vessels
and early draining veins
Hepatic adenoma
.
Liver Cancer
Primary Liver Cancer

Liver malignancy may arise from
Hepatocytes
Biliary epithelial cells
Malignant Liver Tumors

1.
2.
3.
4.
5.
Hepatocellular carcinoma (HCC)

Fibro-lamellar carcinoma of the liver
Hepatoblastoma
Others
A large proportion of patients will have intra- or extra-hepatic

metastases at presentation.
infiltration of the portal venous system with subsequent

dissemination of tumor cells.
Vascular invasion is more common with larger tumors (> 5

cm).
Most common mets include the hilar and celiac lymph nodes and
the lungs; metastases to bone and brain are less common and
peritoneal disease (ie, carcinomatosis)
Risk Factors - HCC

Chronic HBV and HCV
Cirrhosis
Chronic underlying liver disease.
Risk Factors - cholangioCA
Infrequently associated with cirrhosis.

Primary sclerosing cholangitis
Widespread infection with liver flukes (Clonorchis
sinensis
HEPATOCELLULAR
CARCINOMA HCC
HCC: Incidence
The most common primary liver cancer
The most common tumor in Saudi men
Increasing in US and all the world
HCC: Risk Factors

The most important risk factor is cirrhosis from any
cause:
1. Hepatitis B (integrates in DNA)
2. Hepatitis C
3. Alcohol
4. Aflatoxin
5. Other
HCC: Clinical Features

Wt loss and RUQ pain (most common)
Asymptomatic
Worsening of pre-existing chronic liver dis
Acute liver failure
O/E:
Signs of cirrhosis
Hard enlarged RUQ mass
Liver bruit (rare)
HCC: Metastases
Rest of the liver

Portal vein
Lymph nodes
Lung
Bone
Brain
HCC: Systemic Features
Hypercalcemia
Hypoglycemia
Hyperlipidemia
Hyperthyroidism
Signs & symptoms
Nonspecific symptoms
abdominal pain
Fever, chills
anorexia, weight loss
jaundice
Physical findings
abdominal mass in one third

splenomegaly
ascites
abdominal tenderness
HCC: Diagnosis
Clinical presentation
Elevated AFP
US
Triphasic CT scan: very early arterial perfusion
MRI
Biopsy
HCC: labs
Labs of liver cirrhosis
AFP (Alfa feto protein)
Is an HCC tumor marker
Values more than 100ng/ml are highly suggestive of
HCC
Elevation seen in more than 70% of pt
Diagnosis
(b) what investigations are required to make a definite diagnosis
1)
AFP produced by 70% of HCC

> 400ng/ml
AFP over time
2)
Imaging
- focal lesion in the liver of a patient with cirrhosis is highly likely
to
be HCC
- Spiral CT of the liver
- MRI with contrast enhancement
Diagnosis
3) Biopsy is rarely required for diagnosis

seeding
in 13%.
Biopsy of potentially operable lesions
should be avoided where possible
US: HCC
CT: Venous Phase
CT: Arterial Phase
Diagnosis
.
Cirrhosis + Mass < 2 cm
Normal
AFP
Raised
AFP
CT, MRI
Assess for
surgery
lesion by exam
Confirmed
diagnosis
FNAC or biopsy
Liver Cancer Treatment
Treatment (Surgery)
The only proven potentially curative therapy for HCC
Hepatic resection or liver transplantation
Patients with single small HCC (5 cm) or up to three lesions 3 cm
Involvement of large vessels (portal vein, Inferior vena cava) doesnt

automatically mitigate against a resection; especially in fibrolamellar
histology
No randomised controlled trials comparing the outcome of

surgical resection and liver transplantation for HCC.
Treatment (Surgery)
Hepatic resection should be considered in HCC and a non-cirrhotic

liver (including fibrolamellar variant)
Resection can be carried out in highly selected patients with

cirrhosis and well preserved hepatic function (Child-Pugh A) who are
unsuitable for liver transplantation. It carries a high risk of
postoperative decompensation.
Perioperative mortality in experienced centres remains between 6%

and 20% depending on the extent of the resection and the severity of
preoperative liver impairment.
The majority of early mortality is due to liver failure.
Treatment (Surgery)
Recurrence rates of 5060% after 5 years after resection are usual

(intrahepatic)
Liver transplantation should be considered in any patient with

cirrhosis
Patients with replicating HBV/ HCV had a worse outlook due to

recurrence and were previously not considered candidates for
transplantation.
Effective antiviral therapy is now available and patients with small

HCC, should be assessed for transplantation
Treatment (non-Surgical)
should only be used where surgical therapy is not possible.
1) Percutaneous ethanol injection (PEI)
has been shown to produce necrosis of small HCC.

It is best suited to peripheral lesions, less than 3 cm in
diameter
2) Radiofrequency ablation (RFA)
High frequency ultrasound to generate heat

good alternative ablative therapy
No survival advantage
Useful for tumor control in patients awaiting liver transplant
3) Cryotherapy
intraoperatively to ablate small solitary tumors outside a

planned resection in patients with bilobar disease
4) Chemoembolisation
Concurrent administration of hepatic arterial chemotherapy

(doxirubicin) with embolization of hepatic artery
Produce tumour necrosis in 50% of patients
Effective therapy for pain or bleeding from HCC
Affect survival in highly selected patients with good liver

reserve
Complications: (pain, fever and hepatic decompensation)
5) Systemic chemotherapy
very limited role in the treatment of HCC with poor
esponse rate
Best single agent is doxorubicin (RR: 10- 20%)
Combination chemotherapy didnt
response but
survival
should only be offered in the context of clinical trials
6) Hormonal therapy
- Nolvadex, stilbestrol and flutamide
7) Interferon-alfa
8) retinoids and adaptive immunotherapy (adjuvant)
HCC: Local Ablation
For non resectable pt

For pt with advanced liver cirrhosis
Alcohol injection
Radiofrequency ablation
Temporary measure only
Radio Frequency Ablation
Ethanol Injection
HCC:
Chemoembolization
Inject chemotherapy selectively in hepatic artery

Then inject an embolic agent
Only in pt with early cirrhosis
No role for systemic chemotherapy
Chemoembolization
HCC: Prognosis
Tumor size
Extrahepatic spread
Underlying liver disease
Pt performance status
HCC: Liver
Transplantation
Best available treatment

Removes tumor and liver
Only if single tumor less than 5cm or less than 3 tumors
less than 3 cm each
Recurrence rate is low
Not widely available
Name
Selection of agents for targeted

therapy in HCC
Gefitinib
Erlotinib
Lapatanib
Cetuximab
Bevacizumab
Sorafenib (Nexavar)
Sunitinib
Vatalanib
Cediranib
Rapamycin
Everolimus
Bortezomib (Velcade)
Target
EGFR
EGFR
EGFR
EGFR
VEGF
Raf1, B-Raf, VEGFR , PDGFR
PDGFR, VEGFR, c-KIT, FLT-3
VEGFR, PDGFR, c-KIT
VEGFR
mTOR (mammalian target of rapamycin)
mTOR
Proteasome
Targeting angiogenesis for HCC
HCC is one of the most vascular tumor
Major driver of angiogenesis is vascular endothelial growth

factor (VEGF)
Sorafenib and bevacezumab target VEGF in HCC
Bevacizumzb: Median OS of approximately 12 months

Bevacizumab + erlotinib: Medain OS 15-17 months
Investigational combination therapies

in HCC
Combinations under investigations
Bevacizumzb + erlotinib
Sorafenib +erlotinib
Combination therapy will likely be used to treat HCC

in the future
Clinical Importance of Early Detection

& Precise staging of HCC
T1: Resection
Ablation
T2: Transplant
5-yr survival rates
50 70%
HCCs detected in T1 & T2 stages show much better survival

Sensitive imaging modalities to detect HCCs in its early stages
El-Serag HB, et al. Gastroenterology 2008; 134:1752-1763.
Liver Failure
Liver failure:
Liver failure:
Clinical syndrome: sudden loss of
liver
parenchymal and metabolic function
Manifest as coagulopathy and
encephalopathy
Liver failure
Hyper - acute liver failure
Acute liver failure
Greatest risk of cerebral
oedema, CVS failure
Greatest chance of
spontaneous survival
Sub - acute liver failure
Lowest risk of cerebral oedema/
encephalopathy
Easily confused with CLD
Ascites
Lowest chance of spontaneous
survival
Multi system
disease
Coagulopathy
INR important prognostic indicator in established ALF
Platelet dysfunction DIC - rare
Metabolic
Insulin resistance : Clarke et al Hepatology
Hyperlactataemia :Bernal et al Lancet 2002 : useful to track
Liver net producer of lactate Murphy et al Crit Care Med
2001
P04, Mg, Na, glucose, K, pH

High incidence of pancreatitis
Nutrition
Frequent poor recent oral intake vomiting
No evidence for protein restriction in either acute or
CLD
Gastric prophylaxis
Acute liver failure

Acute liver failure :
Defined as interval between onset of the illness and
appearance of encephalopathy < 8 weeks

Etiology:
: heterogenous, drugs
(acetaminophen, NSAID), viruses
: viruses, regional
Difference (endemic area ?)
Acute liver failure

Uncommon causes:
Wilsons disease, other infections (CMV, HSV,
EBV), vascular abnormality, toxin, acute fatty liver
of pregnancy, antoimmune hepatitis, ischemia,
malignant infiltration
Acute liver failure

Symptoms and signs:
Jaundice, altered mental status, nausea/
vomiting, anorexia, fatigue, malaise,
myalgia/arthralgia
Most of them present hepatoencephalopathy
and icteric appearance.
Non-specific Management
Hypoglycemia
Encephalopathy
Infections
Hemorrhage
Coagulopathy
Hypotension(hypovolemia, vascular resistance )
Respiratory failure
Renal failure
Pancreatitis
Hypoglycemia: monitoring blood glucose, IV glucose
supplement.
Infection: aseptic care, high index of suspicion,
preemptive antibiotic.
Hemorrhage (i.e. GI): NG placement, H2 blocker or
PPI.
Hypotension: hemodynamic monitoring or central
pressures, volume repletion
Respiratory failure (ARDS): mechanical ventilation.
Renal failure (hypovolemia, hepatorenal syndrome,
ATN): hemodynamic monitor, central pressure,
volume repletion, avoid nephrotoxic agent
Encephalopathy
major complication
precise mechanism remains unclear
Hypothesis: Ammonia production
Treatment toward reducing ammonia production
Watch out airway, prevent aspiration
Encephalopathy
Portal Systemic Encephalopathy

Portal systemic shunt
spontaneous collateral
Surgical
TIPPS
Not at risk of cerebral oedema
Precipitating factors
Sepsis
SBP Rx fluids ++
Albumin
HE of Acute Liver Failure

Rapid onset
Cerebral oedema
Myoinositol levels not reduced
Cytotoxic and vasogenic
Avoid renal failure
CNS active drugs

Electrolyte abnormalities
Diuretics - over use
Gastrointestinal bleeding
Encephalopathy
Stage 1: day-night reversal, mild confusion,
somnolence
Stage 2: confusion, drowsiness
Stage 3: stupor
Stage 4: coma
Encephalopathy
Predisposing factor of hepatic encephalopathy:
GI bleeding, increased protein intake, hypokalemic
alkalosis, hyponatremia, infection, constipation,
hypoxia, infection, sedatives and tranquilizers
Encephalopathy
TX upon ammonia hypothesis
Correction of hypokalemia
Reduction in ammoniagenic substrates: cleansing
enemas and dietary protein restriction.
Lactulose: improved encephalopathy, but not
improved outcome.
Dose 2-3 soft stools per day
Encephalopathy
Oral antibiotics: neomycin lack of evidence
nephrotoxicity limited use.
Stage 1: shorted attention span, reversal of sleep-wake
cycle, subtle personality changes (anxiety, irritability)
Stage 2: lethargy, personality change, disorientation.
Asterixis.
Stage 3: stupor but responsive, severe confusion and
disorientation, abnormal behaviour, incomprehensible
speech
Stage 4: coma
Cerebral Edema
Cerebral edema develops in 75 - 80 % of patients
with grade IV encephalopathy.
precise mechanism : not completely understood
Possible contributing factor:
1-osmotic derangement in astrocytes
2-changes in cellular metabolism
3-alterations in cerebral blood flow
Cerebral Edema
Clinical manifestations:
intracranial pressure (ICP) and brainstem
Herniation the most common causes of death
in fulminant hepatic failure
ischemic and hypoxic injury to the brain
hypertension, bradycardia, and irregular
respirations, muscle tone, hyperreflexia
Coagulopathy
diminished capacity of the failing liver to synthesize
coagulation factors.
The most common bleeding site: GI tract.
Prophylactic administration of FFP: not
recommended.
performed before transplant or invasive procedure
Liver transplant
Liver transplant: remain backbone of treatment of
fulminant hepatic failure
reliable criteria to identify these patients who really
need transplant.
remain unresolved in fulminant hepatic failure.
Liver support system

Non-cell-based:
plasmapheresis and charcoal-based

hemoabsorption
Cell-based systems :
known as bioartificial liver support systems
Non-cell-based: not improved survival.
Available systems:
(MARS) Molecular Adsorbents Recirculation
System
Liver Dialysis
Bridge to transplant
Dialyze 6 hours at a time
Molecular Adsorbents
Recirculation System
(MARS)
MARS Therapy
, encephalopathy
Controls: biochemistry static, worsening
encephalopathy
Coagulopathy and
MARS treatment in CLD
Single Pass Albumin Dialysis (SPAD)
Clearance of bilirubin, bile acids, NH4 : improved
MARS
Significant improvement in encephalopathy
No change in renal function or creatinine
No change in ammonia or cytokine levels (TNF, IL-6, IL-10, IL-8),

MDA, MELD fell in both groups
No differences in survival
LIVER TRANSPLANT
Liver Transplantation
for
Liver
Alcoholic Liver Disease
Transplantation
Live Donor Liver Transplant
Liver transplant complications

Rejection. About 70% of all liver-transplant patients
have some degree of organ rejection prior to
discharge.
Anti-rejection medications are given to ward off the
immune attack.
Infection
Most infections can be treated successfully as they
occur.
Cancer
Biliary Complications
The Achilles heel of liver
transplantation
Early (< 30 days)
Late (> 30 days)
Anastomotic bile leak

Anastomotic stricture
Bile leak at T tube exit
Obstruction of T tube
Sphincter of Oddi
dysfunction
Anastomotic stricture
Nonanastomotic
strictures
Bile leak on T tube
removal
Sphincter of Oddi
dysfunction
QUESTIONS
PAUZA !!!!!!!---GATA ????
Gallbladder
Disorders
ANATOMY & PHYSIOLOGY

BILIARY SYSTEM
a. Canaliculi the smallest bile ducts located
between liver lobules, receive bile from
hepatocytes. The canaliculi form larger bile
ducts, which lead to hepatic duct.
b.Hepatic duct from the liver joins the cystic
duct from the gallbladder to form the common
bile duct, which empties into the duodenum.
c. Sphincter of Oddi controls the flow of bile
into the intestine.
d.Gallbladder is a hollow pear-shaped organ
that is 30-40mm long. Normally holds 30-50mL
of bile and can hold up to 70mL when fully
distended.
BILIARY SYSTEM
Draining bile from hepatocytes to the gallbladder
by way of biliary tree
Storing bile in the gallbladder and releasing it to the
duodenum, which is mediated by the hormone
cholecystokinin-pancreozymin.
Stores and concentrates bile

Contracts during the digestion of fats to deliver the
bile
Cholecystokinin is released by the duodenal cells,
causing the contraction of the gallbladder and
relaxation of the sphincter of Oddi
CHOLELITHIASIS
CHOLELITHIASIS
Refers to formation of calculi (ie,
gallstones in the bladder.
Predisposing Factors:
1.Obese
2.Female
3.>40 yrs
4.OC, Estrogen, intake
5.Fair
CHOLELITHIASIS
Supersaturated bile, Biliary
stasis
Stone formation
Blockage of Gallbladder
Inflammation, Mucosal Damage and
WBC infiltration
Gall Stones
CHOLECYSTITIS
inflammation of gallbladder with gallstone formation.
CHOLECYSTITIS/
CHOLELITHIASIS
Signs and Symptoms:
Severe Right abdominal pain radiating to the
back
Fever
Fat intolerance
Anorexia, n/v
Jaundice
Pruritus
Easy bruising
Tea colored urine
Steatorrhea
Cholecystitis & Cholelithiasis

by: Gari Glaser
What is it?
By definition,
cholecystitis is an
inflammation of the
gallbladder wall and
nearby abdominal
lining.
Abdomi
nal wall Gallbl
adder
Etiology / Pathophysiology
Can be caused by an obstruction, gallstone or a tumor.
90% of all cases caused by gallstones.
The exact cause of gallstone formation is unknown.
When there is an obstruction, gallstone or

tumor it prevents bile from leaving the
gallbladder.
Bile gets trapped and acts as an irritant which causes
cellular infiltration within 3 4 days.
This infiltration causes an

inflammatory process the
gallbladder becomes
enlarged and edematous.
Eventually this
occlusion along with
bile stasis causes the
mucosal lining of the
gallbladder to become
necrotic.
Bacterial growth
occurs due to
ischemia.
Necrotic
Gallbladder
Rupture of the gallbladder becomes a danger, along with spread

of infection of the hepatic duct and liver.
If the disease is severe and interferes with the blood supply it
can cause the gallbladder to become gangrenous.
Gangr
enous
gallbl
adder
Gallst
ones
Gallstones . .
The presence of
gallstones in the
gallbladder is called
cholelithiasis.
Those who are most at risk.

These are all adjectives to describe the person most at
risk of developing symptomatic gallstones.
FAIR
FAT
FORTY
FEMALE
Signs and Symptoms.
Complaints of indigestion after

eating high fat foods.
Localized pain in the rightupper quadrant epigastric
region.
Anorexia, nausea, vomiting
and flatulence.
Increased heart and respiratory rate

causing patient to become diaphoretic
which in turn makes them think they
are having a heart attack.
Signs and Symptoms.
Low grade fever.

Elevated leukocyte count.
Mild jaundice.
Stools that contain fat steatorrhea.
Clay colored stools caused by a lack of bile in the
intestinal tract.
Urine may be dark amber- to tea-colored.
Diagnostics.
Fecal studies.
Serum bilirubin tests.
Ultrasound of the
gallbladder.
Diagnostics.
HIDA scan -
imaging test used to

examine the gallbladder and the ducts
leading into and out of the gallbladder - also
referred to as cholescintigraphy.
Oral cholecystogram -
the
patient takes iodine-containing tablets by
mouth - iodine is absorbed from the
intestine into the bloodstream - removed
from the blood by the liver and excreted by
the liver into the bile it is concentrated in
the gallbladder - outlines the gallstones that
are radiolucent (x-rays pass through them).
Operative cholangiography
common bile duct is directly injected with
radiopaque dye.
Recap. Stages of Acute Cholecystitis.
- Gallbladder has a grayish

appearance & is edematous.
-There is an obstruction of the
cystic duct and the gallbladder
begins to swell.
- It no longer has the "robin
egg blue" appearance of a
normal gallbladder.
- As acute cholecystitis
progresses, the gallbladder
begins to become necrotic
and gets a speckled
appearance as the wall
begins to die.
- Gallbladder undergoes
gangrenous change and
the wall becomes very
dark green or black.
- This is the stage when
perforation occurs.
Medical Management.
Lithotripsy
for patients with only
a FEW stones.
If the attack of
cholelithiasis is mild
bed rest is prescribed.
patient is placed on
NPO to allow GI tract
and gallbladder to rest.
an NG tube is placed
on low suction.
fluids are given IV in
order to replace lost
fluids from NG tube
suction.
Medical Management.
Cholecystectomy
or
Laparoscopic Cholecystectomy
removal of the gallbladder.
This is the treatment of choice.
The gallbladder along with the cystic
duct, vein and artery are ligated.
Medical Management.
If stones are present in the

common bile duct, an
endoscopic sphincterotomy
must be performed to remove
them BEFORE a
cholecystectomy is done.
A number of various
instruments are inserted
through the endoscope in
order to "cut" or stretch the
sphincter.
Once this is done, additional
instruments are passed that
enable the removal of stones
and the stretching of
narrowed regions of the
ducts.
Drains (stents) can also be
used to prevent a narrowed
area from rapidly returning to
its previously narrowed state.
Will you survive?
Prognosis is usually excellent with prompt treatment.
Laparoscopic surgery has decreased the number of

complications.
Prognosis is NOT favorable for those who develop

pancreatitis.
Ill leave you with these.
Eww!
CHOLELITHIASIS/CHOLECYSTITIS
Surgical procedures- Surgical Cholecystectomy,
Choledochotomy,
Laparoscopic cholecystectomy
QUESTIONS
LIVER DISEASE
The future:
Increasing liver disease
alcohol, HCV, NAFLD
HCC
Treatment changing
Innovative treatment options
liver support systems - further
Controlled trials required
Transplantation is a real option
Early discussion
Assume fluid deplete: time is tissue
Infection is common
Agitation=HE
Close observation
PATHOLOGY OF THE
PANCREAS
1
II. Detailed Anatomy

A. Landmark structures
1. Splenic Artery:
a. Branch of celiac
trunk
b. passes right to
left
c. Course is along
upper margin of
body and tail
Arterial Supply to Pancreas
Proper Hepatic
Artery
Common
Hepatic Artery
Superior
Mesenteric
Artery
Detailed Anatomy continued

. Head of Pancreas
. Head , Body and Tail of Pancreas

1. Important clinically because:
a. Numerous ducts and vessels traverse it
b. Carcinoma usually located here
Duct of Wirsung (Main pancreatic duct)
DISEASES OF THE
PANCREAS
Congenital anomalies:
Agenesis, hypoplasia, ectopia, duct anomalies
Exocrine pancreas:
Cystic fibrosis
Acute pancreatitis
Chronic pancreatitis
Carcinoma of the pancreas
Endocrine pancreas:
Diabetes mellitus
Islet cell tumors
IV. Pancreatic Disorders

A. Pancreatitis: diagnosis depends on
clinical evidence
1. Usually secondary to biliary tract
disease
2. Surgery of biliary tract or stomach

alcoholism are other causes
DISEASES OF THE EXOCRINE PANCREAS
ACUTE PANCREATITIS
Inflammation of the pancreas, which is almost always

associated with acinar cell injury
A clinical & histologic spectrum of severity & duration
Etiologic factors:
1) Metabolic: alcohol, hyperlipoproteinemia,
hypercalcemia, drugs (e.g. thiazides), genetic
2) Mechanical: gallstones, traumatic & perioperative
injury
3) Vascular: shock, atheroembolism, polyarteritis
nodosa
4) Infections: Mumps, Coxsackie virus, Mycoplasma
5) Idiopathic : 10-20% ; ? Genetic basis
ACUTE PANCREATITIS
Pathology:
4 basic alterations:
1) Proteolytic destruction of pancreatic substance

2) Necrosis of blood vessels & interstitial hemorrhage
3) Fat necrosis by lipolytic enzymes
4) Associated acute inflammatory reaction
Pathologic lesions:
a. Acute pancreatic necrosis

b. Acute hemorrhagic pancreatitis
c. Suppurative peritonitis
d. Pancreatic pseudocysts
ACUTE PANCREATITIS
Pathogenesis:
Autodigestion of pancreatic tissue by inappropriately

activated pancreatic enzymes
Trypsin has a major role:
a. Activates other proenzymes (proelastase ,prophospholipase )

b. Converts prekallikrein to kallikrein (Kinin system)
c. Hageman factor is activated
Mechanisms of pancreatic enzyme activation:
1) Pancreatic duct obstruction

2) Primary acinar cell injury
3) Defective intracellular transport of proenzymes within acinar cells
ACUTE PANCREATITIS
Clinical features:
Abdominal pain is the cardinal manifestation: epigastric, radiating
to back, variable in severity
Shock: due to pancreatic hemorrhage & release of vasodilatory
agents (BK & PGs)
Lab: serum amylase and lipase; Ca;

bilirubin, glucose & glycosuria
CT scan: inflammation, pseudocysts
Px: severe cases have high mortality rate (20-40%)
Death due to: 1) shock, 2) secondary abdominal
sepsis, 3) adult respiratory distress syndrome
CHRONIC PANCREATITIS
Repeated bouts of mild to moderate pancreatic
inflammation, with continued loss of pancreatic
parenchyma & replacement by fibrous tissue
Distinction from acute pancreatitis may be
difficult; distinction is made if there is evidence of
previous attacks
Middle-aged men, mostly in alcoholics but may
due to biliary tract disease, hyperlipoproteinemia
& hypercalcemia; no apparent cause in 50% of
cases
Pathogenesis:
Protein hypersecretion from acinar cells
Precipitation of proteins forming ductal plugs
Plugs enlarge forming laminar aggregates
Pathology:
Hard organ with dilated ducts & calcified concretions
Fibrosis, chronic inflammatory cells, obstruction of
ducts by protein plugs
Extensive atrophy of exocrine glands
Pseudocysts
Clinical features:
Repeated attacks of abdominal pain or may be silent
Dx: clinical suspicion, lab & CT
Px: chronic disabling disease due to its major
complications: pancreatic insufficiency & diabetes
mellitus
Pancreatic Diseases, continued
D. Chronic Pancreatitis
1. organ usually appears as
small,
atrophic
2. Contains scattered echoes
from
calcifications
3. Primary cause is alcoholism
E. Dilation of Pancreatic Duct

1. Seen in acute or chronic
pancreatitis
2. Frequently associated with
neoplasm of pancreas
3. Biliary tract problems
F. Abscess or Hemorrhagic Pancreatitis

1. Similar in sonographic appearance
2. Hemorrhagic:
a. Mass with inhomogeneous texture
b. Acute hemorrhage: sonolucent to
echogenic
c. CT scan used for differentiation
G. Pancreatic Tumors
1. Malignant tumors usually arise

as adenocarcinomas
2. In head of Pancreas: Sx
a. Painless jaundice
b. Anorexia
Pancreatic Tumors, In head, continued
c. Nausea
d. Weight loss
e. Increased plasma amylase
f. Increased alkaline phosphatase
g. May involve compression of
pancreatic duct, CBD
Pancreatic Tumors in the Head
Tumors in the head

may compress
biliary ducts or
pancreatic ducts
Pancreatic tumors, continued
3. In Body of Pancreas: Sx
a. Gnawing pain radiating to back
b. Pain increases after eating or
lying down
c. Weight loss, anorexia
d. Large tumor may compress
IVC,
portal vein
Pancreatic tumors,
continued
4. In Tail of
Pancreas: Sx
a. Often silent until
local
metastasis occurs
b. May metastasize to:
1. para-aortic lymph
nodes
2. spleen
5. Identified by organ enlargement,

subtle echo changes, irregular outline
6. Metastases to stomach, liver & lungs
are common
7. Often causes dilation of ducts
Pancreatic Disorders, continued
H. Fibrocystic Disease
1. Result of cystic fibrosis
2. Diagnosed by methods other than
ultrasound
I. Pancreaticolithiasis
1. Characteristic stone echoes in pancreatic
duct
2. May see atrophied pancreatic parenchyma
3. Associated with chronic alcoholic
pancreatitis
4. Contours of body, tail show irregularities
Pancreatolithiasis, continued
5. Incidence slightly higher in head

6. Associated with occult pancreatic
carcinoma
a. Mass < 2mm diameter
b. Seen with dilation of pancreatic
duct or CBD
FUNCTION/DYSFUNCTION OF
ENDOCRINE PANCREAS
Diabetes
329
330
Endocrine Function :
Cells of the Islet of Langerhans
synthesize and release hormones into
the circulation.
Hormones travel through the bloodstream
to target tissues (especially liver and
muscle)
At the target cells, hormones bind specific
receptors and cause cell changes that
control metabolism
331
332
Pancreatic endocrine cells regulate

carbohydrate, fat, protein metabolism:
Alpha cells secrete the hormone
glucagon
Beta cells secrete the hormones insulin
and amylin
Delta cells secrete the hormones
gastrin and
somatostatin
F cells - secrete hormone pancreatic
polypeptide
333
Beta Cells
Synthesize pre-proinsulin, a protein
This is cleaved by enzymes proinsulin,
then cleaved again insulin
Insulin is the biologically active hormone
that is released into the bloodstream
334
Insulin secretion is controlled

through several mechanisms:
Chemically high levels of glucose and amino acids
in the blood
Hormonally beta cells are sensitive to several
hormones that may inhibit or cause insulin secretion
Neurally stimulation of the parasympathetic
nervous system causes insulin to be secreted.
335
Insulin secretion is decreased by:

Decreased blood glucose
concentration
Increased blood insulin
concentration
Sympathetic stimulation
336
Insulin
Transported through the blood to target tissues where
it binds to specific receptors
The binding of insulin to target cells:
Acts as a biochemical signal to the inside of the cell
Overall, cell metabolism is stimulated

There is increased glucose uptake into the cell
Regulation of glucose breakdown within the cell
Regulation of protein and lipid breakdown within
the cell
337
Blood glucose is decreased because insulin causes

glucose to leave the bloodstream and enter the
metabolizing cells.
With the exception of brain, liver and erythrocytes,
tissues require membrane glucose carriers.
338
Disorder Diabetes mellitus

The single most common endocrine disorder group
of glucose intolerance disorders
Incidence is estimated at 1-2% of the North American
population
Many of these cases are undiagnosed
339
Diabetes mellitus
Historically distinguished by weight
loss, excessive urination, thirst, hunger
Excessive urination = polyuria
Excessive thirst = polydipsia
Excessive hunger = polyphagia
Modern characterization is by
hyperglycemia and other metabolic
disorders
340
Modern classifications (Table17.7)

Type 1 or IDDM Insulin Dependent Diabetes
Mellitus
Type 2 or
NIDDM NonInsulin Dependent Diabetes
Mellitus
Other Types of Diabetes Mellitus
GDM Gestational Diabetes Mellitus
341
Clinical Manifestations:
Glucose in urine- Because when insulin is not present,
glucose is not taken up out of the blood at the target
cells.
So blood glucose is very highly increased increased
glucose filtered and excreted in the urine (exceeds
transport maximum)
342
Weight loss - Patient eats, but nutrients are not taken up
by the cells and/or are not metabolized properly
Osmotic diuresis results in fluid loss

Loss of body tissue by metabolism of fats and proteins
343
Polyuria, polydipsia, pholyphagia

Ketoacidosis
Fats and proteins are metabolized
excessively, and byproducts known as
ketone bodies are produced. These are
released to the bloodstream and cause:
Decreased pH (so increased acidity)
Compensations for metabolic
acidosis
Acetone given off in breath
344
Treatment
1. Administer insulin
May be of animal or human origin
Cannot be given orally
Patient must monitor their blood
glucose
concentration and
administer insulin with the correct
timing
345
2. Control diet
Carbohydrates should make up
about 55-60% of patients total
calories
Fats should make up <30% of
patients total calories
Proteins should make up about 1520% of
346
3. Monitor exercise
Remember: muscles are a target tissue of
insulin, and metabolize much glucose for
energy
Sometimes exercise irregular blood
glucose levels So diabetic patients should
be monitored when they are exercising
347
Other:
Pancreatic transplant so far not
successful
Experimental therapies not as
successful as hoped
348
Type 2 or NIDDM
More common than IDDM, often
undiagnosed
It has a slow onset
Most common in those > 40 years,
though children are being diagnosed
more regularly
May be genetic
Obesity is the greatest risk factor for
this disease
And is related to increased incidence
in children
349
NIDDM insulin resistance in target cells

See decreased cell responsiveness
Decreased insulin secreted by cells
Also abnormal amount of glucagon
secreted
350
These effects may be due to:

1.Abnormally functioning cells
2. Decreased cell mass,
or a combination of the two
3. Target cell resistance to insulin
Due to:
Decreased number of insulin receptors
Postreceptor events may be responsible
Cells burn out and become insensitive
351
Clinical manifestations
Overweight, hyperlipidemia common

(but these are precursors, not
symptoms)
Recurrent infections
Visual changes, paresthesias, fatigue
352
Treatment
1. Weight loss
2. Appropriate diet (see IDDM above)

3. Sulfonyl ureas
stimulate cells to increase insulin
secretion
Works only when cells are still
functioning
An enhancement of insulins effect
at target
cells
4. Exercise - promotes weight loss
353
Complications of Diabetes Mellitus

Acute:
Hypoglycemia = rapid decrease in plasma
glucose = insulin shock
Neurogenic responses probably due
to decreased glucose to
hypothalamus.
Symptoms include:
Tachycardia, palpitations, tremor,
pallor
Headache, dizziness, confusion
Visual changes
354
Treatment :
provide glucose (I.V. or subcutaneous if
unconscious)
Observe for relapse
355
Ketoacidosis involves a precipitating event:

Increased hormones released w/ trauma
increased glucose produced by the bodys cells
This antagonizes the effects of any glucose
present
Increased ketones in blood
Acid/base imbalance
Polyuria, dehydration
Electrolyte disturbances
Hyperventilation (Kussmaul deep,
gasping)
CNS effects
Acetone on breath
356
Treatment:
low dose insulin
Also, administer fluids, electrolytes
357
Chronic Complications of DM
Neuropathies = nerve dysfunctions
slowing of nerve conduction. In these
patients, see:
Degeneration of neurons
Sensory, motor deficits Muscle
atrophy, paresthesias
Depression
G.I. problems, as muscle motility
decreased
Sexual dysfunction
358
Microvascular disease chronic

diabetes w/ improper glucose
metabolism thickening of the
basement membrane of capillaries,
particularly in the eye and the kidney.
As the capillary changes in this way,
Decreased tissue perfusion
So ischemia hypoxia
359
In the eye the retina is metabolically quite

active, so hypoxia here is a big problem
So see:
Retinal ischemia
Formation of microaneurisms, hemorrhage,
tissue infarct, formation of new vessels,
retinal detachment
360
361
In the kidney diabetes is the most

common cause of endstage renal
disease
Injured glomeruli
(glomerulosclerosis)
In these patients, see:
Proteinuria (protein is excreted into
the urine) Generalized body
edema, hypertension
362
Macrovascular disease atherosclerosis

Plaque formation increases
Increased risk of coronary artery
disease, so increased risk of
myocardial infarction
Increased risk of congestive heart
failure
Stroke
Peripheral vascular disease
why diabetic patients face
problems with their lower legs and
feet
Increased risk of infections363
Endoscopic Stenting for

Pancreatic Diseases
1
Pancreatic Stents
Shape
Geenen - curve, multiple
side holes/distal flaps
Sherman - straight,
multiple side holes,
proximal flap/distal
pigtail
Modified Cotton-Leung
stent S-shaped with
distal flap
Size 3,5,7 or 10 Fr
Length 3,5,7,9,12 cm
Pancreatic Stents Design and

Application
Optimal design of stents
Size (small)
Material (soft)
Less irritation to ductal
epithelium
Migrate out
spontaneously
Common Indications
Acute pancreatitis
Drainage to prevent
post ERCP pancreatitis
Assist endoscopic
therapy
Papillotomy
Leaks
Malignancy
Drainage to relief pain
Adjuvant therapy for
stone and stricture
Technique of Pancreatic Stent

Placement
Deep cannulation
with guide wire
across papilla or
stricture
+ Pancreatic
papillotomy
Stent inserted
over wire and
positioned with
pusher
Post-ERCP Pancreatitis
Incidence
Most common
complication of
ERCP
Incidence 5-10%, 1%
severe, 0.1% fatal
Significant medical/
social/economic and
liability problem
Possible causes
Acinarization
overfilling
Hyperosmolarity /
contrast allergy
Trauma guide wire
Coagulation injury
Impaired drainage from
pancreas
Bacterial contamination
Bile contamination
Mechanism of Post ERCP

Pancreatitis
Papillary manipulation results in edema and sphincter
spasm obstructing PD flow, leading to intracellular
activation of enzymes
Improving drainage with PD stent may prevent post
ERCP pancreatitis
PD Stenting Prevents PEP in

SOD Pts
80 Pts with pancreatic SOD after biliary EST were
randomized to PD stent or no stent
Post ERCP pancreatitis occurred in
10/39 (26%) with No stent
1/41 (2.4%) with Stent
2 Pts (7%) developed PEP after stent removal
Tarnasky
Gastroenterol
1998
PD Stenting for High Risk Patients

76 high-risk pts: SOM or difficult cannulation + EST were
randomized
10/36 (28%) with No stent (5 mild, 2 moderate, 3 severe)
2/38 (5%) with Stent (mild pancreatitis)
PD cannulation failed in 2/40 pts (5%)
Fazel GIE 2003
Is PD Stent Necessary for Every

ERCP?
Probably NOT
Increased time and difficulty
Increased risk
Increased cost
Risk of ductal changes from stent irritation
Need followup to insure stent migration
May need 2nd procedure for stent removal
Who Will Benefit from PD Stenting?

Patient Factors
Suspected SOD
Young female
Prior post-ERCP
pancreatitis
Normal serum bilirubin
Technical Factors
Difficult cannulation
Pre-cut sphincterotomy
Pancreatic
sphincterotomy
Ampullectomy
Balloon sphincteroplasty
Potential Risks of Pancreatic

Stenting
Risks
Failed stent placement
Proximal tip of stent
damages PD
Stent occlusion
causing pancreatitis
Chronic ductal
changes
Inward stent migration
Dilemma
To consider PD stent
placement in a highrisk patient is a serious
decision
If successful, risk of
PEP is reduced.
However, failed attempt
INCREASES the risks
Balloon Sphincteroplasty & Double

Stents
Double wires
Balloon
sphincteroplast
y
Double stents
for drainage
PD stent for
prophylactic
drainage
Pancreas Divisum
Minor Papillotomy with PD Stenting
Chronic Pancreatitis - Stone &

Stricture
EndoTherapy for Chronic

Pancreatitis
Less invasive than
surgery
Results comparable to
surgery
Surgery is still possible
after failed endotherapy
? Predicts outcome
after surgery
Dilation/Stenting of Pancreatic
Stricture
Guide wire (hydrophilic)
across stricture
Dilators
Graded dilators
Pneumatic balloons (4-6
mm)
Short-term pancreatic
stenting to insure drainage
Dilation of Tight PD Stricture with

Soehendra Stent Retriever
Dilation of Pancreatic Stricture

via Minor Papilla
Pancreatic Stone Extraction
Pancreatic sphincterotomy
.035 guide wire
Dilation of orifice/stricture
Stone extraction with wire
basket (e.g. 22Q)
? Mechanical lithotripsy
limitations
PD stent for drainage
ESWL to fragment large
(calcified) stone
Summary
Successful pancreatic stenting and drainage
prevents post ERCP pancreatitis
Pancreatic stenting is a useful adjunct for assisted
papillotomy
Pancreatic stenting provides drainage in patients
undergoing ESWL for stone obstruction
Stenting helps to improve stricture post dilation and
provides short term pancreatic drainage
Pancreatic Neoplasm
1
Types of Pancreatic Neoplasms

Broadly speaking, there are three basic types:
Ductal adenocarcinoma >90% of pancreatic
cancers with a 4% 5-year survival (worst of any
cancer)
Neuroendocrine tumors aka islet-cell tumors, rare
Cystic neoplasms account for <1% of pancreatic
cancers
Clinical Scenario #1
Adenocarcinoma of the
Pancreas
What are typical symptoms of pancreatic CA?

Abdominal pain->pain can suggest neural plexus,
tail lesion, unresectability, poor prognosis
Anorexia
Weight loss
Jaundice
Pruritis ->biliary obstruction
Steatorrhea->pancreatic duct obstruction
Risk Factors for Pancreatic

Cancer?
Firmly linked to cigarette smoking

No clear dietary factors
Increased BMI associated with increased risk
Occupational exposures to amines (chemistry,
hairdressing, rubber work) associated with increased
risk
Pancreas:
CT
scan
CT can confirm pancreatic cancer with a
sensitivity of 85-95% (sensitivity is limited by

smaller tumor size)
Other than the presence of a pancreatic
mass, what else can you determine from CT
scan?
PRESENCE of METASTASES (along with CXR)
RESECTABILITY
Pancreas: CT scan
What makes a pancreatic mass likely resectable?
No evidence of extrapancreatic disease
Evidence of nonobstructive superior mesenteric-portal vein
confluence
No evidence of direct tumor extension to the celiac axis and
SMA
EUS, laparoscopy are universally regarded as useful
adjuncts to CT, not as essential however
Pancreas: CT scan
Borderline Resectable lesions include:
SMV occlusion of a short segment (open vein
proximally and distally)
Body and tail lesions with + celiac, para-aortic nodes
in the vicity
Tumors briefly involving the IVC may be borderline
Pancreas: CT scan
Pancreatic Cancer: Endoscopic

Adjuncts
ERCP can be utilized to:
detecting small tumors not visualized on CT (irregular
solitary duct stenoses >1cm long, abrupt cutoff of main
pancreatic duct, or panc and bile duct obstruction)
palliating biliary obstruction
brush cytology of the pancreatic duct has fair sensitivity
(70%) but excellent specificity
EUS can be utilized to:

aid in diagnosis and characterization of lesion
obtain tissue biopsy; may be associated with lower risk of
peritoneal seeding c/w percutaneous approach
Pancreatic Cancer: Serum Markers

Is there a role for serum markers? If so, what?
CA 19-9 is a sialylated Lewis A blood group antigen
commonly expressed and shed in pancreatic and
hepatobiliary disease, not tumor specific
This antigen, when significantly increased, can assist in
differentiating between pancreatic adenocarcinoma and
inflammatory pancreatic disease
decrease in serial CA 19-9 correlates with survival of
pancreatic patients after surgery or chemotherapy
Debatable as to whether this is useful as early treatment of
recurrences have not been shown to improve outcomes
Pancreatic Cancer: Neoadjuvant

Therapy
This 70yo female has borderline resectable
features, has been stented to answer obstructive
jaundice via ERCP with EUS demonstrating a
positive adenocarcinoma
Is there any role for neoadjuvant therapy for this
patient? If so, what sort of regimen and with what
objectives?
Insulinoma
Whipples Triad:
symptoms of hypoglycemia during fasting or exercise
serum glucose <45mg/dL during symptoms
relief of symptoms with administration of glucose
Definitive test is 72-hour fast with measurement of

insulin and glucose
75% of patients develop symptoms and GB<40 within 24 hours
insulin:glucose ratio >0.4 is indicative of insulinoma
Elevated c-peptide proinsulin levels are confirmatory

along with screening for antiinsulin antibodies,
sulfonylureas
How are insulinomas localized?

Non-invasive preoperative imaging studies fail to
localize 30-35% of insulinomas
CT/MRI, etc. generally reserved by most endocrine
surgeons to r/o hepatic metastases
Intraoperative U/S and palpation are the GOLD
standard for finding an insulinoma, 96-100%
sensitivity
What is proper operation for

insulinoma?
Generally wide Kocher maneuver, superior and inferior
pancreatic border mobilization, medial reflection of the
spleen
Bimanual palpation with U/S
Enucleation of the lesion
Secretin can assist in identifying pancreatic duct leak
after enucleation completed
What about lesion in pancreatic head?
Need to monitor glucose levels q15 minutes until lesion
out
METASTATIC NEOPLASMS
20 times more common than primary tumors in the

liver
via the systemic or portal venous circulation
colon, pancreas, esophagus, stomach,
neuroendocrine, breast, lung, kidney, adrenal, ovary
and uterus, melanoma, and sarcomas
Tx: most > chemotherapy is the only treatment option
TX-Partial Hepatectomy
most effective therapy
minimal criteria
disease confined to the liver

disease amenable to a complete resection.
For small and peripherally placed lesions, sublobar,

segmental resections are preferred
Anatomical segmentectomies are preferred to nonanatomical resections.
cirrhosis constitutes the major obstacle to resection in

patients with HCC.
Careful patient selection
cirrhotic patients have a late risk of death
highly selected patients may be better treated with liver

transplantation rather than resection.
Metastasis
Direct invasion
Lymph node dissemination
Blood spread
Intraperitoneal colonization
LIVER FAILURE
Acute liver failure, uncommon, approx. 5000 new cases annually in

the US.
In chronic liver failure - progressive hepatocyte necrosis produces a

fibrotic response and liver cell regeneration that leads to cirrhosis.
Twenty-five thousand people die each year from cirrhosis, making it

the eighth leading cause of death from disease in the United States.
Liver stellate cells (Ito cells) are the principal mediators of fibrosis in
the liver, and are stimulated by hepatocyte necrosis and cytokines
(tumor necrosis factor- , interleukin-1, interleukin-6), growth
factors (epidermal growth factor, platelet-derived growth factor,
transforming growth factor 1) released by platelets, and Kupffer
and endothelial cells.
Liver Failure
Mackay Memorial Hospital
Department of Internal Medicine
Division of Gastroenterology
R4
97/6/22
Pathology
>90 adenocarcinoma: three types
Sclerosing (scirrous)
Intense desmoplastic reaction
Fibrosis makes diagnosis more difficult
Invade bile duct walls with reduced surgical options and cure
Leads to as PSC-like appearance on ERCP
Most are of this type
Nodular
Annular lesion
Present at advanced stage
Papillary
Bulky mass in CBD
Best resectability
Clinical Manifestation and Diagnosis
Pruritis: 66%
Abdominal pain: 30-50%
Weight loss: 30-50%
Fever: up to 20%
Pain: dull ache RUQ
Jaundice: 90%
Hepatomegaly: 25-40%
RUQ mass: 10%
Clinical Manifestation and Diagnosis

Pruritis: 66%
Abdominal pain: 3050%
Weight loss: 30-50%
Fever: up to 20%
Pain: dull ache
RUQ
Jaundice: 90%
Hepatomegaly:
25-40%
RUQ mass:
10%
Tumor Markers?
CEA: value > 5.2 = sensitivity 68%, specificity
82%
CA 19-9: varies results-sensitivity 53% through 89%
Results may be related to cut-off value
Cholestasis and cholangitis also play a role
Both CEA and CA-19-9: (CA-19-9 + [CEA x 40])
Radiology
Ultrasound
Can detect vascular invasion
Computer tomography
Bile ducts and nodal involvement
Multiphasic
Cholangiography
Brush cytology and bile sampling
Therapeutic
MRCP
PET
EUS
Treatment
Surgical
Distal disease highest resectability
90% resectability rate
Criteria
Absence of lymph nodes, or distant liver metastases
Absence of vascular (portal vein or hepatic artery) invasion
Absence of extrahepatic adjacent organ invasion
Absence of disseminated disease
Operate with bilirubin < 3 mg/dl
Whipple procedure for distal disease
Treatment
Adjuvant
Radiotherapy
Radiation plus chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Treatment
Palliative
Surgical bypass vs stenting

Metal stents associated with longer patency rates
Plastic suited for patients with shorter survival
No increase in survival
Chemotherapy
5-FU based therapy

Gemcitabine
Capecitabine
Nexavar
Liver Transplantation?
Bile Acid metabolism
Liver involved in synthesis and excretion

Bile acids synthesized from cholesterol
Hydrophobic and hydrophilic properties
Act as detergents
Form micelles to for lipid absorption
Primary, secondary, and tertiary bile acids
Bile Acid metabolism
Enterohepatic circulation
secretion rate of bile acids greater than pools
small amounts lost in stool, made up by synthesis
bile acids reabsorbed in terminal ileum
95-98% reabsorbed, serum levels are low
bile acids may be deconjugated by bacteria
deconjugated absorbed rapidly by diffusion
Disorders of bile acid metabolism
Obstructed or diseased secretory system

Defective synthesis of bile acids
Bacterial overgrowth in small intestine
Increased loss of bile acids in stool
compensated
decompensated
Bile Acid metabolism in liver disease

Decreased hepatic synthesis, uptake, transport
Hepatocellular diseases have decreased:
-uptake, synthesis and conjugation
Biliary diseases may also have decreased:
-secretion into bile ducts
High plasma bile acids levels may result
Decreased enterohepatic circulation
Very high levels in cholestatic diseases
Adult Cholestatic Liver Disease
PBC
PSC
Intrahepatic cholestasis
GVHD liver
TPN induced cholestasis
Sarcoidosis
idipathic ductopenia
Liver transplant rejection
Cystic fibrosis
AIDS cholangiopathy
Drug induced cholestasis

Anabolic steroids
Oral
contraceptives
Cyclosporine
Antibiotics
Neuroleptics
Pediatric cholestatic diseases
Cystic fibrosis
Alagilles syndrome
Biliary atresia
Bylers disease
Inborn errors of
metabolism
Liver disease in cholestasis
Mediated by high levels of toxic bile acids

Preferential retention of hydrophobic bile acids
Direct damage to hepatocytes and bile duct cells
Lithocholic and chenodeoxycholic acids are toxic
Degree of liver damage related to bile acid level
Damage to cell membranes, necrosis
Cholestasis may lead to immune activation
Liver disease in cholestasis
Mechanism is probably multifactorial

Initial immunologic insult
Bile duct loss and failure to transport bile acids
Retention of hydrophobic bile acids
Cholate, chenodeoxycholate accumulate
further direct and immune-mediated damage
Clinical complications of cholestasis
Pruritus very common and may be disabling

Exact mechanism unknown
Possible relationship with bile acid levels
Fat malabsorption and steatorrhea
Fat-soluble vitamin deficiencies (A, D, E, K)
Marked elevation in cholesterol levels
Xanthomas and xantholesmas
Early and severe osteoporosis may occur
Laboratory tests in cholestatic

disease
Very high serum alkaline phosphatase, GGT

Less striking elevation in other liver enzymes
Serum bilirubin is elevated late in the disease
Four stages of disease:
one: no symptoms
two: fatigue and pruritus
three: liver fibrosis and elevated bilirubin
four: cirrhosis and liver failure

Differential diagnosis
Sarcoidosis
Granulamatous hepatitis
Hepatitis C
Drug induced hepatitis
PSC
Alcoholic liver disease
Idiopathic adult onset ductopenia
Epidemiology of PBC
Rochester, MN Epidemiology Project
Incidence and prevalence of PBC
Age adjusted incidence 2.7/100,000
4.5 per 100,000 (women)
0.7 per 100,000 (men)
Age and sex adjusted prevalence 40.2/100,000
65.4 per 100,000 (women)
12.1 per 100,000 (men)
Kim et al., Gastroenterology 2000;119:1631-6
Features of PBC
Clinical Features
Sicca syndrome 50%

Thyroid disease 15%
Arthritis 10%
Less Common <5%
Raynauds
Breast cancer
Scleroderma
Renal stones
Laboratory
features
AMA positive (95%)
OR
ANA positive
ASMA positive
Elevated cholesterol
Elevated IgM level
Symptoms and Signs of PBC
Fatigue
65% Ascites1%
Pruritus
55% Encephalopathy 2%
Asymptomatic 20%
Jaundice 16%
Bleeding 3%
Histologic Staging of PBC
From Diseases of the Liver, Schiff (Ed
Bile Duct Diseases

PBC
PSC
Population
Females (9:1)
Males (5:1)
Bile Ducts
Interlobular
Intra &
Extrahepatic
ERCP
AMA
UC Association
Cholangio CA Risk
Normal
Abnormal
Complications
Pathogenesis of PSC
Bacterial translocation to biliary tree
Animal model of bacterial overgrowth
Link with ulcerative colitis
Immunologically mediated
CEP in bile
HLA associations
Deficient biliary chloride transport

CFTR mutations
Treatment of cholestatic diseases
Nonspecific and specific

Cholestyramine and anti-pruritic therapies
Vitamin supplementation
Nutritional support
UDCA reasonable in all cholestatic diseases
Immunosuppressants
Antifibrotics
Possible mechanisms of UDCA
Hepatoprotective
Cytoprotective
Effect on biliary transport
Immunomodulatory
Properties of UDCA
Hepatoprotective
-displace hydrophobic acids
-prevent liver damage by hydrophobic acids
-? block dissolution of membrane-bound lipids
-mdr2 knockout mouse model
-after 6 months 10-12 mg/kg/day, UDCA is
50-60% of bile acid pool
Properties of UDCA
UDCA effect on biliary transport

-increased secretion of bile acids by ducts
- Decreased CDCA levels in PBC patients
-Increased secretion of phospholipids
- Bilirubin reduction may be due to increased
biliary transport
-decreased acidity of bile
- increased bile flow
Immunomodulatory
Abnormal HLA antigens on cells in cholestasis

May lead to immune activated damage
Treatment with UDCA reduces HLA expression
Unknown whether this is primary or secondary
May be major beneficial effect in PBC
Conditions treated with UDCA
Primary biliary cirrhosis

Intrahepatic cholestasis of pregnancy
Graft versus host disease of the liver
Cystic fibrosis liver disease
TPN-related cholestasis
Liver graft rejection
Nonalcoholic steatohepatitis
Veno-occlusive disease of the liver
Cardiac graft rejection
Doses of 10-15 mg/kg/day studied

Combined analysis of three studies
Over 500 patients treated
Median follow up 4 years
Survival free of transplantation improved
32% reduction in death or transplantation
Benefit greatest with elevated bilirubin
US multicenter also showed survival benefit
UDCA (Ursodeoxycholic acid) in

PBC
May delay onset of esophageal varices

Improvement in pruritus variable
Ten year survival without OLT improved
Decrease in florid bile duct lesions
Improved inflammation and necrosis
Possible stabilization of fibrosis
UDCA is cost effective therapy
High Dose UDCA for PSC
Randomized trial in 26 patients with PSC

20 mg/kg UDCA vs placebo for 2 years
22 patients had repeat ERCP and biopsy
Evaluation every 3 months
No change in symptoms with UDCA
Increased total serum bile acids
Saturation with UDCA > 70%
High Dose UDCA for PSC
Significantly improved:
Serum AP
Serum GGT
Cholangiograms
Fibrosis grade
Mitchell et al., Gastroenterology 2001;121:900-907
Effect of UDCA on histology

Biopsy done before and after 4
years
Florid bile duct lesions
Granulomas
Lobular inflammation
Lobular necrosis
Degott et al.,Hepatology 1999;29:1007-12
Effect of UDCA on survival
40 symptomatic patients treated 10 years

2 stopped early for worsened symptoms
Both alive 4 years later
38 treated for up to 10 years
Survival benefit for Stage I disease
Trend for improved survival in II-IV
Symptoms improved but recurred in 50%
Bateson and Gedling, Postgraduate Med J 1998;74:482-5
Serum bilirubin during UDCA
Survival with UDCA vs placebo

Database of 548 patients studied
Survival after normalization of bilirubin
Transplant-free survival improved (RR 3.7)
Similar to normal bilirubin placebo group
Bilirubin predicted death, OLT in both
bili> 30mol/l: RR of death, OLT (6, 5.7)
Bonnand et al., Hepatology 1999;29:39-43
Effect of UDCA on histology
No change in ductular proliferation

No change in ductopenia
No change in piecemeal necrosis
Fibrosis worse in 12, stable in 30
Progression related to
necroinflammation
Degott et al.,Hepatology 1999;29:1007-12
Effect of UDCA on fibrosis

Rate early to late stage
162 paired liver biopsies
5 X lower rate from early
to late stage
Maintained lower stage
No regression seen
(3% per yr)
Corpechot Hepatology 2000;32:1196-9
Long-term effects of UDCA
10 year survival examined

Need for OLT, risk of death
225 patients treated UDCA 13-15 mg/kg
No control group
Expected survival using Mayo model
Survival better than predicted
Lower than general French population
Comparable in patients without cirrhosis
Poupon Hepatology 29:1668-71
Effect of UDCA on varices

180 patients in
controlled trial
Endoscopy
performed every two
years
139 had no varices
on entry
Lower incidence of
varices with UDCA
after 4 years
P<0.001
58
%
16%
Lindor et al., Mayo Clin Proc 1997;72:1137-40
Long-term UDCA therapy
192 randomized to UDCA versus placebo

Decreased liver enzymes with UDCA
Apparent after 3 months of therapy
Death or transplant defined failure
No difference in time to failure
UDCA improved portal inflammation
UDCA slowed histologic stage progression
Pares J Hepatol 2000;32:561-6
UDCA effect on histology

US 2 year
multicenter trial
UDCA versus
placebo
Prevalence of florid
duct lesions
decreased
More common with
early stage disease
Combes Hepatology 1999;30:602-5
Which patients respond to UDCA?
70 patients treated 10-15 mg/kg 6-13 years

33% with Stage I or II had normal LFT
Histology improved
67% without normal LFT
Histology was not improved to same degree
Incomplete responders had higher alkaline
phosphatase, GGT
AP > 600, GGT>131
Leuschner Gut 2000;46:121-6
Summary
Cholestatic liver diseases common

Recognize associated complications
UDCA accepted therapy in PBC
Long-term improvement in responders
Ongoing studies in PSC
Cirrhosis of the Liver
Description
A chronic, progressive disease of the liver
Extensive parenchymal cell

degeneration
Destruction of parenchymal cells
Description
Regenerative process is disorganized, resulting in

abnormal blood vessel and bile duct relationships
from fibrosis
Description
Normal lobular structure distorted by fibrotic
connective tissue
Lobules are irregular in size and shape with impaired
vascular flow
Insidious, prolonged course

Cell necrosis occurs
Destroyed liver cells are replaced by scar tissue
Normal architecture becomes nodular

Four types of cirrhosis:
Alcoholic (Laennecs) cirrhosis

Postnecrotic cirrhosis
Biliary cirrhosis
Cardiac cirrhosis
Exactly How Much Do You Drink?

Estimated that the development of cirrhosis requires,
on average, the ingestion of 80 grams of ethanol
daily for 10 to 20 years
This corresponds to approximately one liter of wine,
eight standard sized beers, or one half pint of hard
liquor each day

Alcoholic (Laennecs) Cirrhosis
Associated with alcohol abuse
Preceded by a theoretically reversible fatty infiltration of the
liver cells
Widespread scar formation

Postnecrotic Cirrhosis
Complication of toxic or viral hepatitis
Accounts for 20% of the cases of cirrhosis
Broad bands of scar tissue form within the liver

Biliary Cirrhosis
Associated with chronic biliary obstruction and infection
Accounts for 15% of all cases of cirrhosis

Cardiac Cirrhosis
Results from longstanding severe right-sided heart failure
Manifestations of Liver Cirrhosis
Fig. 42-5
Onset usually insidious
GI disturbances:
Anorexia
Dyspepsia
Flatulence
N-V, change in bowel habits
Abdominal pain
Fever
Lassitude
Weight loss
Enlarged liver or spleen
Late Manifestations
Two causative mechanisms
Portal hypertension
Jaundice
Occurs because of insufficient conjugation of bilirubin
by the liver cells, and local obstruction of biliary ducts
by scarring and regenerating tissue
Jaundice
Intermittent jaundice is characteristic of biliary
cirrhosis
Late stages of cirrhosis the patient will usually be
jaundiced
Skin
Spider angiomas (telangiectasia, spider nevi)
Palmar erythema
Steroid hormones of the adrenal cortex (aldosterone),
testes, and ovaries are metabolized and inactivated
by the normal liver
Alteration in hair distribution
Decreased amount of pubic hair
Axillary and pectoral alopecia
Bleeding tendencies as a result of decreased
production of hepatic clotting factors (II, VII, IX, and
X)
Anemia, leukopenia, and thrombocytopenia are
believed to be result of hypersplenism
Peripheral Neuropathy
Dietary deficiencies of thiamine, folic acid, and
vitamin B12
Complications
Portal hypertension and esophageal varices

Peripheral edema and ascites
Fetor hepaticus
Complications
Portal Hypertension
Characterized by:
Increased venous pressure in portal circulation

Splenomegaly
Esophageal varices
Systemic hypertension
Complications
Portal Hypertension
Primary mechanism is the increased resistance to
blood flow through the liver
Complications
Portal Hypertension
Esophageal Varices
Increased blood flow through the
portal system results in dilation
and enlargement of the plexus
veins of the esophagus and
produces varices
Complications
Portal Hypertension
Esophageal Varices
Varices have fragile vessel walls
which bleed easily
Complications
Portal Hypertension
Internal Hemorrhoids
Occurs because of the dilation of the
mesenteric veins and rectal veins
Complications
Portal Hypertension
Caput Medusae
Collateral circulation involves the superficial veins of the
abdominal wall leading to the development of dilated veins
around the umbilicus
Complications

Ascites:
amounts of protein
Complications

Factors involved in the pathogenesis of ascites:
- Hypoalbuminemia
Levels of aldosterone
Portal hypertension
Complications
Liver damage causes blood to enter systemic
circulation without liver detoxification
Complications
Main pathogenic toxin is NH3 although other
etiological factors have been identified
Frequently a terminal complication
Complications
Fetor Hepaticus
Musty, sweetish odor detected on the patients breath
From accumulation of digested by-products
Development of Ascites
Fig. 42-6
Diagnostic Studies

Liver biopsy
Liver scan
Liver ultrasound
Diagnostic Studies
Esophagogastroduodenoscopy
Prothrombin time
Testing of stool for occult blood
Collaborative Care
Rest
Avoidance of alcohol and anticoagulants
Management of ascites
Collaborative Care
Prevention and management of esophageal variceal
bleeding
Management of encephalopathy
Collaborative Care
Ascites
High carbohydrate, low protein, low Na+ diet
Diuretics
Paracentesis
Collaborative Care
Ascites
Peritoneovenous shunt
Provides for continuous reinfusion of ascitic fluid from the
abdomen to the vena cava
Fig. 42-8
Collaborative Care
Esophageal Varices
Avoid alcohol, aspirin, and irritating foods
If bleeding occurs, stabilize patient and manage the
airway, administer vasopressin (Pitressin)
Collaborative Care
Esophageal Varices
Balloon tamponade
Surgical shunting procedures (e.g., portacaval shunt,
TIPS)
Sengstaken-Blakemore Tube
Fig. 42-9
Fig. 42-11
Collaborative Care
Goal: reduce NH3 formation
Protein restriction (0-40g/day)

Sterilization of GI tract with antibiotics (e.g., neomycin)
lactulose (Cephulac) traps NH3 in gut
levodopa
Drug Therapy
There is no specific drug therapy for cirrhosis
Drugs are used to treat symptoms and complications of
Nutritional Therapy
Diet for patient without complications:
High in calories
CHO
Moderate to low fat
Amount of protein varies with degree of liver damage
Nutritional Therapy
Patient with hepatic encephalopathy

Very low to no-protein diet
Low sodium diet for patient with ascites and edema
Nursing Management
Nursing Assessment
Past health history

Medications
Chronic alcoholism
Weight loss
Nursing Management
Nursing Diagnoses
Imbalanced nutrition: less than body requirements

Impaired skin integrity
Ineffective breathing pattern
Risk for injury
Nursing Management
Planning
Overall goals:
Relief of discomfort
Minimal to no complications
Return to as normal a lifestyle as possible
Nursing Management
Nursing Implementation
Health Promotion
Treat alcoholism
Identify hepatitis early and treat
Identify biliary disease early and treat
Nursing Management
Acute Intervention
Rest
Edema and ascites
Paracentesis
Skin care
Dyspnea
Nutrition
Nursing Management
Acute Intervention
Bleeding problems
Balloon tamponade
Altered body image
Nursing Management
Ambulatory and Home Care
Symptoms of complications
When to seek medical attention
Remission maintenance
Abstinence from alcohol
Nursing Management
Evaluation
Maintenance of normal body weight

Maintenance of skin integrity
Effective breathing pattern
No injury
No signs of infection
Liver Cirrhosis
K. Dionne Posey, MD, MPH
Internal Medicine & Pediatrics December 9,
2004
Histopathology
Morphologic Classification
Relatively nonspecific with regard to etiology
The morphologic appearance of the liver may change
as the liver disease progresses
micronodular cirrhosis usually progresses to macronodular
cirrhosis
Serological markers available today are more specific

than morphological appearance of the liver for
determining the etiology of cirrhosis
Accurate assessment of liver morphology may only
be achieved at surgery, laparoscopy, or autopsy
Evaluation of Cirrhosis
Complications
Ascites
Spontaneous Bacterial Peritonitis
Variceal hemorrhage
Complications
Other Pulmonary syndromes
Hepatic hydrothorax
Portopulmonary HTN
Hepatocellular carcinoma
Ascites
Accumulation of fluid within the peritoneal cavity
Most common complication of cirrhosis
Two-year survival of patients with ascites is
approximately 50 percent
Ascites
Assessment of ascites
Grading
Grade 1 mild; Detectable only by US
Grade 2 moderate; Moderate symmetrical distension of the
abdomen
Grade 3 large or gross asites with marked abdominal
distension
Older system -subjective
1+ minimal, barely detectable

2+ moderate
3+ massive, not tense
4+massive and tense
Ascites
Imaging studies for confirmation of ascites
Ultrasound is probably the most cost-effective modality
Ascites
Who gets a belly tap?
What do I want to order ?
Ascites
Treatment aimed at the underlying cause of the
hepatic disease and at the ascitic fluid itself
Dietary sodium restriction
Limiting sodium intake to 88 meq (2000 mg) per day
Ascites
The most successful therapeutic regimen is the
combination of single morning oral doses of
Spironolactone and Furosemide, beginning with 100
mg and 40 mg
Two major concerns with diuretic therapy for cirrhotic
ascites:
Overly rapid removal of fluid
Progressive electrolyte imbalance

Infection of ascitic fluid
Almost always seen in the setting of end-stage liver
disease
The diagnosis is established by
A positive ascitic fluid bacterial culture
Elevated ascitic fluid absolute polymorphonuclear leukocyte
(PMN) count ( >250 cells/mm3)

Fever
Abdominal pain
Abdominal tenderness
Altered mental status
acute renal failure coupled with advanced
hepatic disease (due to cirrhosis or less often
metastatic tumor or severe alcoholic hepatitis)
characterized by:
Oliguria
benign urine sediment
very low rate of sodium excretion
progressive rise in the plasma creatinine
concentration
Reduction in GFR often clinically masked
Prognosis is poor unless hepatic function improves
Nephrotoxic agents and overdiuresis can precipitate
HRS
Variceal hemorrhage
Occurs in 25 to 40 percent of patients with cirrhosis
Prophylactic measures
Screening EGD recommended for all cirrhotic
patients
Liver disease
Increased alveolar-arterial gradient while breathing room air
Evidence for intrapulmonary vascular abnormalities, referred
to as intrapulmonary vascular dilatations (IPVDs)
Hepatic Hydrothorax
Pleural effusion in a patient with cirrhosis and
no evidence of underlying cardiopulmonary
disease
Movement of ascitic fluid into the pleural
space through defects in the diaphragm, and
is usually right-sided
Diagnosis -pleural fluid analysis
reveals a transudative fluid
serum to fluid albumin gradient greater than 1.1
Hepatic hydrothorax
Confirmatory study:
Scintigraphic studies demonstrate tracer in the chest cavity
after injection into the peritoneal cavity
Treatment options:
diuretic therapy
periodic thoracentesis
TIPS
Portopulmonary HTN
Refers to the presence of pulmonary hypertension in
the coexistent portal hypertension
Prevalence in cirrhotic patients is approximately 2
percent
Diagnosis:
Suggested by echocardiography
Confirmed by right heart catheterization
Spectrum of potentially reversible neuropsychiatric
abnormalities seen in patients with liver dysfunction
Diurnal sleep pattern pertubation

Asterixis
Hyperactive deep tendon reflexes
Transient decerebrate posturing
Monitoring for events likely to precipitate HE [i.E.-
variceal bleeding, infection (such as SBP),

the administration of sedatives, hypokalemia,
and hyponatremia]
Reduction of ammoniagenic substrates
Lactulose / lactitol
Dietary restriction of protein
Zinc and melatonin
Patients with cirrhosis have a markedly increased risk
of developing hepatocellular carcinoma
Incidence in well compensated cirrhosis is
approximately 3 percent per year
Prognostic Tools
MELD (model for end-stage liver disease)
Identify patients whose predicted survival post-procedure
would be three months or less
MELD = 3.8[serum bilirubin (mg/dL)] + 11.2[INR] +

9.6[serum creatinine (mg/dL)] + 6.4
Prognostic Tools
Child-Turcotte-Pugh (CTP) score
initially designed to stratify the risk of portacaval shunt
surgery in cirrhotic patients
based upon five parameters: serum bilirubin, serum albumin,
prothrombin time, ascites and encephalopathy
good predictor of outcome in patients with complications of
portal hypertension
Prognostic Tools
APACHE III (acute physiology and chronic health
evaluation system)
Designed to predict an individual's risk of dying in the hospital
Treatment Options
The major goals of treating the cirrhotic patient

include:
Slowing or reversing the progression of liver disease

Preventing superimposed insults to the liver
Preventing and treating the complications
Determining the appropriateness and optimal timing for liver
transplantation
Liver transplantation is the definitive treatment for
patients with decompensated cirrhosis
Depends upon the severity of disease, quality of life
and the absence of contraindications
Minimal criteria for listing cirrhotic patients on the liver
transplantation list include
A child-Pugh score 7
Less than 90 percent chance of surviving one year without a
transplant
An episode of gastrointestinal hemorrhage related to portal
hypertension
An episode of spontaneous bacterial peritonitis
Vaccinations
Hepatitis A and B
Pneumococcal vaccine
Influenza vaccination
Surveillance
Screening recommendations:
serum AFP determinations and ultrasonography every six
months
Avoidance of Superimposed Insults
Avoidance of:
Alcohol
Acetaminophen
Herbal medications
Collaborative Care
Rest
Avoidance of alcohol and anticoagulants
Management of ascites
Collaborative Care
Prevention and management of esophageal variceal
bleeding
Management of encephalopathy
Collaborative Care
Ascites
High carbohydrate, low protein, low Na+ diet
Diuretics
Paracentesis
Collaborative Care
Ascites
Peritoneovenous shunt
Provides for continuous reinfusion of ascitic fluid from the
abdomen to the vena cava
Collaborative Care
Esophageal Varices
Avoid alcohol, aspirin, and irritating foods
If bleeding occurs, stabilize patient and manage the
airway, administer vasopressin (Pitressin)
Collaborative Care
Esophageal Varices
Balloon tamponade
Surgical shunting procedures (e.g., portacaval shunt,
TIPS)
Sengstaken-Blakemore Tube
Drug Therapy
There is no specific drug therapy for cirrhosis
Drugs are used to treat symptoms and complications of
Nutritional Therapy
Diet for patient without complications:
High in calories
CHO
Moderate to low fat
Amount of protein varies with degree of liver damage
Nutritional Therapy
Patient with hepatic encephalopathy

Very low to no-protein diet
Low sodium diet for patient with ascites and edema
Nursing Management
Nursing Assessment
Past health history

Medications
Chronic alcoholism
Weight loss
Nursing Management
Nursing Diagnoses
Imbalanced nutrition: less than body requirements

Impaired skin integrity
Ineffective breathing pattern
Risk for injury
Nursing Management
Planning
Overall goals:
Relief of discomfort
Minimal to no complications
Return to as normal a lifestyle as possible
Nursing Management
Health Promotion
Treat alcoholism
Identify hepatitis early and treat
Identify biliary disease early and treat
Nursing Management
Acute Intervention
Rest
Edema and ascites
Paracentesis
Skin care
Dyspnea
Nutrition
Nursing Management
Acute Intervention
Bleeding problems
Balloon tamponade
Altered body image
Nursing Management
Ambulatory and Home Care
Symptoms of complications
When to seek medical attention
Remission maintenance
Abstinence from alcohol
Nursing Management
Evaluation
Maintenance of normal body weight

Maintenance of skin integrity
Effective breathing pattern
No injury
No signs of infection
Diseases of the Liver & Biliary Tract
The circulation of blood through the intestines & liver is unique in human
anatomy: blood from one capillary system, the intestinal, flows into another
capillary system, the hepatic, before returning to the heart
Enterohepatic Circulation
Major Determinants of Disease
The metabolic consequences of liver disease are serious

& include
toxic accumulations of
metabolic waste (especially ammonia & bilirubin)
drugs & toxins
endogenous hormones (especially estrogen)
bleeding, associated with a deficiency of coagulation factors

edema, associated with a deficiency of albumin
failure to absorb intestinal fat because of a deficiency of bile
acids
Viral hepatitis is a common contagious disease

Cirrhosis is the final endpoint for many liver diseases
Portal HTN is the most important consequence of
cirrhosis & can be associated with liver failure & severe
hemorrhage
Stones often form in the gallbladder & may pass into &
obstruct the bile duct
Response to Injury
Responds well as it has a functional reserve that must
suffer a large loss before become symptomatic
Liver function tests (LFTs)
enzymes
Lactic dehydrogenase (LDH)

Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase (ALKP)
bilirubin
albumin
PT & PTT
viral antigens & antibodies
autoimmune antibodies
Anatomic Patterns of Injury

Inflammation
hepatitis
Degeneration
hydropic
fatty
Necrosis
infarct
Councilman bodies
Fibrosis
cirrhosis
Functional Patterns of Liver Injury

Direct metabolic
consequences
jaundice
cholestasis
accumulation of bile
acids & cholesterol in
blood due to
obstruction
hepatic failure
Jaundice
Bilirubin > 2mg/dl
Cholestasis
Usually accompanied by jaundice & pruritis
Due to
primary liver disease
drug interference with bile secretion
pregnancy
Elevated blood cholesterol

Xanthomas
Increased ALKP
Hepatic Failure
Die within a few weeks or months

May be sudden injury or chronic injury
Loss of 90% of function
Clinically
jaundice
ascites
fetor hepaticus
hypoalbuminemia
hypoglycemia
palmar erythema
spider angiomata
testicular atrophy
balding
gynecomastia
bleeding disorders
hepatorenal syndrome
hepatic encephalopathy
Cirrhosis
Final, common endstage for a variety of

chronic liver diseases
Patterned fibrosis
characterized by
interconnecting bands
of scar tissue
divides liver into small
nodules separated by
dense fibrous tissue
Progressive
Irreversible
Incurable
Portal
Anatomic Types of Cirrhosis
caused by diffuse liver cell

injury
repeated episodes of necrosis
followed by regeneration &
growth of fibrous tissue from
portal triad area
most common type
usually due to alcoholic liver
disease or chronic viral
hepatits
Biliary
caused by chronic disease of
the biliary tree
chronic inflammation of bile
ducts due to
autoimmune disease
obstruction by gallstones
sclerosing cholangitis
Causes portal hypertension
Viral Hepatitis
Several viruses involved
HAV
HBV
HCV
HDV
HEV
Hepatitis A is a mild, epidemic disease spread by

contaminated food & H2O
does not cause chronic hepatitis or cirrhosis
Hepatitis B & C are spread from individual to individual

by needles or sexual contact
can cause chronic hepatitis or cirrhosis
Clinical Syndromes of Viral

Hepatitis
Asymptomatic hepatitis
no lasting liver injury
Carrier state
harbors virus but is asymptomatic
can transmit to others
mostly HCV
Acute viral hepatitis

4 clinical phases
Chronic viral hepatitis

Fulminant hepatic failure
increased risk with HBV & HCV
Acute Viral Hepatitis

Incubation
a few weeks
Symptomatic
prejaundice phase
malaise
fatigue
nausea/vomiting
anorexia
RUQ pain
fever
headache
Symptomatic jaundice
phase
jaundice appears & other
symptoms fade
increase in conjugated
bilirubin
pale stools
Convalescence
jaundice fades
infectivity disappears
Abs in blood
Chronic Viral Hepatitis

Liver biopsy & 6 months or more of clinical or lab
evidence
About 10% of HBV patients & 50% of HCV patients
Lab tests reveal extent of disease as there are few
signs/symptoms
prolonged PT & PTT
increased enzymes
increased bilirubin
Present with
hepatomegaly
splenomegaly
palmar erythema
spider angiomas
Fulminant Hepatic Failure

Acute liver disease that progresses to hepatic failure or
encephalopathy in just a few weeks
More than of the cases are fulminant hepatitis usually involving
HAV or HBV
Other causes include drugs, heat stroke
Hepatitis A
HAV
Epidemic hepatitis
Primarily fecal-oral transmission
Benign & self-limiting
Incubation is about 2-6 weeks
Most common type in the world
infection more common than the disease
more common in developing nations
about 10,000 new cases/yr in US
Fatalities rare
No carrier state
Vaccine
Hepatitis B
HBV
Infects hundreds of millions worldwide
Incubation varies from a few weeks to 6 months
Acute Infection
Detected by presence of hepatitis B surface antigen (HBsAg)

Viremia may last for many weeks
1st antibody to appear is hepatitis B core antigen antibody (anti-HBc)
Beginning of recovery marked by appearance of hepatitis B surface
antigen antibodies (anti-HBs)
confers immunity
Transmitted in
blood
saliva
semen
almost any bodily fluid
Spread by
sexual contact
blood transfusion
renal dialysis
needlestick
IV drug users
fetus in utero or during
vaginal delivery
1/3 of cases, not
known
Hepatitis C
Major cause of chronic liver disease
Incubation varies from a few weeks to 6 months
About 40,000 new cases/yr
About 2% have antibodies indicating previous infection

About 50% of these have detectable virus in blood
indicates a chronic carrier state
Transmission
over 12/ of new infections due to IV drug abuse
about 15% through sexual contact, infected health care workers,
& neonates
in about 1/3 of cases, not known
Mutating RNA virus with dozens of subtypes has made

developing a vaccine difficult
Hepatitis D
HDV
delta virus
co-exist with HBV
co-infect
infect a carrier of HBV
mostly in
IV drug abusers
hemophiliacs
Hepatitis E
rare in US but most
common form of
epidemic hepatitis in
India
transmitted like HAV
mild & self-limiting
Anatomic Pathology of Hepatitis

Carrier state
liver biopsy normal usually
in HCV, may have evidence
of low-grade inflammation
in HBV, may have ground
glass appearance due to
virus particles
Acute hepatitis
hydropic degeneration
chronic inflammation
necrosis of individual cells
Fulminant hepatitis or
hepatic failure
extensive necrosis
Chronic hepatitis
see those changes seen in
acute but more severe
damage
disorganized
more intense inflammatory
reaction
more extensive necrosis
scar tissue
About 20% of cases of chronic hepatitis

Not associated with viral infection
Mostly in young women
High titers of autoantibodies
antinuclear
anti-smooth muscle
anti-mitochondrial
In about of the cases, they have an autoimmune

disease
Liver Abscess
Focal collection of necrotic
tissue, inflammatory
debris, & fluid
Rare in industrialized
nations
usually due to bacteria or
fungi
Most caused by E.
histolytica
Toxic
Liver
Injury
Symptoms from imperceptible to fatal & onset from instantaneous to weeks after
exposure
Mild injury
Severe injury
hepatic failure
hepatic coma
death
Dose related reactions
asymptomatic
modest elevation of enzymes
damage certain if enough chemicals present

uncommon
suicidal doses of acetaminophen
Unpredictable toxic injury
damage out of proportion to the dose

cannot metabolize a chemical as well as others
may initiate autoimmune hepatitis
drugs involved include
sulfonamides
isoniazid
halothane
May cause neoplastic growth

Alcoholism is the leading cause of liver disease
in industrialized nations
About 20 million Americans abuse alcohol
About 25% of hospitalized patients have some
alcohol-related problem
Amount necessary to produce cirrhosis is about
200gms/day for 10-16 years
Sequence of damage
fatty liver
alcoholic hepatitis
cirrhosis
Fatty Liver
1st sign of alcohol
injury
aka steatosis
Can be 2-3X its size,
yellow, greasy
Usually asymptomatic
May have elevated
enzymes
Histologically, see
Councilman bodies,
Mallory bodies
Alcoholic
Hepatitis
Subacute or chronic form of alcohol liver injury
Characterized by inflammation, necrosis, & early fibrosis
Can progress to cirrhosis
Clinically
malaise
anorexia
RUQ pain
jaundice
elevated enzymes
leukocytosis
Each bout has 10-20% chance of death from

liver disease
intestinal hemorrhage
pancreatitis
Severe damage if
abnormal clotting tests
low albumin
signs of hepatic failure
May not be reversible
Alcoholic Cirrhosis
Final & irreversible
stage of alcoholic
liver disease
Only about 15% of
alcoholics develop
One of the leading
causes of liver
transplantation in
US
Hemochromatosis
Toxic accumulation of iron in cells, especially
liver, heart, & pancreas
Primary
inherited autosomal recessive disorder
abnormally high absorption of Fe from intestine
one of the most common inborn errors of metabolism
in US
Secondary
acquired
usually due to repeated transfusions given for sickle
cell, thalassemia, aplastic anemia
chelate it to an excretable form
Takes years to
accumulate enough
Fe to cause damage
Cirrhosis if untreated
Diagnosis depends on
clinical features
increased blood levels of
Fe, ferritin, transferrin
confirmed by liver biopsy
Primary
regular phlebotomy
Secondary
chelation of Fe
Wilson Disease
Autosomal recessive disorder

Toxic accumulation of copper mainly in brain & liver
Copper absorbed in GI tract & excreted in bile
albumin transports to liver
bound to ceruloplasmin then secreted
if biliary excretion decreases, accumulates in liver &
brain
Manifests as behavioral oddities, psychosis, tremors,

abnormal gait
Diagnosis confirmed by liver biopsy
Early diagnosis critical
Chelation therapy
Hereditary Alpha-1-Antitrypsin
Deficiency
Protein made by liver
Accumulate excessive amounts of defective AAT in
liver
Only 10% of patients develop clinically significant
liver disease

Autoimmune disease
Usually have another
autoimmune disease
Evolves from
inflammatory destruction
of intrahepatic bile ducts
Early on see
accumulation of
lymphocytes around bile
ducts
Death due to hepatic
failure & portal HTN

Chronic liver disease
2/3 of patients have ulcerative colitis
Inflammation & fibrosis of intrahepatic & extrahepatic
bile ducts
Typical patient is male under 40 with long-standing
ulcerative colitis
Circulatory Disorders
Portal vein obstruction as it flows into the liver
changes similar to portal HTN caused by cirrhosis
usually due to thrombosis
As it flows through the liver

most common cause is chronic passive congestion
usually with R heart failure
Obstruction in the hepatic vein as it flows out of

the liver
hepatic vein thrombosis
Infarcts uncommon
Metastatic Carcinoma
Most common neoplasm in the liver

Usually from colon, lung, breast
Usually related to HBV & HCV

Hematogenous metastases are common
High levels of alpha fetoprotein
Prognosis is grim
Cholelithiasis
Gallstones in the gallbladder or biliary tree

Form in gallbladder
Usually have multiple stones
About 1 million new cases/yr in US
50% require surgery
Cholesterol gallstones
80% of cases
Bile saturated with
cholesterol
Conditions associated
with their development
age & gender
weight
ethnic, hereditary, &
geographic factors
drugs
acquired conditions
Pigment gallstones
20% of cases
Form in gallbladder & in biliary tree
Composed of bilirubin & bile substances other than
cholesterol
Usually no symptoms until they begin to move; mid-size

stones are the worst
Painful cramps in RUQ
Nausea/vomiting
Complications include
cholecystitis
pancreatitis
perforation
empyema of gallbladder
Acute Cholecystitis
Most common major
complication of
gallstones
90% associated with
obstruction of the neck
Gallbladder is
enlarged, tense, &
inflamed
Persistent rather mild
RUQ pain to very
severe pain
Chronic Cholecystitis
Do not have to have a
history of acute attacks
Almost always associated
with gallstones although
obstruction not necessary
Mild to moderate RUQ
pain
Nausea/vomiting
Intolerance of fatty foods
Obstruction of the Extrahepatic

Bile Ducts
HEPATIC BENIGN
TUMORS
Cysts
Simple hepatic cysts, the most common, are unilocular
fluid-filled lesions that generally produce no symptoms.
The possibility of echinococcosis should be
considered.
Solitary cysts lined with cuboidal epithelium are
classified as cystadenomas and should be resected,
since they are premalignant.
There are few indications for aspirating hepatic cysts.
Cysts
Large symptomatic cysts are difficult to
eradicate with alcohol injections, and serious
superinfection of the cyst cavity may occur.
The simplest method consists of
laparoscopic cyst fenestration (wide excision
of the cyst wall).
A tongue of omentum is fixed so it lies in the
residual cyst cavity as an ancillary measure
to prevent the edges from coapting.
Hepatic Adenoma
oral contraceptives - Small adenomas may regress when agents are

discontinued
Two-thirds are solitary
Transition from benign to HCC may occur
association of acute bleeding episodes with pregnancy.
The general consensus is that adenomas should be resected because

of the risks of malignant change and spontaneous hemorrhage.
Symptomatic and large asymptomatic should be resected.
Emergent resection or hepatic artery embolization for hemorrhage.
Focal Nodular Hyperplasia
young women
oral contraceptive agents does not appear to predispose to

the development of FNH
Symptomatic lesions should be removed, while asymptomatic

tumors (the majority) should be left undisturbed
Inability to distinguish FNH from adenoma or malignant

disease is an indication for resection in some patients.
Discontinuation of oral contraceptives probably has no impact.
HEPATIC ABSCESS
bacterial, parasitic, or fungal in origin
USA, pyogenic abscesses are the most common, followed by

amebic abscesses
90% of right lobe abscesses are solitary, while only 10% of left
lobe abscesses are solitary.
40% of patients have an underlying malignancy
25% of cases, no antecedent infection can be documented

("cryptogenic" abscesses).
most cases, the organism is of enteric origin
LIVER FAILURE

the US.


Portal Hypertension
Normal pressure ranges from 7 to 10 mm Hg.
In portal hypertension, pressure exceeds 10 mm Hg, averaging

around 20 mm Hg and occasionally rising as high as 5060 mm
Hg.
In extrahepatic portal vein thrombosis (without liver disease),

collaterals in the diaphragm and in the hepatocolic,
hepatoduodenal, and gastrohepatic ligaments transport blood
into the liver around the occluded vein (hepatopetal).
In cirrhosis, collateral vessels circumvent the liver and deliver

portal blood directly into the systemic circulation (hepatofugal);
these collaterals give rise to esophageal and gastric varices.
Portal Hypertension
Isolated thrombosis of the splenic vein causes localized splenic

venous hypertension and gives rise to large collaterals from spleen
to gastric fundus.
From there, the blood returns to the main portal system through the
coronary vein.
In this condition, gastric varices are often present without
esophageal varices.
spontaneous bleeding is relatively uncommon except from those at
the gastroesophageal junction; spontaneous bleeding from gastric
varices can sometimes occur.
Compared with adjacent areas of the esophagus and stomach, the
gastroesophageal junction is especially rich in submucosal veins,
which expand disproportionately in patients with portal hypertension.
The cause of variceal bleeding is most probably rupture due to
sudden increases in hydrostatic pressure.

Liver malignancy may arise from
Hepatocytes
Biliary epithelial cells
Risk Factors - HCC

Chronic HBV and HCV
Cirrhosis
Chronic underlying liver disease.
Risk Factors - cholangioCA
Infrequently associated with cirrhosis.

Widespread infection with liver flukes (Clonorchis
sinensis
A large proportion of patients will have intra- or extra-hepatic

metastases at presentation.
infiltration of the portal venous system with subsequent

dissemination of tumor cells.
Vascular invasion is more common with larger tumors (> 5 cm).
Most common mets include the hilar and celiac lymph nodes
and the lungs; metastases to bone and brain are less common
and peritoneal disease (ie, carcinomatosis)
DX
percutaneous core biopsy or aspiration biopsy.
Fine-needle aspiration
A negative result therefore does not rule out malignant

disease
In patients with cirrhosis, the presence of a hypervascular

mass > 2 cm on two different imaging studies or a
hypervascular mass > 2 cm on one imaging study combined
with a serum alpha-fetoprotein level > 400 ng/mL is dx of
HCC
Tumor Marker - AFP

hepatomas and testicular tumors.
upper limit of normal is 20 ng/mL;
values above 200 ng/mL are suggestive of
hepatoma
>400 ng/mL in a cirrhotic patients with a
hypervascular liver mass > 2 cm in diameter are dx.
METASTATIC NEOPLASMS
20 times more common than primary tumors in the

liver
via the systemic or portal venous circulation
colon, pancreas, esophagus, stomach,
neuroendocrine, breast, lung, kidney, adrenal, ovary
and uterus, melanoma, and sarcomas
Tx: most > chemotherapy is the only treatment option
most effective therapy
minimal criteria
disease confined to the liver

disease amenable to a complete resection.
For small and peripherally placed lesions, sublobar,

segmental resections are preferred
Anatomical segmentectomies are preferred to nonanatomical resections.
cirrhosis constitutes the major obstacle to resection in

patients with HCC.
Careful patient selection
cirrhotic patients have a late risk of death
highly selected patients may be better treated with liver

transplantation rather than resection.
Metastasis
Direct invasion
Lymph node dissemination
Blood spread
Intraperitoneal colonization
LIVER FAILURE

the US.


Liver Failure
Mackay Memorial Hospital
Department of Internal Medicine
Division of Gastroenterology
R4
97/6/22
Liver failure:
Clinical syndrome: sudden loss of
liver
parenchymal and metabolic function
Manifest as coagulopathy and
encephalopathy

Defined as interval between onset of the illness and
appearance of encephalopathy < 8 weeks
Etiology:
Western countries: heterogenous, drugs
(acetaminophen, NSAID), viruses
Developing countries: viruses, regional
Difference (endemic area ?)
Journal of Gastroenterology and Hepatology(2002)17,

S268S273
Acetaminophen toxicity
Idiosyncratic drug toxicity
Hepatotropic viruses
Miscellaneous causes
Indeterminate acute liver failure (viruses can not be
demonstrated ? )
Uncommon causes:
Wilsons disease, other infections (CMV, HSV,
EBV), vascular abnormality, toxin, acute fatty liver
of pregnancy, antoimmune hepatitis, ischemia,
malignant infiltration
Symptoms and signs:

Jaundice, altered mental status, nausea/
vomiting, anorexia, fatigue, malaise,
myalgia/arthralgia
Most of them present hepatoencephalopathy
and icteric appearance.
Hypoglycemia
Encephalopathy
Infections
Hemorrhage
Coagulopathy
Hypotension(hypovolemia, vascular resistance )
Respiratory failure
Renal failure
Pancreatitis
Hypoglycemia: monitoring blood glucose, IV glucose

supplement.
Infection: aseptic care, high index of suspicion,
preemptive antibiotic.
Hemorrhage (i.e. GI): NG placement, H2 blocker or
PPI.
Hypotension: hemodynamic monitoring or central
pressures, volume repletion
Respiratory failure (ARDS): mechanical ventilation.

Renal failure (hypovolemia, hepatorenal syndrome,
ATN): hemodynamic monitor, central pressure,
volume repletion, avoid nephrotoxic agent
Encephalopathy
major complication
precise mechanism remains unclear
Hypothesis: Ammonia production
Treatment toward reducing ammonia production
Watch out airway, prevent aspiration
Encephalopathy
Stage 1: day-night reversal, mild confusion,
somnolence
Stage 2: confusion, drowsiness
Stage 3: stupor
Stage 4: coma
Encephalopathy
Predisposing factor of hepatic encephalopathy:
GI bleeding, increased protein intake, hypokalemic
alkalosis, hyponatremia, infection, constipation,
hypoxia, infection, sedatives and tranquilizers
Encephalopathy
TX upon ammonia hypothesis
Correction of hypokalemia
Reduction in ammoniagenic substrates: cleansing
enemas and dietary protein restriction.
Lactulose: improved encephalopathy, but not
improved outcome.
Dose 2-3 soft stools per day
Encephalopathy
Oral antibiotics: neomycin lack of evidence
nephrotoxicity limited use.
Cerebral Edema
Cerebral edema develops in 75 - 80 % of patients
with grade IV encephalopathy.
precise mechanism : not completely understood
Possible contributing factor:
osmotic derangement in astrocytes
changes in cellular metabolism
alterations in cerebral blood flow
Cerebral Edema
intracranial pressure (ICP) and brainstem
Herniation the most common causes of death
in fulminant hepatic failure
ischemic and hypoxic injury to the brain
hypertension, bradycardia, and irregular
respirations, muscle tone, hyperreflexia
Cerebral Edema
Monitoring of ICP:
routinely used by more than one-half of liver
transplantation programs in the United States
Tx: to maintain ICP below 20 mmHg and the CPP
above 50 mmHg.
Coagulopathy
diminished capacity of the failing liver to synthesize
coagulation factors.
The most common bleeding site: GI tract.
Prophylactic administration of FFP: not
recommended.
performed before transplant or invasive procedure
Specific Treatment
ACT intoxication: charcol followed by NAC
Drug induced hepatotoxicity: discontinue drugs
supportive treatment
Viral hepatitis:
HBV: anti-HBV treatment, lamivudine
HSV/varicella zoster: acyclovir
others: supportive care
Wilsons disease: early diagnosis liver transplant

autoimmune hepatitis: confirm diagnosis (liver
biopsy), corticosteroid liver transplant
acute fatty liver of pregnancy or the HELLP
syndrome: obstetrical services, and expeditious
delivery are recommended
Acute ischemic injury (shock liver): cardiovascular

support
Malignant infiltration: liver biopsy for diagnosis
treat underlying disease.
Indeterminate etiology: consider biopsy for diagnosis
and further guide of treatment
Liver transplant
Liver transplant: remain backbone of treatment of
fulminant hepatic failure
reliable criteria to identify these patients who really
need transplant.
remain unresolved in fulminant hepatic failure.
At Kings College hospital in London (not due to ACT)

either PT>100 second
or the presence of any three of the following variables:
1. age < 10 or > 40 years ;
2. an etiology of non-A, non-B hepatitis, halothane,
drug induced liver failure;
3. duration of jaundice before onset of encephalopathy
> 7 days, prothrombin time >50 s, and serum
bilirubin > 300 mmol/L.
Encephalopathy
Coagulopathy (PT)
Liver transplant
Criteria:
In chronic liver disease
most commonly used prognostic model
MELD score (Model for End-stage Liver
Disease )
3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR]
+ 9.6[Ln serum creatinine (mg/dL)] + 6.4
Ln: natural logarithm.
Liver transplant
1.
2.
3.
CONTRAINDICATIONS:
Cardiopulmonary disease can not be corrected, or
preclude surgery.
Malignancy outside of the liver within 5 years of
evaluation, or can not be cured.
Active alcohol and drug use
Advanced age and HIV disease: relative contraindication (site-specific management)

Non-cell-based: plasmapheresis and charcoal-based
hemoabsorption
Cell-based systems : known as bioartificial liver
support systems

Non-cell-based: not improved survival.
Available systems:
molecular adsorbents recirculation system (MARS)
Cell-based systems: undergoing trial.
Acute Liver Failure

,
Foie Gras
Foie gras (pronounced /fwr/ in English; French
for "fat liver") is a food product made of the liver of a
duck or goose that has been specially fattened.
Functions of the Liver

Metabolic
Carb metabolism
Protein and lipoprotein metabolism
Fatty acid metabolism
Biotransformation of drugs
Storage
Glycogen
Vitamins A, D, E, and K
Iron and copper
Functions of the Liver

Immunological function s
Synthesis of immunoglobulins
Phagocytosis by Kupffer cells
Filtration of bacteria
Degradation of endotoxins
Excretion of bilirubin and urea formation

Haematological functions
Blood reservoir
Haematopoiesis in the foetus
ALF
Syndrome that leads to MOF and
death
o Previously
normal liver may fail within
days
High grade encephalopathy,

survival is <20%
Early death:
o cerebral
oedema, CVS collapse
Late death:
o
Definition and Classifications

ALF: Sd. defined by
o
o
o
o
Encephalopathy
Coagulopathy
Jaundice
Individual with previously normal liver

Fulminant Hepatic Failure
Potentially reversible condition
Consequence of severe liver injury
Encephalopathy appears within 8 wks. of
initial Sx.
o Absence of pre-existing liver ds.
o
o
o

Kings classification:
o
Hyperacute: encephalopathy within <7 days

Paracetamol, ischaemic, viral, toxins
o
o
Acute: 8-28 days

Subacute: 5-26 weeks
Seronegative, idiopathic, drug-related
Different etiology
Poorer prognosis
Etiology
Cause
Agent Responsible
Viral Hepatitis
Hep. A, B, D, E, CMV, HSV, seronegative

hepatitis (14-25% in UK)
Drug-related
Dose-related, e.g.paracetamol; idiosyncratic

reactions, e.g. anti-TB, statins, recreational
drugs, anticonvulsants, NSAIDs, many others
Toxins
Carbon tetrachloride, amanita phalloides
Vascular events
Iscahemic hepatitis, veno-occlusive disease,

Budd-Chiari, heatstroke
Other
Pregnancy-related liver disease, Wilsons

disease, lymphoma, carcinoma, trauma
Etiology
Most common causes:
o
Worldwide:
Hepatotrophic viruses A-E
UK
Paracetamol overdose
Seronegative or non-A-E hepatitis
Idiosynchratic drug rxs. or Wilsons ds.
Workup
Identify the etiology
o
Hx., examination, viral and autoimmune

profiles
Bloods
o
FBC, EUC, CMP, coags, LFTs, drug levels
Abdo USG and CT

o
Vascular pattern, ascitis, splenomegaly
Workup
Liver Bx.
o
o
o
o
o
Done by transjugular route

Mays suggest specific Dx.
Watch for sample from healthy liver
>50% necrosis assoc. with poor prognosis
Need to reverse coagulopathy before doing
it
Pathophysiology
o
alteration in mental status and cognitive function occurring in

the presence of liver failure
Liver failure leads to:

o
o
o
o
o
portal HTN
splachnic vasodilation
Hypoalbuminaemia
Reduced plasma oncotic pressure
Leads to ascitis and organ oedema
Pathophysiology
Decreased intravascular volume
o
Kidneys try to compensate and retain Na+

and water making oedema worse
Also,
Gut-derived toxins reach the liver
o
o
Ammonia levels are often high

Correlation between ammonia and
symptoms is poor
Clinical Features
Depend on the severity, which depends
on:
o
o
Etiology
Speed of onset of symptoms
Non-specific
o
N&V, abdo pain
Neurological
o
Confusion, agitation, coma
Scale Of Hepatic Encephalopathy

Grade
Level of Consciousness
Personality and Intellect
Neurologic Signs
Electroencephalogram
(EEG) Abnormalities
Normal
Normal
None
None
Subclin
ical
Normal
Normal
Abnormalities only on psychometric

testing
None
Day/night sleep reversal,

restlessness
Forgetfulness, mild confusion, agitation,

irritability
Tremor, apraxia, incoordination, impaired

handwriting
Triphasic waves (5 Hz)
Lethargy, slowed
responses
Disorientation to time, loss of inhibition,

inappropriate behavior
Asterixis, dysarthria, ataxia, hypoactive

reflexes
Somnolence, confusion
Disorientation to place, aggressive

behavior
Asterixis, muscular rigidity, Babinski

signs, hyperactive reflexes
Coma
None
Decerebration
Delta/slow wave activity
Clinical Features
Mortality is higher for Grade III/IV
o
o
Mostly due to cerebral oedema

Occurs in 80% of pts. w/ALF
Due to lack of equilibration of osmotic gradient
30% of those have cerebellar tonsil and/or
temporal lobe herniation causing death
Were now better at treating cerebral

oedema
Clinical Features
Elevated ICP
o
o
o
HTN, bradycardia, blown pupils: occur late

CTB wont tell you
ICP monitor is best way of knowing
CVS changes
o
o
Similar to sepsis
Might be due to infection
Clinical Features
Renal failure
o
o
Oliguric
Poor prognosis
Except with paracetamol overdose where it has
a good prognosis
Impaired immunity
o
Decreased complement synthesis, Kupffer

cell dysfunction, poor neutrophil adhesion
and superoxide production
Clinical Features
Increased susceptibility to infection
80% of pts. have bacteriologically proven
infections
o Major sepsis is contributor to death in 20%
of cases
o
Staph. aureus 70% of gram (+)

E. Coli most common gram (-)
C. albicans in 30% of pts.
Monitoring
Pts. need HDU/ICU
Need CVC and continuous IBP
monitoring and IDC
Baseline ABG and lactate
o
Lactate >3mmo/L after adequate resus has

same sensi. and speci. for death as The
Kings College Hospital criteria
Prognosis
Early indicators of prognosis in fulminant hepatic failure.
O'Grady JG, Alexander GJ, Hayllar KM, Williams R.
Gastroenterology. 1989 Aug;97(2):439-45.
Kings Collage Hospital Criteria
Originally devised as prognostic criteria to predict patient survival

without liver transplant
o Now used as selection criteria for potential liver transplant recipients
o
KCH Criteria
Patients with paracetamol
toxicity
pH <7.3 (7.25 if given NAC)
Or
all three of the following:
o Prothrombin time >100s
o Serum creatinine level >300
mol/l
o Grade III or
IVencephalopathy
o
Other patients
Prothrombin time >100

seconds or
Three of the following
variables:
o Age <10 yr or >40 yr
o Jaundice >7 days before
encephalopathy
o PT > 50s
o Bilirubin > 300mmol/L
KCH Criteria
Positive predictive value for ICU death without
transplantation of 0.98
Negative predictive value of 0.82
Treatment
Intensive care of patients with acute
liver failure: recommendations of the
U.S. Acute Liver Failure Study
Group.
Stravitz RT, Kramer AH, Davern T, Shaikh AO,
Caldwell SH et al.
Critical Care Medicine 2007; 35: 2498-508
Treatment
Adult U.S. Acute Liver Failure Study
Group
o
Data from
23 liver transplant centers
>1,110 pts.
In 2005 convened to
review literature on management
Care of pts. w/high ICPs
Compare practices of different centers
General Management
Admit to hospital and HDU/ICU
o
When evidence of ALF

E.g.: INR>1.5
D/W:
Physician
Intensivist
Nearest transplant center
Regarding best time to refer
General Management
Etiology-specific treatment
o
o
Studies only for paracetamol overdose

NAC regardless of time of overdose
IV if Grade I encephalopathy
Hypotension
Any other reason PO NAC is not tolerated
HELLP or acute fatty liver of pregnancy

Tx. Is immediate delivery
General Management
NAC
o
o
o
150mg/kg IV in 200ml NS over 15-60mins

50mg/kg IV over 4hrs
100mg/kg IV over 16hrs
Total dose: 300mg/kg over 20hrs
Infusion recommended until there is

evidence of improved hepatic function
rather than time or paracetamol levels
Management of Complications
Hepatic encephalopathy and hyperammonaemia

Infections
Sedation and analgesia
Bleeding diathesis
Nutrition
Seizures
Circulatory dysfunction
Encephalopathy
Standard treatment:
o
Lactulose
Watch for:
Abdo distension
Oesophageal varices will need a scope
Avoid intravascular depletion
Non-absorbable ATBs
Neomycin not recommended by ALFSG
because of nephrotoxicity
Infection prophylaxis and surveillance

Infection is one of main causes of death in ALF
Most common sites:
o
o
o
Lung
Urinary tract
Blood
Most common M.O.

o
o
o
Gram (+) cocci: Staph aureus

Gram (-) rods: E. coli
Fungi: candida
Infection prophylaxis and surveillance

Empirical ATBs are recommended by ALFSG when:
o
o
o
o
Surveillance cultures reveal significant isolates

Advanced stage (III/IV) encephalopathy
Refractory hypotension
SIRS
3rd gen. Cephalosporin or Timentin, Vancomycin, Fluconazole
Sedation and analgesia

Agitation contributes to raised ICP
Propofol vs. Benzos
Both increase GABA neurotransmission, therefore may exacerbate
encephalopathy
o Propofol decreases ICP and wears off quickly
o
Opioids
o
o
Shorter acting are preferable

When there is concommitant ARF, avoid morphine or pethidine due
to metabolite accumulation
Correction of bleeding diathesis

Pts. with ALF are by definition coagulopathic
o
o
Low plts. and fibrinogen, Vit. K deficient

Spontaneous bleeding is rare
Very difficult to obtain complete correction

ALFSG recommends aiming for:
o
o
INR 1.5
Plts. 50,000

Prophylactic FFP not recommended
o
Obscures the trend of PT as prognostic marker
Cryo recommended when fibrinogen low

When FFP fails to correct PT/INR, then recombinant factor VIIa
can be given
o
o
Should be given before planned procedures

Avoid in patients with risk of thrombotic complication
MI, DVTs, etc.

UGI bleeding
o
reduced by H2 antagonists or PPIs
TEDS and Scuds
Nutrition
ALF is a catabolic state
o
o
Negative nitrogen balance

Immunodeficiency
Enteral nutrition when possible

o
o
Hi-cal
Avoid free water and hypo-osmolarity
TPN when:
o
Specific contraindication for enteral feeds
Seizure Prophylaxis and Surveillance

Nonconvulsive seizure activity is common
o
o
Prophylactic antiepileptics not recommended

EEG when:
Tx.
o
o
Grade II/IV encephalopathy

Sudden neuro deterioration
Myoclonus
To titrate use of barbiturates
Phenytoin
Propofol, midaz, barbiturates
CVS Dysfunction
Correct hypovolaemia before starting vasopressors
Pressors needed for hypotension and low CPP
o
o
o
Norad is first line, can give high dose dopamine

Adrenaline may compromise HBF
Vasopressin not recommended because directly causes cerebral
vasodilation and high ICPs
Medium doses of steroid may improve pressor response
Mx. of Cerebral Oedema and

Intracranial Hypertension
Raised ICP due to cerebral oedema is
one of major causes of M&M
CTB for Grade III/IV
o
To rule out anything else, i.e. bleed
ICP monitor
o
o
o
Grade III/IV encephalopathy

To optimize CPP
Not routine
Raised ICP
Aim for
o
o
ICP<25mmHg
CPP 50-80
General recommendations
Keep it quiet , minimize chest physio and
ETT suctioning, head at 30o
o Dont treat spontaneous hyperventilation,
keep PaCO2 35-40mmHg, treat fever
aggressively with physical measures
o
Raised ICP
Specific management
o
o
o
o
o
Manitol: first line therapy

Hypertonic Saline
Induced hypothermia
Barbiturate coma
Indomethacin: 25mg IV over 1min.
Mechanical Ventilation
When to intubate:
Respiratory failure
Airway protection in advanced
encephalopathy
o Agitation
o Imminent ICP monitor placement
o
o
Mechanical Ventilation
Pts. w/ALF often develop ALI/ARDS
o
o
Follow ARDSNet protocol

Avoid high PEEP
Use the minimum needed
CRRT
Indicated for:
o
o
o
o
Renal failure
Fluid overload
Metabolic derangements
Need to create space for IV colloids, i.e.
FFP
CRRT preferred over IRRT

o
HD instability common
CRRT
Use citrate over heparin
o
Monitor ionized calcium
Use bicarb buffer over lactate or citrate

buffer
o
Liver wont be able to convert them to

HCO3-
Avoid hyponatraemia
o
May exacerbate cerebral oedema
Liver Transplant
Orthotopic liver transplant is the definitive treatment
for patients who meet the criteria
orthotopic (rth-tpk)adj.In the normal or usual position
1 yr. and 5 yr . survival of patients undergoing OLT for

ALF is about 20% lower than elective cases for
cirrhotic patients
Auxiliary liver transplantation is and alternative
Liver Transplant
Absolute contraindications
Overwhelming sepsis
Refractory hypotension
AIDS
Uncontrolled raised ICP with likely permanent damange
Hepatic assist devices

MARS: molecular absorption and recirculation
system
Adaptation of haemodialysis
Blood is dialysed against 20% albumin
Shown to improve encephalopathy, renal function and
haemodynamic parameters
The efficacy of this technique has not yet been studied
So, what have we learned?
Thank you!
HEPATOCELLULAR CARCINOMA
Epidemiology
Hepatocellular carcinoma is the 5th most common
malignancy worldwide & the 3rd cause of cancer related
death with male-to-female ratio
5:1 in Asia
2:1 in the United States
Tumor incidence varies significantly, depending on

geographical location.
HCC
with age.
53 years in Asia
67 years in the United States.
Incidence of HCC
Etiology
Hepatitis B
-increase risk 100 -200 fold

- 90% of HCC are positive for
(HBs Ag)
Hepatitis C
Cirrhosis
- 70% of HCC arise on top

of cirrhosis
Incidence according to etiology
Abbreviations: WD, Wilsons disease; PBC, primary biliary cirrhosis, HH, hereditary hemochromatosis;
HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.
Signs & symptoms
Nonspecific symptoms
abdominal pain
Fever, chills
anorexia, weight loss
jaundice
Physical findings
abdominal mass in one third

splenomegaly
ascites
abdominal tenderness
Guidlines
(a)
which patients are at high risk for the development of HCC

and should be offered surveillance
(b) what investigations are required to make a definite

diagnosis
(c) which treatment modality is most appropriate in a given
clinical context.
Guidlines
(a) which patients are at high risk for
the development of HCC & should be
- M &F with established cirrhosis due to HBV and/ or HCV, particularly those with
ongoing viral
replication
offered
surveillance
- M &F with established cirrhosis due to genetic haemochromatosis
- M with alcohol related cirrhosis who are abstinent from alcohol or likely to
comply with treatment
- M with primary biliary cirrhosis
Abdominal US and AFP/ 6

months
Diagnosis
(b) what investigations are required to make a definite diagnosis
1)
AFP produced by 70% of HCC

> 400ng/ml
AFP over time
2)
Imaging
- focal lesion in the liver of a patient with cirrhosis is highly
likely to
be HCC
- Spiral CT of the liver
- MRI with contrast enhancement
Diagnosis
3) Biopsy is rarely required for diagnosis

seeding
in 13%.
Biopsy of potentially operable lesions
should be avoided where possible
Diagnosis
Cirrhosis +
Mass > 2 cm
Raise
d
AFP
Confirmr
d
Nor
mal
AFP
CT,
MRI
Diagnosis
Cirrhosis + Mass <
2 cm
Raise
d
AFP
Assess for
surgery
Confirmed
diagnosis
Normal
AFP
CT, MRI
lesion by exam
FNAC or biopsy
Treatment (Surgery)
The only proven potentially curative therapy for HCC
Hepatic resection or liver transplantation
Patients with single small HCC (5 cm) or up to three lesions 3 cm
Involvement of large vessels (portal vein, Inferior vena cava) doesnt

automatically mitigate against a resection; especially in fibrolamellar
histology
No randomised controlled trials comparing the outcome of surgical

resection and liver transplantation for HCC.
Treatment (Surgery)
Hepatic resection should be considered in HCC and a non-cirrhotic

liver (including fibrolamellar variant)
Resection can be carried out in highly selected patients with

cirrhosis and well preserved hepatic function (Child-Pugh A) who are
unsuitable for liver transplantation. It carries a high risk of
postoperative decompensation.
Perioperative mortality in experienced centres remains between 6%

and 20% depending on the extent of the resection and the severity of
preoperative liver impairment.
The majority of early mortality is due to liver failure.
Treatment (Surgery)
Recurrence rates of 5060% after 5 years after resection are usual

(intrahepatic)
Liver transplantation should be considered in any patient with

cirrhosis
Patients with replicating HBV/ HCV had a worse outlook due to

recurrence and were previously not considered candidates for
transplantation.
Effective antiviral therapy is now available and patients with small

HCC, should be assessed for transplantation
should only be used where surgical therapy is not possible.
1) Percutaneous ethanol injection (PEI)
has been shown to produce necrosis of small HCC.

It is best suited to peripheral lesions, less than 3 cm in
diameter
2) Radiofrequency ablation (RFA)
High frequency ultrasound to generate heat

good alternative ablative therapy
No survival advantage
Useful for tumor control in patients awaiting liver transplant
3) Cryotherapy
intraoperatively to ablate small solitary tumors outside a

planned resection in patients with bilobar disease
4) Chemoembolisation
Concurrent administration of hepatic arterial chemotherapy

(doxirubicin) with embolization of hepatic artery
Produce tumour necrosis in 50% of patients
Effective therapy for pain or bleeding from HCC
Affect survival in highly selected patients with good liver

reserve
Complications: (pain, fever and hepatic decompensation)
5) Systemic chemotherapy
very limited role in the treatment of HCC with poor
esponse rate
Best single agent is doxorubicin (RR: 10- 20%)
Combination chemotherapy didnt
response but
survival
should only be offered in the context of clinical trials
6) Hormonal therapy
- Nolvadex, stilbestrol and flutamide
7) Interferon-alfa
8) retinoids and adaptive immunotherapy (adjuvant)
Targeted therapy for HCC
Name
Selection of agents for targeted

therapy in HCC
Gefitinib
Erlotinib
Lapatanib
Cetuximab
Bevacizumab
Sorafenib (Nexavar)
Sunitinib
Vatalanib
Cediranib
Rapamycin
Everolimus
Bortezomib (Velcade)
Target
EGFR
EGFR
EGFR
EGFR
VEGF
Raf1, B-Raf, VEGFR , PDGFR
PDGFR, VEGFR, c-KIT, FLT-3
VEGFR, PDGFR, c-KIT
VEGFR
mTOR (mammalian target of rapamycin)
mTOR
Proteasome
Targeting angiogenesis for HCC
HCC is one of the most vascular tumor
Major driver of angiogenesis is vascular endothelial growth

factor (VEGF)
Sorafenib and bevacezumab target VEGF in HCC
Bevacizumzb: Median OS of approximately 12 months

Bevacizumab + erlotinib: Medain OS 15-17 months
Investigational combination therapies

in HCC
Combinations under investigations
Bevacizumzb + erlotinib
Sorafenib +erlotinib
Combination therapy will likely be used to treat HCC

in the future
HCC (Whats ahead?)

Combinations therapy
Bevacizumzb or Sorafenib + Erlotinib
Sorafenib + mTOR inhibitor
Early sequential therapies

Bucuresti
Liver Disorders
Disorders and Biliary Tract Disease
Lecture III
Prof Univ Dr Ion C. intoiu
GASTROENTEROLOGY
772
Gallbladder
Disorders
ANATOMY &
PHYSIOLOGY
BILIARY SYSTEM
a. Canaliculi the smallest bile ducts located
between liver lobules, receive bile from
hepatocytes. The canaliculi form larger bile
ducts, which lead to hepatic duct.
b. Hepatic duct from the liver joins the cystic
duct from the gallbladder to form the common
bile duct, which empties into the duodenum.
c. Sphincter of Oddi controls the flow of bile
into the intestine.
d. Gallbladder is a hollow pear-shaped organ
that is 30-40mm long. Normally holds 30-50mL
of bile and can hold up to 70mL when fully
distended.
BILIARY SYSTEM
Draining bile from hepatocytes to

the gallbladder by way of biliary tree
Storing bile in the gallbladder and
releasing it to the duodenum, which
is mediated by the hormone
cholecystokinin-pancreozymin.
The Gallbladder
Located below the liver
The cystic duct joins the hepatic
duct to become the bile duct
The common bile duct joins the
pancreatic duct in the sphincter of
Oddi in the first part of the
duodenum
Stores and concentrates bile

Contracts during the digestion of
fats to deliver the bile
Cholecystokinin is released by the
duodenal cells, causing the
contraction of the gallbladder and
relaxation of the sphincter of Oddi
CHOLELITHIASIS
Refers to formation of calculi (ie,

gallstones in the bladder.
Predisposing Factors:
1. Obese
2. Female
3. >40 yrs
4. OC, Estrogen, intake
5. Fair
CHOLELITHIASIS
Supersaturated bile, Biliary stasis
Stone formation
Blockage of Gallbladder
Inflammation, Mucosal Damage and WBC
infiltration
CHOLECYSTITIS
Common locations of gallstones
Gall Stones
CHOLECYSTITIS
inflammation of gallbladder with
gallstone formation.
CHOLECYSTITIS/
CHOLELITHIASIS
Signs and Symptoms:
Severe Right abdominal pain radiating to
the back
Fever
Fat intolerance
Anorexia, n/v
Jaundice
Pruritus
Easy bruising
Tea colored urine
Steatorrhea
CHOLECYSTITIS/
CHOLELITHIASIS
Diagnosis:
US detects the presence of gallstone
Serum alkaline phosphatase 50120 u/L
WBC
Endoscopic retrograde
cholangiopancreatography (ERCP) -
CHOLECYSTITIS/
CHOLELITHIASIS
Nursing Management:
Administer Rx Medications
Diet increase CHO, moderate CHON,
decrease fats
Meticulous skin care
Instruct patient to AVOID HIGH- fat diet
and GAS-forming foods
Assist in surgical and non-surgical
measures
ESWL non-invasive fragmentation of
stones by using repeated shockwaves
directed at the gallstones in the
gallbladder or common bile duct.
CHOLELITHIASIS/CHOLECYSTITI
S
Surgical procedures- Surgical

Cholecystectomy, Choledochotomy,
Laparoscopic cholecystectomy
CHOLELITHIASIS/CHOLECYSTI
TIS
Post-operative nursing interventions
1. Monitor for surgical complications

2. Post-operative position after recovery from
anesthesia- LOW FOWLERs
3. Encourage early ambulation
4. Administer medication before coughing and
deep breathing exercises
5. Advise client to splint the abdomen to
prevent discomfort during coughing
6. Administer analgesics, antiemetics,
antacids
7. Care of the biliary drainageor T-tube
drainage
8. Fat restriction is only limited to 4-6 weeks.
Normal diet is resumed
Thank you

Bucuresti
LECTURE V
GASTROENTEROLOGY
792
PATHOLOGY OF THE
PANCREAS
1
II. Detailed Anatomy

A. Landmark structures
1. Splenic Artery:
a. Branch of celiac
trunk
b. passes right to
left
c. Course is along
upper margin of
body and tail
Arterial Supply to Pancreas
Proper Hepatic
Artery
Common
Hepatic Artery
Superior
Mesenteric
Artery
Detailed Anatomy continued

. Head of Pancreas
. Head , Body and Tail of Pancreas

1. Important clinically because:
a. Numerous ducts and vessels traverse it
b. Carcinoma usually located here
Duct of Wirsung (Main pancreatic duct)
DISEASES OF THE
PAN C R E AS
Congenital anomalies:
Agenesis, hypoplasia, ectopia, duct anomalies
Exocrine pancreas:
Cystic fibrosis
Acute pancreatitis
Carcinoma of the pancreas
Endocrine pancreas:
Diabetes mellitus
Islet cell tumors
IV. Pancreatic Disorders

A. Pancreatitis: diagnosis depends on
clinical evidence
1. Usually secondary to biliary tract
disease
2. Surgery of biliary tract or stomach

alcoholism are other causes
ACUTE PANCREATITIS
Inflammation of the pancreas, which is almost always

associated with acinar cell injury
A clinical & histologic spectrum of severity & duration
Etiologic factors:
1) Metabolic: alcohol, hyperlipoproteinemia,
hypercalcemia, drugs (e.g. thiazides), genetic
2) Mechanical: gallstones, traumatic & perioperative
injury
3) Vascular: shock, atheroembolism, polyarteritis
nodosa
4) Infections: Mumps, Coxsackie virus, Mycoplasma
5) Idiopathic : 10-20% ; ? Genetic basis
ACUTE PANCREATITIS
Pathology:
4 basic alterations:
1) Proteolytic destruction of pancreatic substance
2) Necrosis of blood vessels & interstitial
hemorrhage
3) Fat necrosis by lipolytic enzymes
4) Associated acute inflammatory reaction
Pathologic lesions:
a. Acute pancreatic necrosis
b. Acute hemorrhagic pancreatitis
c. Suppurative peritonitis
d. Pancreatic pseudocysts
ACUTE PANCREATITIS
Pathogenesis:
Autodigestion of pancreatic tissue by inappropriately

activated pancreatic enzymes
Trypsin has a major role:
a. Activates other proenzymes (proelastase
,prophospholipase )
b. Converts prekallikrein to kallikrein (Kinin system)

c. Hageman factor is activated
Mechanisms of pancreatic enzyme activation:
1) Pancreatic duct obstruction
2) Primary acinar cell injury
3) Defective intracellular transport of proenzymes
within acinar cells
ACUTE PANCREATITIS
Clinical features:
Abdominal pain is the cardinal manifestation:
epigastric, radiating to back, variable in severity
Shock: due to pancreatic hemorrhage & release
of vasodilatory agents (BK & PGs)
Lab: serum amylase and lipase; Ca;
bilirubin, glucose & glycosuria
CT scan: inflammation, pseudocysts
Px: severe cases have high mortality rate (20-40%)
Death due to: 1) shock, 2) secondary abdominal
sepsis, 3) adult respiratory distress syndrome
Repeated bouts of mild to moderate pancreatic
inflammation, with continued loss of pancreatic
parenchyma & replacement by fibrous tissue
Distinction from acute pancreatitis may be difficult;
distinction is made if there is evidence of previous
attacks
Middle-aged men, mostly in alcoholics but may due
to biliary tract disease, hyperlipoproteinemia &
hypercalcemia; no apparent cause in 50% of cases
Pathogenesis:
Protein hypersecretion from acinar cells
Precipitation of proteins forming ductal plugs
Plugs enlarge forming laminar aggregates
Pathology:
Hard organ with dilated ducts & calcified concretions
Fibrosis, chronic inflammatory cells, obstruction of
ducts by protein plugs
Extensive atrophy of exocrine glands
Pseudocysts
Clinical features:
Repeated attacks of abdominal pain or may be silent
Dx: clinical suspicion, lab & CT
Px: chronic disabling disease due to its major
complications: pancreatic insufficiency & diabetes
mellitus
D. Chronic Pancreatitis
1. organ usually appears as
small,
atrophic
2. Contains scattered echoes
from
calcifications
3. Primary cause is alcoholism
E. Dilation of Pancreatic Duct

1. Seen in acute or chronic
pancreatitis
2. Frequently associated with
neoplasm of pancreas
3. Biliary tract problems
F. Abscess or Hemorrhagic Pancreatitis

1. Similar in sonographic appearance
2. Hemorrhagic:
a. Mass with inhomogeneous texture
b. Acute hemorrhage: sonolucent to
echogenic
c. CT scan used for differentiation
G. Pancreatic Tumors
1. Malignant tumors usually arise

as adenocarcinomas
2. In head of Pancreas: Sx
a. Painless jaundice
b. Anorexia
Pancreatic Tumors, In head, continued
c. Nausea
d. Weight loss
e. Increased plasma amylase
f. Increased alkaline phosphatase
g. May involve compression of
pancreatic duct, CBD
Pancreatic Tumors in the Head
Tumors in the head

may compress
biliary ducts or
pancreatic ducts
3. In Body of Pancreas: Sx
a. Gnawing pain radiating to back
b. Pain increases after eating or
lying down
c. Weight loss, anorexia
d. Large tumor may compress
IVC,
portal vein
Pancreatic tumors,
continued
4. In Tail of
Pancreas: Sx
a. Often silent until
local
metastasis occurs
b. May metastasize to:
1. para-aortic lymph
nodes
2. spleen
5. Identified by organ enlargement,

subtle echo changes, irregular outline
6. Metastases to stomach, liver & lungs
are common
7. Often causes dilation of ducts
H. Fibrocystic Disease
1. Result of cystic fibrosis
2. Diagnosed by methods other than
ultrasound
I. Pancreaticolithiasis
1. Characteristic stone echoes in pancreatic
duct
2. May see atrophied pancreatic parenchyma
3. Associated with chronic alcoholic
pancreatitis
4. Contours of body, tail show irregularities
Pancreatolithiasis, continued
5. Incidence slightly higher in head

6. Associated with occult pancreatic
carcinoma
a. Mass < 2mm diameter
b. Seen with dilation of pancreatic
duct or CBD
FUNCTION/DYSFUNCTION OF
ENDOCRINE PANCREAS
Diabetes
823
824
Endocrine Function :
Cells of the Islet of Langerhans
synthesize and release hormones into
the circulation.
Hormones travel through the bloodstream
to target tissues (especially liver and
muscle)
At the target cells, hormones bind specific
receptors and cause cell changes that
control metabolism
825
826
Pancreatic endocrine cells regulate

carbohydrate, fat, protein metabolism:
Alpha cells secrete the hormone
glucagon
Beta cells secrete the hormones insulin
and amylin
Delta cells secrete the hormones
gastrin and
somatostatin
F cells - secrete hormone pancreatic
polypeptide
827
Beta Cells
Synthesize pre-proinsulin, a protein
This is cleaved by enzymes proinsulin,
then cleaved again insulin
Insulin is the biologically active hormone
that is released into the bloodstream
828
Insulin secretion is controlled

through several mechanisms:
Chemically high levels of glucose and amino acids
in the blood
Hormonally beta cells are sensitive to several
hormones that may inhibit or cause insulin secretion
Neurally stimulation of the parasympathetic
nervous system causes insulin to be secreted.
829
Insulin secretion is decreased by:

Decreased blood glucose
concentration
Increased blood insulin
concentration
Sympathetic stimulation
830
Insulin
Transported through the blood to target tissues where
it binds to specific receptors
The binding of insulin to target cells:
Acts as a biochemical signal to the inside of the cell
Overall, cell metabolism is stimulated

There is increased glucose uptake into the cell
Regulation of glucose breakdown within the cell
Regulation of protein and lipid breakdown within
the cell
831
Blood glucose is decreased because insulin causes

glucose to leave the bloodstream and enter the
metabolizing cells.
With the exception of brain, liver and erythrocytes,
tissues require membrane glucose carriers.
832
Disorder Diabetes mellitus

The single most common endocrine disorder group
of glucose intolerance disorders
Incidence is estimated at 1-2% of the North American
population
Many of these cases are undiagnosed
833
Diabetes mellitus
Historically distinguished by weight
loss, excessive urination, thirst, hunger
Excessive urination = polyuria
Excessive thirst = polydipsia
Excessive hunger = polyphagia
Modern characterization is by
hyperglycemia and other metabolic
disorders
834
Modern classifications (Table17.7)

Type 1 or IDDM Insulin Dependent Diabetes
Mellitus
Type 2 or
NIDDM NonInsulin Dependent Diabetes
Mellitus
Other Types of Diabetes Mellitus
GDM Gestational Diabetes Mellitus
835
Glucose in urine- Because when insulin is not present,
glucose is not taken up out of the blood at the target
cells.
So blood glucose is very highly increased increased
glucose filtered and excreted in the urine (exceeds
transport maximum)
836
Weight loss - Patient eats, but nutrients are not taken up
by the cells and/or are not metabolized properly
Osmotic diuresis results in fluid loss

Loss of body tissue by metabolism of fats and proteins
837
Polyuria, polydipsia, pholyphagia

Ketoacidosis
Fats and proteins are metabolized
excessively, and byproducts known as
ketone bodies are produced. These are
released to the bloodstream and cause:
Decreased pH (so increased acidity)
Compensations for metabolic
acidosis
Acetone given off in breath
838
Treatment
1. Administer insulin
May be of animal or human origin
Cannot be given orally
Patient must monitor their blood
glucose
concentration and
administer insulin with the correct
timing
839
2. Control diet
Carbohydrates should make up
about 55-60% of patients total
calories
Fats should make up <30% of
Proteins should make up about 1520% of
840
3. Monitor exercise
Remember: muscles are a target tissue of
insulin, and metabolize much glucose for
energy
Sometimes exercise irregular blood
glucose levels So diabetic patients should
be monitored when they are exercising
841
Other:
Pancreatic transplant so far not
successful
Experimental therapies not as
successful as hoped
842
Type 2 or NIDDM
More common than IDDM, often
undiagnosed
It has a slow onset
Most common in those > 40 years,
though children are being diagnosed
more regularly
May be genetic
Obesity is the greatest risk factor for
this disease
And is related to increased incidence
in children
843
NIDDM insulin resistance in target cells

See decreased cell responsiveness
Decreased insulin secreted by cells
Also abnormal amount of glucagon
secreted
844
These effects may be due to:

1.Abnormally functioning cells
2. Decreased cell mass,
or a combination of the two
3. Target cell resistance to insulin
Due to:
Decreased number of insulin receptors
Postreceptor events may be responsible
Cells burn out and become insensitive
845
Clinical manifestations
Overweight, hyperlipidemia common

(but these are precursors, not
symptoms)
Recurrent infections
Visual changes, paresthesias, fatigue
846
Treatment
1. Weight loss
2. Appropriate diet (see IDDM above)

3. Sulfonyl ureas
stimulate cells to increase insulin
secretion
Works only when cells are still
functioning
An enhancement of insulins effect
at target
cells
4. Exercise - promotes weight loss
847
Complications of Diabetes Mellitus

Acute:
Hypoglycemia = rapid decrease in plasma
glucose = insulin shock
Neurogenic responses probably due
to decreased glucose to
hypothalamus.
Symptoms include:
Tachycardia, palpitations, tremor,
pallor
Headache, dizziness, confusion
Visual changes
848
Treatment :
provide glucose (I.V. or subcutaneous if
unconscious)
Observe for relapse
849
Ketoacidosis involves a precipitating event:

Increased hormones released w/ trauma
increased glucose produced by the bodys cells
This antagonizes the effects of any glucose
present
Increased ketones in blood
Acid/base imbalance
Polyuria, dehydration
Electrolyte disturbances
Hyperventilation (Kussmaul deep,
gasping)
CNS effects
Acetone on breath
850
Treatment:
low dose insulin
Also, administer fluids, electrolytes
851
Chronic Complications of DM
Neuropathies = nerve dysfunctions
slowing of nerve conduction. In these
patients, see:
Degeneration of neurons
Sensory, motor deficits Muscle
atrophy, paresthesias
Depression
G.I. problems, as muscle motility
decreased
Sexual dysfunction
852
Microvascular disease chronic

diabetes w/ improper glucose
metabolism thickening of the
basement membrane of capillaries,
particularly in the eye and the kidney.
As the capillary changes in this way,
Decreased tissue perfusion
So ischemia hypoxia
853
In the eye the retina is metabolically quite

active, so hypoxia here is a big problem
So see:
Retinal ischemia
Formation of microaneurisms, hemorrhage,
tissue infarct, formation of new vessels,
retinal detachment
854
855
In the kidney diabetes is the most

common cause of endstage renal
disease
Injured glomeruli
(glomerulosclerosis)
In these patients, see:
Proteinuria (protein is excreted into
the urine) Generalized body
edema, hypertension
856
Macrovascular disease atherosclerosis

Plaque formation increases
Increased risk of coronary artery
disease, so increased risk of
myocardial infarction
Increased risk of congestive heart
failure
Stroke
Peripheral vascular disease
why diabetic patients face
problems with their lower legs and
feet
Increased risk of infections857
Endoscopic Stenting for

Pancreatic Diseases
1
Pancreatic Stents
Shape
Geenen - curve, multiple
side holes/distal flaps
Sherman - straight,
multiple side holes,
proximal flap/distal
pigtail
Modified Cotton-Leung
stent S-shaped with
distal flap
Size 3,5,7 or 10 Fr
Length 3,5,7,9,12 cm
Pancreatic Stents Design and

Application
Optimal design of stents
Size (small)
Material (soft)
Less irritation to ductal
epithelium
Migrate out
spontaneously
Common Indications
Acute pancreatitis
Drainage to prevent
post ERCP pancreatitis
Assist endoscopic
therapy
Papillotomy
Leaks
Malignancy
Drainage to relief pain
Adjuvant therapy for
stone and stricture
Technique of Pancreatic Stent

Placement
Deep cannulation
with guide wire
across papilla or
stricture
+ Pancreatic
papillotomy
Stent inserted
over wire and
positioned with
pusher
Post-ERCP Pancreatitis
Incidence
Most common
complication of
ERCP
Incidence 5-10%, 1%
severe, 0.1% fatal
Significant medical/
social/economic and
liability problem
Possible causes
Acinarization
overfilling
Hyperosmolarity /
contrast allergy
Trauma guide wire
Coagulation injury
Impaired drainage from
pancreas
Bacterial contamination
Bile contamination
Mechanism of Post ERCP

Pancreatitis
Papillary manipulation results in edema and sphincter
spasm obstructing PD flow, leading to intracellular
activation of enzymes
Improving drainage with PD stent may prevent post
ERCP pancreatitis
PD Stenting Prevents PEP in

SOD Pts
80 Pts with pancreatic SOD after biliary EST were
randomized to PD stent or no stent
10/39 (26%) with No stent
1/41 (2.4%) with Stent
2 Pts (7%) developed PEP after stent removal
Tarnasky
Gastroenterol
1998
PD Stenting for High Risk Patients

76 high-risk pts: SOM or difficult cannulation + EST were
randomized
10/36 (28%) with No stent (5 mild, 2 moderate, 3 severe)
2/38 (5%) with Stent (mild pancreatitis)
PD cannulation failed in 2/40 pts (5%)
Fazel GIE 2003
Is PD Stent Necessary for Every

ERCP?
Probably NOT
Increased time and difficulty
Increased risk
Increased cost
Risk of ductal changes from stent irritation
Need followup to insure stent migration
May need 2nd procedure for stent removal
Who Will Benefit from PD Stenting?

Patient Factors
Suspected SOD
Young female
Prior post-ERCP
pancreatitis
Normal serum bilirubin
Technical Factors
Difficult cannulation
Pre-cut sphincterotomy
Pancreatic
sphincterotomy
Ampullectomy
Balloon sphincteroplasty
Potential Risks of Pancreatic

Stenting
Risks
Failed stent placement
Proximal tip of stent
damages PD
Stent occlusion
causing pancreatitis
Chronic ductal
changes
Inward stent migration
Dilemma
To consider PD stent
placement in a highrisk patient is a serious
decision
If successful, risk of
PEP is reduced.
However, failed attempt
INCREASES the risks
Balloon Sphincteroplasty & Double

Stents
Double wires
Balloon
sphincteroplast
y
Double stents
for drainage
PD stent for
prophylactic
drainage
Pancreas Divisum
Minor Papillotomy with PD Stenting
Chronic Pancreatitis - Stone &

Stricture
EndoTherapy for Chronic

Pancreatitis
Less invasive than
surgery
Results comparable to
surgery
Surgery is still possible
after failed endotherapy
? Predicts outcome
after surgery
Dilation/Stenting of Pancreatic
Stricture
Guide wire (hydrophilic)
across stricture
Dilators
Graded dilators
Pneumatic balloons (4-6
mm)
Short-term pancreatic
stenting to insure drainage
Dilation of Tight PD Stricture with

Soehendra Stent Retriever
Dilation of Pancreatic Stricture

via Minor Papilla
Pancreatic Stone Extraction
Pancreatic sphincterotomy
.035 guide wire
Dilation of orifice/stricture
Stone extraction with wire
basket (e.g. 22Q)
? Mechanical lithotripsy
limitations
PD stent for drainage
ESWL to fragment large
(calcified) stone
Summary
Successful pancreatic stenting and drainage
prevents post ERCP pancreatitis
Pancreatic stenting is a useful adjunct for assisted
papillotomy
Pancreatic stenting provides drainage in patients
undergoing ESWL for stone obstruction
Stenting helps to improve stricture post dilation and
provides short term pancreatic drainage
Pancreatic
Neoplasm
1
Types of Pancreatic
Neoplasms
Broadly speaking, there are three basic

types:
Ductal adenocarcinoma >90% of
pancreatic cancers with a 4% 5-year
survival (worst of any cancer)
Neuroendocrine tumors aka isletcell tumors, rare
Cystic neoplasms account for <1% of
pancreatic cancers
Clinical Scenario #1
Pancreas
What are typical symptoms of pancreatic

CA?
Abdominal pain->pain can suggest neural

plexus, tail lesion, unresectability, poor
prognosis
Anorexia
Weight loss
Jaundice
Pruritis ->biliary obstruction
Steatorrhea->pancreatic duct obstruction
Risk Factors for Pancreatic

Cancer?
Firmly linked to cigarette smoking

No clear dietary factors
Increased BMI associated with
increased risk
Occupational exposures to amines
(chemistry, hairdressing, rubber
work) associated with increased risk
Pancreas: CT scan
CT can confirm pancreatic cancer with

a sensitivity of 85-95% (sensitivity is
limited by smaller tumor size)
Other than the presence of a pancreatic
mass, what else can you determine
from CT scan?
PRESENCE of METASTASES (along with

CXR)
RESECTABILITY
Pancreas: CT scan
What makes a pancreatic mass likely

resectable?
No evidence of extrapancreatic disease
Evidence of nonobstructive superior
mesenteric-portal vein confluence
No evidence of direct tumor extension to
the celiac axis and SMA
EUS, laparoscopy are universally regarded
as useful adjuncts to CT, not as essential
however
Pancreas: CT scan
Borderline Resectable lesions

include:
SMV occlusion of a short segment
(open vein proximally and distally)
Body and tail lesions with + celiac,
para-aortic nodes in the vicity
Tumors briefly involving the IVC
may be borderline
Pancreas: CT scan
Pancreatic Cancer:
Endoscopic Adjuncts
ERCP can be utilized to:
detecting small tumors not visualized on CT (irregular

solitary duct stenoses >1cm long, abrupt cutoff of
main pancreatic duct, or panc and bile duct
obstruction)
palliating biliary obstruction
brush cytology of the pancreatic duct has fair
sensitivity (70%) but excellent specificity
EUS can be utilized to:
aid in diagnosis and characterization of lesion

obtain tissue biopsy; may be associated with lower
risk of peritoneal seeding c/w percutaneous approach
Pancreatic Cancer:
Serum Markers
Is there a role for serum markers? If so,

what?
CA 19-9 is a sialylated Lewis A blood group antigen

commonly expressed and shed in pancreatic and
hepatobiliary disease, not tumor specific
This antigen, when significantly increased, can assist in
differentiating between pancreatic adenocarcinoma and
inflammatory pancreatic disease
decrease in serial CA 19-9 correlates with survival of
pancreatic patients after surgery or chemotherapy
Debatable as to whether this is useful as early treatment
of recurrences have not been shown to improve
outcomes
Pancreatic Cancer:
Neoadjuvant Therapy
This 70yo female has borderline

resectable features, has been stented
to answer obstructive jaundice via
ERCP with EUS demonstrating a
positive adenocarcinoma
Is there any role for neoadjuvant
therapy for this patient? If so, what
sort of regimen and with what
objectives?
Insulinoma
Whipples Triad:
Definitive test is 72-hour fast with

measurement of insulin and glucose
symptoms of hypoglycemia during fasting or exercise

serum glucose <45mg/dL during symptoms
relief of symptoms with administration of glucose
75% of patients develop symptoms and GB<40 within 24

hours
insulin:glucose ratio >0.4 is indicative of insulinoma
Elevated c-peptide proinsulin levels are

confirmatory along with screening for
antiinsulin antibodies, sulfonylureas
How are insulinomas

localized?
Non-invasive preoperative imaging

studies fail to localize 30-35% of
insulinomas
CT/MRI, etc. generally reserved by
most endocrine surgeons to r/o
hepatic metastases
Intraoperative U/S and palpation are
the GOLD standard for finding an
insulinoma, 96-100% sensitivity
What is proper operation

for insulinoma?
Generally wide Kocher maneuver, superior

and inferior pancreatic border mobilization,
medial reflection of the spleen
Bimanual palpation with U/S
Enucleation of the lesion
Secretin can assist in identifying pancreatic
duct leak after enucleation completed
What about lesion in pancreatic head?
Need to monitor glucose levels q15 minutes
until lesion out
LEARNING OBJECTIVES

Viral Hepatitis
Primary Biliary
Cirrhosis
Primary Sclerosing
Cholangitis
Hemochromatosis
Wilsons
Gallstones and
cholecystitis
Complications of end stage

liver disease
Ascites
SBP
Encephalopathy
LIVER FUNCTION TESTS
ALT
AST (SGOT)
ALKALINE PHOSPHATASE
BILIRUBIN
ALT and AST

Enzymes, found in Hepatocytes
Released when liver cells damaged
ALT is specific for liver injury
AST (SGOT) is also found in skeletal
and cardiac muscle
Transaminitis: < 5 x
normal
ALT predominant
Chronic Hep B / C
Acute A-E, EBV, CMV
Steatosis / Steatohep
Hemochromatosis
Medications / Toxins
Alpha-1-antitrypsin
Wilsons Disease
Celiac Disease
AST predominant
Alcohol-related liver dz
Steatosis/ Steatohep
Cirrhosis
Non-hepatic source
Hemolysis
Myopathy
Thyroid disease
Strenuous exercise
Severe AST & ALT Elev:

>15x
does not predict

outcome
Bili > 20 poor
prognosis
Ischemic Hepatitis
hypotension
sepsis
hemorrhage
MI
Wilsons Disease
Acute bile duct obstr
Hepatic Artery ligation
Budd-Chiari Syndrome
Medications /
Toxins
acetaminophen
CCl4
ALKALINE
PHOSPHATASE
Found in hepatocytes that line the bile

canaliculi
Level is raised in Biliary obstruction
(causes stretch of the bile canaliculi)
BUT also found in BONE and PLACENTA
GGT is also found in bile canaliculi and
therefore can be used in conjunction with
Alk Phos for predicting liver origin
BUT GGT can be raised by many drugs
including Alcohol and therefore non
specific
BILIRUBIN
Water insoluble product of heme

metabolism
Taken up by liver and conjugated to
become water soluble so it can be
excreted in bile and into bowel.
Patient looks Jaundiced if bilirubin >2.5
If patient is vomiting GREEN, then they
have bowel obstruction below the level of
the Ampulla of Vater.
WHAT IS THE DEAL WITH

DIRECT AND INDIRECT
BILIRUBIN?
Prehepatic disease (eg hemolysis)

causes high bilirubin which is non
conjugated ie. Indirect fraction higher
Hepatic disease causes increased
conjugated and unconjugated bilirubin
Post hepatic disease eg. Gallstones have
increased conjugated (direct) bilirubin
and lead to dark urine and pale stool.
So these are markers

of liver disease but
are they tests of liver
function?
NO!
TESTS OF LIVER
FUNCTION
PROTHROMBIN TIME/ INR

ALBUMIN
PROTHROMBIN
TIME/INR
Measure of the Vitamin K dependent

clotting factors ie. II, VII, IX and X.
The liver is involved in activating Vitamin
K. Therefore in liver damage, these clotting
factors cannot be produced.
Before you believe that prolonged INR is
due to liver disease just make sure the
patient has adequate Vitamin K by giving
10mg sc.
Giving Vitamin K has no effect on INR if
patient has impaired synthetic function.
ALBUMIN
Albumin has a half life of 21 days, so the

drop that occurs with hepatic dysfunction
does not occur acutely
That said, acute illness can cause albumin
to drop rapidly a process thought to be
due to cytokines increasing the rate of
albumin metabolism
HOWEVER, dont forget that low albumin
also occurs in NEPHROTIC syndrome, so
always check the urine for protein.
TYPICAL PATTERNS
HEPATOCELLULAR
Increased
transaminases
CHOLESTATIC
Viral Hepatitis
Drugs/alcohol
Autoimmune
NASH
Hemochromatosis
Increased Alk Phos and

Bilirubin
Also may cause
increased
transaminases
Gallstones
Primary Biliary
Cirrhosis
Sclerosing Cholangitis
Pancreatic C/a
AST > ALT

2:1 - 3:1 ratio
AST < 300
Why the discrepancy?
ETOH AST
synthesis
Vit B6 def inhibits
ALT
ETOH
Steatosis 90- 100%

hepatitis 10- 35%
cirrhosis
8- 20%
GGT
VIRAL HEPATITIS
All exam questions rely on you

understanding that acute infection
has IgM antibodies and chronic has
IgG
Viral Hepatitis
HAV
Incubation
Onset
Transmission
4 weeks
Acute
Fecal oral
HBV
4 12 weeks
HCV
7 weeks
HDV
4 12 weeks
Acute / insidious
Insidious
Acute / insidious
Parenteral ++
+
Perinatal ++
+
Sexual ++
+++
variable
+
+++
+
++
0.1 1 %
Neonates 90%
Adults 1-10%
0.1 %
Infect 80-90%
Hepatitis
70%
5 20 %
Common
HEV
6 weeks
Acute
Fecal - oral
Clinical
Fulminant
Progression to
chronicity
0.1 %
None
HCCancer
Prophylaxis
Immune globulin
Inactivated vacc
Immune globulin
Recombinan vacc
Therapy
NONE
IFN
Lamivudine
1 2%
None
NONE
HBV vaccine
NONE
Interferon
Ribavirin
Interferon +
None
HEPATITIS A
RNA Virus
Fecal-oral
Incubation 15-50 days
Anti -Hepatitis A IgM present during
acute illness.
TX/Prevention: Vaccine, Immune serum
globulin for contacts
Px: Good doesnt become chronic rarely
fulminant liver failure.
HEPATITIS B
DNA Virus
Consists of surface and core
Core consists of Core antigen and eantigen
Most infections are subclinical, but
can present with arthralgias,
glomerulonephritis, urticaria
Parenteral or sexual transmission.
Hepatitis B continued
Hepatocellular necrosis occurs due to the bodys

reaction to the virus rather than due to the virus
itself
Therefore patients who have a severe illness from
hep B are more likely to clear the virus.
SEROLOGY:
Remember Acute infection has IgM chronic has IgG

Anti Core IgM is present during acute phase
Anti Core IgG indicates chronic infection.
Patients with Hep B e Ag have continued active replication
Immunized or previously exposed people have Negative
HBsAg and HBeAg, they have IgG Anti HB Core, and
Positive anti Hep Bs and e.
LEARNING OBJECTIVES

Viral Hepatitis
Primary Biliary
Cirrhosis
Primary Sclerosing
Cholangitis
Hemochromatosis
Wilsons
Gallstones and
cholecystitis
Complications of end stage

liver disease
Ascites
SBP
Encephalopathy
LIVER FUNCTION TESTS
ALT
AST (SGOT)
ALKALINE PHOSPHATASE
BILIRUBIN
ALT and AST

Enzymes, found in Hepatocytes
Released when liver cells damaged
ALT is specific for liver injury
AST (SGOT) is also found in skeletal
and cardiac muscle
Transaminitis: < 5 x
normal
ALT predominant
Chronic Hep B / C
Acute A-E, EBV, CMV
Steatosis / Steatohep
Hemochromatosis
Medications / Toxins
Alpha-1-antitrypsin
Wilsons Disease
Celiac Disease
AST predominant
Alcohol-related liver dz
Steatosis/ Steatohep
Cirrhosis
Non-hepatic source
Hemolysis
Myopathy
Thyroid disease
Strenuous exercise
Severe AST & ALT Elev:

>15x
does not predict

outcome
Bili > 20 poor
prognosis
Ischemic Hepatitis
hypotension
sepsis
hemorrhage
MI
Wilsons Disease
Acute bile duct obstr
Hepatic Artery ligation
Budd-Chiari Syndrome
Medications /
Toxins
acetaminophen
CCl4
ALKALINE
PHOSPHATASE
Found in hepatocytes that line the bile

canaliculi
Level is raised in Biliary obstruction
(causes stretch of the bile canaliculi)
BUT also found in BONE and PLACENTA
GGT is also found in bile canaliculi and
therefore can be used in conjunction with
Alk Phos for predicting liver origin
BUT GGT can be raised by many drugs
including Alcohol and therefore non
specific
BILIRUBIN
Water insoluble product of heme

metabolism
Taken up by liver and conjugated to
become water soluble so it can be
excreted in bile and into bowel.
Patient looks Jaundiced if bilirubin >2.5
If patient is vomiting GREEN, then they
have bowel obstruction below the level of
the Ampulla of Vater.
WHAT IS THE DEAL WITH

DIRECT AND INDIRECT
BILIRUBIN?
Prehepatic disease (eg hemolysis)

causes high bilirubin which is non
conjugated ie. Indirect fraction higher
Hepatic disease causes increased
conjugated and unconjugated bilirubin
Post hepatic disease eg. Gallstones have
increased conjugated (direct) bilirubin
and lead to dark urine and pale stool.
So these are markers

of liver disease but
are they tests of liver
function?
NO!
TESTS OF LIVER
FUNCTION
PROTHROMBIN TIME/ INR

ALBUMIN
PROTHROMBIN
TIME/INR
Measure of the Vitamin K dependent

clotting factors ie. II, VII, IX and X.
The liver is involved in activating Vitamin
K. Therefore in liver damage, these clotting
factors cannot be produced.
Before you believe that prolonged INR is
due to liver disease just make sure the
patient has adequate Vitamin K by giving
10mg sc.
Giving Vitamin K has no effect on INR if
patient has impaired synthetic function.
ALBUMIN
Albumin has a half life of 21 days, so the

drop that occurs with hepatic dysfunction
does not occur acutely
That said, acute illness can cause albumin
to drop rapidly a process thought to be
due to cytokines increasing the rate of
albumin metabolism
HOWEVER, dont forget that low albumin
also occurs in NEPHROTIC syndrome, so
always check the urine for protein.
TYPICAL PATTERNS
HEPATOCELLULAR
Increased
transaminases
CHOLESTATIC
Viral Hepatitis
Drugs/alcohol
Autoimmune
NASH
Hemochromatosis
Increased Alk Phos and

Bilirubin
Also may cause
increased
transaminases
Gallstones
Primary Biliary
Cirrhosis
Pancreatic C/a
AST > ALT

2:1 - 3:1 ratio
AST < 300
Why the discrepancy?
ETOH AST
synthesis
Vit B6 def inhibits
ALT
ETOH
Steatosis 90- 100%

hepatitis 10- 35%
cirrhosis
8- 20%
GGT
VIRAL HEPATITIS
All exam questions rely on you

understanding that acute infection
has IgM antibodies and chronic has
IgG
HEPATITIS A
RNA Virus
Fecal-oral
Incubation 15-50 days
Anti -Hepatitis A IgM present during
acute illness.
TX/Prevention: Vaccine, Immune serum
globulin for contacts
Px: Good doesnt become chronic rarely
fulminant liver failure.
HEPATITIS B
DNA Virus
Consists of surface and core
Core consists of Core antigen and eantigen
Most infections are subclinical, but
can present with arthralgias,
glomerulonephritis, urticaria
Parenteral or sexual transmission.
Hepatitis B continued
Hepatocellular necrosis occurs due to the bodys

reaction to the virus rather than due to the virus
itself
Therefore patients who have a severe illness from
hep B are more likely to clear the virus.
SEROLOGY:
Remember Acute infection has IgM chronic has IgG

Anti Core IgM is present during acute phase
Anti Core IgG indicates chronic infection.
Patients with Hep B e Ag have continued active replication
Immunized or previously exposed people have Negative
HBsAg and HBeAg, they have IgG Anti HB Core, and
Positive anti Hep Bs and e.
Hepatitis B Antigen and Serology
Core antigen (HepBcAg)
- detected in anyone w/ previous exposure
- Induces cellular immune response *
- does NOT confer protectivity

- IgM - acute infection / lasts 3-6 mos.
- IgG - implies chronic hep B
- present in window period
E antigen (HepB e Ag)
HBV DNA
- Best indicator of viral replication
- Usually parallels HB e Ag
E Antibody (Anti HepB e )

- indicates antigen is cleared / virus not repli
- decrease infectivity
Surface Ag (HepB S Ag)

- Protein found on envelope
- First evidence of infection (before biochem )
- Signifies INFECTION & implies INFECTIVITY
CoreAntibody (Anti HepBc)
- Nucleocapsid encloses viral DNA
- Circulating peptide exported

- Marker for active viral replicat / INFECTIVITY
- Only persists in persons c/ circul. DNA
Surface Ab (Anti HepB S)

- confers PROTECTIVITY
- signifies recovery from HBV infection
non-infectivity, vaccination
Serological Patterns of Acute & Chronic Hepatitis B
Anti-HBs Anti-HBc HBeAg Anti-HBe

Serologic
Patterns of HepInterpretation
B Inf.
HBsAg
IgM
Acute HBV Infection

HIGH INFECTIVITY
IgG
Chronic HBV Infection

HIGH INFECTIVITY
IgG
Chronic / Late acute HBV Inf

LOW INFECTIVITY
IgM
+/-
+/-
IgG
+
+
IgG
-
+/-
IgG
1. Acute HBV Infection

2. Window Period
1. False Positive
2. Less likely inf romote past
Recovery from HBV infection
1. Immunization
2. Remote Infection
Precore mutation (Meditteranean)
HIGH INFECTIVITY
Question
A.
B.
C.
D.
E.
A 48 yo woman plans to travel to Mexico with her

husband and 11 year old child. The family have no known
history of liver disease or hepatitis and no members of
the family have had immunizations for hepatitis. What
immunizations would you recommend:
Hepatitis A vaccination for both parents and child
Hepatitis A Vaccination for parents and child and
Hepatitis B vaccination for the child
Hepatitis A and Hepatitis B vaccination for both parents
and the child
Screen parents for previous Hep A infection, and
recommend Hep A vaccination for the child
Screen all members of the family for Hep A and B
exposure.
ANSWER B
All children should now get Hep B.

vaccination as babies, if they miss
this they should have catch up
vaccination as 11-12 year olds
Previous Hep A infection is unlikely
in children and adults not in high risk
populations therefore it is safe to
vaccinate without antibody testing.
QUESTION
A 40 yo married man with two children was recently evaluated for fatigue
and elevations of liver function tests and was found to have chronic Hep
B. Physical examination reveals a few spider angiomata on his chest and
upper extremities.
Labs:
HBsAg
Pos
HBeAg
Pos
HBV DNA
90 (low)
ALT
156 U/L
Albumin
3.8
INR
1.5
A liver biopsy is performed and shows cirrhosis with moderate

inflammatory activity
The most appropriate recommendation for this patient is

A.
He should receive the Hepatitis A Vaccine
B.
His Wife and Childern should receive the Hepatitis B Vaccine
C.
He should be treated with Interferon Alpha
D.
All of the above
ANSWER: D
All patients with Liver disease should have the

Hepatitis A vaccine as they have decreased
hepatic reserve and the mortality of Hepatitis A
in a patient with Hepatitis B is considerably
increased
Household contacts of patients with Hepatitis B
should be vaccinated
Patients with HBeAg are candidates for
Interferon therapy, this is most likely to benefit
patients with HBV DNA <200 and evidence of
ongoing immune mediated liver cell damage on
biopsy.
Hepatitis C
RNA virus
Blood bourne ie. Transmission from IV
drug use and transfusion of blood
products prior to 1990.
Can also be transmitted by snorting
cocaine.
Sexual transmission is low.
Testing involves Anti HCV Antibody, and
then viral load if positive.
85% of patients develop chronic infection.
Complications of Hep C
Cirrhosis
Cryoglobulinaemia
Prophyria cutanea tarda
Management of Hep C
Interferon alpha with ribavirin for 6

to 12 months clears virus in approx
40% of patients.
There is an algorithm which is used to
decide who is treated, but basically
anyone with Hep C, high ALT and less
than 40 yo. If older than 40 should
have biopsy first which should at least
show periportal inflammation or
fibrosis.
Other issues re. Hep C
Once pt with Hep C is cirrhotic their

risk of developing hepatocellular Ca
is 1-4% per year
Alcohol increases risk
Other viral hepatitis
Hep E: Acute hepatitis just like hep

A unless you are PREGNANT in
which case can progress to
fulminant hepatitis
EBV, CMV, Herpes viruses can all
cause acute hepatitis especially in
immunocompromised.
Question
A.
B.
C.
D.
A 38 yo woman was found to be Hep C positive 6 months ago after

evaluation for raised AST. The infection was attributed to blood
transfusions received during a car accident 15 years ago. She was
pleased to learn last month that she is pregnant with her first child.
The physical examination is within normal limits
She would like further information concerning her prognosis and
the risk of transmission of HCV to her husband and her child.
All of the following statements about HCV infection are true except:
The chance of transmission of HCV to the newborn is low in the 5%
range.
Barrier precautions including safe sex are recommended for all
couples in a monogamous relationship because of high risk of
transmission to the partner
Low level transmission of Hep C is recognized within households
(5-10%), and the risk for such transmission should be minimized by
practices that avoid blood-blood exposure such as sharing dental
implements and razors
In patients with Hep C the chance of developing cirrhosis over
several decades is 20-35%
Answer B
Maternal-fetal HCV transmission is approx

5%, however if mother is co-infected with
HIV then risk increases to 30%
Risk of sexual transmission between
monogamous spouses is also low approx 5%
Transmission can occur between non-sexual
household contacts therefore should be told
to avoid sharing razors etc.
20-35% of patients with Hep C develop
cirrhosis
Three autoimmune
liver diseases
They are easily confused:

AUTOIMMUNE
HEPATITIS
ANA positive
Anti smooth muscle positive
High bilirubin and ALT but normal Alk Phos (cf.
Primary biliary cirrhosis)
Presentation: tiredness, anorexia, RUQ pain,
cushingoid facies despite no exogenous steroids.
Stigmata of liver disease
Pathology: Piecemeal necrosis with lymphocyte
infiltration
Tx: immunosupression, liver transplant
Complications: All the complications of chronic
liver disease
Increased Alk phos and Antimitochondrial positive

Damage to intralobular bile ducts by chronic
granulomatous inflammation
Associated with other autoimmune diseases (Thyroid, RA,
Sjogrens, Systemic Sclerosis)
NB. See granulomas on Bx not piecemeal necrosis
Unable to excrete bile, therefore present with
malabsorption of fat soluble vitamins. And with evidence of
portal hypertension.
Present with lethargy, itching and increased Alk Phos in a
middleaged woman.
May have hyperlipidaemia
Consider in any patient with autoimmune disease
presenting with liver disease.
Primary Sclerosing
Cholangitis
Seen in patients with UC and HIV

Inflammation, fibrosis and strictures of biliary tree causing
Beaded biliary tree on ERCP
Chronic biliary obstruction leads to cirrhosis
Presentation: Asymptomatic high Alk Phos, Jaundice,
pruritis abdo pain and fatigue
Dx: High bilirubin and Alk phos but NEGATIVE
antimitochondrial Ab (Cf. primary biliary cirrhosis)
Mgt: Steroids, Cholestyramine or ursodeoxycholic acid to
treat the pruritis and cholestasis but does not affect
disease process
Liver transplant for endstage disease but 20% recur.
NB. PSC is independent of activity of UC.
What does this ERCP

show?
NASH
Non-Alcoholic Steatohepatitis
Common cause of elevated liver
function tests
Often patients have metabolic
syndrome with obesity,
hyperlipidemia and diabetes
20-30% progress to cirrhosis
Weight loss, control of lipids and
diabetes should reduce progression.
Genetic Liver disease
Wilsons
Hemochromatosis
Alpha-1-Antitrypsin deficiency
Hemochromatosis
Autosomal recessive
Gene on Chromosome 6
Increased Fe absorption from gut, depositied in tissues
causing fibrosis and functional failure.
Presentation: BRONZE DIABETES, but also arthralgias,
Hepatosplenomegally and stigmata of liver disease,
testicular atrophy, CCF due to restrictive cardiomyopathy
Dx: High Fe and Ferritin, low TIBC, Low testosterone,
Diabetic. Joint XRays show chondrocalcinosis
Dual energy CT scan shows iron overload
Liver Bx shows Fe staining
NB. Hemochromatosis can be secondary to B Thalassemia
and repeated blood transfusions.
Skin color of
Hemochromatosis
QUESTION
A.
B.
C.
D.
During evaluation of an elevated ALT a 45 year old

alcoholic man is found to have a serum iron
concentration of 245mg/dL, a total iron binding capacity
of 290 mg/dL 84% transferrin saturation and a serum
ferritin of 2120ng/mL. The physical examination shows
no evidence of chronic liver or cardiac disease
Which one of the following is the most appropriate
course of management for this patient?
Biopsy to make a definitive diagnosis
MRI evaluation for iron overload
Weekly phlebotomy
HLA typing
Answer A
Definitive diagnosis of
Hemochromatosis requires liver
biopsy to determine hepatic iron
index.
If positive the patients siblings
should be screened
What is this sign called and

what is it associated with ?
Wilsons Disease
Autosomal Recessive
Deletion on Chromosome 13
Defective intrahepatic formation of caeruloplasmin
therefore failure of biliary excretion and high total body
and tissue levels of copper.
Dx High serum caeruloplasmin, increased urinary copper.
PRESENTATION: Cirrhosis, Kaiser-Fleischer rings,
hypoparathyroidism, arthropathy, Fanconi syndrome (renal
tubular acidosis) CNS: Psychosis, extrapyramidal
syndrome, mental retardation and seizures.
Think of this in a young patient with strange neurology and
liver disease
Tx: Copper chelation with penicillamine, can cure with
liver transplant BUT the CNS sequalae will not resolve.
-1 Antitrypsin
Deficiency
THE AUTOSOMAL DOMINANT ONE!

Severity of disease is dependent on which
alleles are affected (ie which phenotype)
Gene on Chromosome 14
Intrahepatic accumulation of -1
Antitrypsin causes liver disease and can
lead to cirrhosis
May have Lung disease (emphysema)
Budd Chiari Syndrome
Just know that it is thrombosis of hepatic veins

May be acute or chronic
May be associated with hypercoagulable state
therefore must do thrombophilia screen. Also
look for underlying maliganacy
Can occur with hydatid cysts
Presentation: Nausea, Vomiting, Abdo pain,
Tender hepatomegally and loss of hepatojugular
reflex
Tx: call a hepatologist: may need TIPPS or may
need portocaval or splenorenal anastomosis. May
be thrombolysable. Always call for help.
Hepatocellular
Carcinoma
Risk factors: Hep B and C, Cirrhosis

of any cause, Exposure to
Aspergillus Flavus toxin
Screening Alphafetoprotein should
be checked annually in patients with
cirrhosis. Need USS if high
Less than 15% are resectable at
diagnosis.
To understand gallstones
You first need to know the anatomy

of the biliary tree
Complications of
gallstones
1.
In the gall bladder:
2.
In the bile ducts
3.
biliary colic
Acute and chronic cholecystitis
Empyema, mucocele
Carcinoma
Obstructive Jaundice
Pancreatitis
Cholangitis
In the Gut
Gallstone ileus
Acute Cholecystitis
Stone impacting in neck of

gallbladder
Continuous RUQ pain, vomiting,
fever, MURPHYS SIGN Positive
USS: Thickened gall bladder wall
HIDA scan: Blocked cystic duct
Tx NPO, IV Abx, analgesia
Needs cholecystectomy either within
48 hours or wait 3 months
Chronic Cholecystitis
Vague abdominal pain, flatulence, fat

intolerance
Fair fat fertile females of forty
USS and ERCP reveal stones. May
need sphincterotomy
Biliary colic
RUQ pain radiating to back

Tx analgesia and cholecystectomy
Cholangitis
RUQ pain, rigors and Jaundice.

Needs IV Abx
Gallstone ileus
So rare there is hardly any point

mentioning it
Stone perforates Gallbladder into
duodenum passes through bowel
and obstructs terminal ileum.
Abdo XR diagnositic: Air in CBD with
small bowel obstruction
ERCP
Indications
Jaundice with dilated ducts on USS

Recurrent pancreatitis
Post cholecystectomy pain (check for retained stone)
Complications
Procedure
Acute pancreatitis
Bleeding
Infection cholangitis
Perforation
Sideviewing endoscope used to insert catheter into CBD and
inject contrast. XRay screening will then show up lesions in
biliary tree
Your job ie. what prep does my patient need
NPO for 12 hours

Check clotting and plt count
Prophylactic antibiotics as per endoscopy department
protocol
What is the signand who

was it named for?
Medusa
Stigmata of liver disease
HANDS:
HEENT/UPPER BODY
Palmar Erythema
Clubbing
Dupytrens
Leuconychia
FLAPPING TREMOR
Jaundice
Spider Angiomata
Gynaecomastia and scant body hair
Scratch marks
ABDOMEN
Ascites
Hepatosplenomegally
Caput Medusa
Hemorrhoids on PR
Small testes
Cirrhosis
4 Stages
1.
2.
3.
4.
Liver cell necrosis

Inflammatory cell infiltate
Fibrosis
Nodular regeneration which may be
macronodular (alcohol), micronodular
(viral) or mixed
CAUSES OF CIRRHOSIS
Alcohol
Viral B/C
Cryptogenic
Hemochromatosis
Wilsons
Alpha 1 antitrypsin deficiency
Autoimmune
COMPLICATIONS
Portal Hypertension causing variceal

bleed
Splenomegally causing low platelets
Ascites
Encephalopathy
SBP
Demonstrate the examination

necessary to identify the cause of
abdominal distension
Ascites
Accumulation of free fluid in

peritoneum
Assessment involves taking sample of
fluid and checking albumin content
SAAG: Serum Ascites Albumin
Gradient
SAAG = Serum Albumin Ascites

Albumin
SAAG
HIGH ie. 1.1

Portal
hypertension
present
Cirrhosis
Alcoholic hepatitis
Congestive cardiac
failure
Hepatic mets
LOW ie <1.1
Inflammatory
causes
Peritoneal
carcinomatosis
Peritoneal TB
Pancreatitis
Serositis
Management of Ascites
Salt Restrict
Fluid Restrict
Diuretics
Spironolactone 100-200mg /day to increase urinary

sodium excretion. Aim to reduce weight by 1Kg per day
May also need Lasix
Large volume paracentesis
Should give 6g Salt poor Albumin per liter of Ascitic

fluid removed in patients with HIGH SAAG otherwise
can cause precipitous fall in BP and Hepatorenal
syndrome.
Varices and portal

gastropathy
Variceal Hemorrhage
Varices develop at Esophagogastric junction due

to portal hypertension
First bleed has 10-30% mortality
Early endoscopy band ligation
Octreotide decreases the portal pressure and
may stop the bleeding
80% rebleed within 2 years
Bblockers esp Propranolol reduce portal
pressure and may prevent rebleeding
Serial endoscopy and banding to obliterate the
varices is also indicated to prevent rebleeding
Spontaneous Bacterial
Peritonitis
Occurs in 10-20% of cirrhotic

patients with ascites
Cell count and culture of ascitic fluid
should be performed in all patients
PMN cells >250 is criteria for
diagnosis
Renal failure with normal tubular

function in patient with portal
hypertension.
May be ppted by aggressive diuresis.
Low urine sodium (but so does prerenal)
No casts in urine
Renal function returns to normal after
transplant.
Encephalopathy
Decreased consciousness in patient with

severe liver disease
Always look for cause
Infection
Bleeding
Electrolyte disturbance
Constipation
Increased protein intake
Usually has increased serum ammonia which

you should check, although, it doesnt need to
be that high for pt to be encephalopathic
Tx: Lactulose
Childs-Pugh
classification
Dont learn this, just know the name and the principle.
It is a scoring system used to assess how risky surgery
will be in pts with liver disease
Meld scores and Mayo scores used to assess pts for
liver transplant and transplant allocation
LEARNING OBJECTIVES

Viral Hepatitis
Primary Biliary
Cirrhosis
Primary Sclerosing
Cholangitis
Hemochromatosis
Wilsons
Gallstones and
cholecystitis
Complications of end stage liver

disease
Ascites
SBP
Encephalopathy
Hepatitis C
Treatment in
Corrections:
New Medicine, New Challenges
Spencer Epps, MD, MBA,

Medical Director
Delaware Department of Correction
James Welch, RN, HNB-BC

Chief, Bureau of Healthcare Services
Objectives
Discuss Hep C Infection & Current

Treatment
Describe Hep C Treatment in Corrections
Explain New Medications for Hep C
Outline Challenges Presented by New
Medications
Propose Strategies to Address these
Challenges
Hepatitis C
Hepatitis C (HCV) is a
flavivirus related to
Yellow Fever and West
Nile Virus
Most common chronic
bloodborne infection
in the US
Contagious liver
disease causing mild
illness to serious,
lifelong illness or
death
Hep C Transmission
Spread by blood to blood contact:

IV drug use
Mother to child transmission
Can be sexually transmitted but less
common
Since 1992, screening has limited spread
through transfusions and transplants
For most, acute infection leads to

chronic infection
There is no vaccine for Hepatitis C
Current Hepatitis C
Treatment
PEG-Interferon
Increases expression of proteins that

interfere with Hep C viral replication
Ribavirin
Enhances the antiviral effect of
interferon
Precise mechanism of action uncertain
Treatment lasts for one year; if

successful, induces cure
Side Effects Current Hep C

Treatment
INTERFERON - Hematologic complications (i.e.,

neutropenia, thrombocytopenia), neuropsychiatric
complications (i.e., memory and concentration
disturbances, visual disturbances, headaches,
depression, irritability), flulike symptoms, metabolic
complications (i.e., hypothyroidism,
hyperthyroidism, low-grade fever), gastrointestinal
complications (i.e., nausea, vomiting, weight loss),
dermatologic complications (i.e., alopecia), and
pulmonary complications (i.e., interstitial fibrosis)
RIBAVIRIN - Hematologic complications (i.e.,

hemolytic anemia), reproductive complications (i.e.,
birth defects), and metabolic complications (i.e.,
gout)
New Hepatitis C
Treatment
FDA recently approved two new protease

inhibitors for treatment of Hep C
Boceprevir
Telaprevir
Are added to, do not replace, original therapy

Indications:
treatment of chronic Hep C genotype 1

with compensated liver disease, including
cirrhosis
previously untreated or who have failed previous
interferon and ribavirin therapy.
New Hepatitis C
Treatment
In previously untreated patients, 79% of

those receiving telaprevir experienced a
sustained virologic response (SVR) compared
with less than 50% with peginterferon alfa
and ribavirin treatment alone.
Cure rate for patients treated with telaprevir
across all studies, and across all patient
groups, was between 20-45% higher than
current regimen.
Course of treatment decreased from 48
weeks to 24 weeks.
US Food and Drug Administration (FDA).
Challenges of New
Treatment
Cannot be given alone or resistance will

develop
Same side effects plus additional side
effects
Anemia
Neutropenia
Thrombocytopenia
Severe Rash
Logistical Challenges in the correctional

environment:
Must be given at same time every day

Must be given with fatty food (e.g., ice cream)
Cost of New Treatment
Both boceprevir and telaprevir are

priced for cure
$45,000 to $75,000 per patient
Prevalence of Hep C higher in
correctional patient population
In Delaware, 800/7000 patients with Hep
C
Treatment of entire population with new
regimen would cost up to $60,000,000.
Entire healthcare budget = $55,000,000.
Strategies for Hep C

Treatment
The Federal Bureau of Prisons uses

the following criteria for limiting
Hep C treatment
PEG-interferon contraindicated
Incarceration period insufficient for
treatment
Inmate has unstable medical or mental
health condition
Patient refuses treatment
Strategies for Hep C

Treatment
Monitoring early stages of Hep C rather

than treatment acceptable and occurs in
free world
Treatment based on progression:
Liver biopsy
Other factors: age, co-infection with HIV, etc.
Monitor patients with earlier stages of

fibrosis & sentences under 5 years &
coordinate with community providers for
potential treatment
Consensus on Use of New

Medications
If fibrosis progression indicates treatment,

patients are tried on current therapy first
If therapy found to be futile at 12 weeks,
patients are tried on new medical
regimen, provided there are no
contraindications
As with current practice, patients should
be involved in the decision to treat
whether using old or new regimen
Conclusion
Discussed Hep C Infection & Current

Treatment
Described Hep C Treatment in Corrections
Explained New Medications for Hep C
Outlined Challenges Presented by New
Medications
Proposed Strategies to Address these
Challenges
Hepatitis C
Treatment in
Corrections:
New Medicine, New Challenges
Spencer Epps, MD, MBA,

Medical Director
James Welch, RN
Chief, Bureau of Healthcare Services
Drug treatment for

chronic hepatitis B
Implementing NICE guidance
Updated 2009
NICE technology appraisal guidance 96, 153, 154, 173
Background:
who is the guidance for
Adults with chronic hepatitis B.

These recommendations do not
apply to people who are also
infected with hepatitis C or D, or
HIV.
Recommendations:
peginterferon alfa-2a
Peginterferon alfa-2a is recommended as

an option for the initial treatment of
adults with chronic hepatitis B (HBeAgpositive or HBeAg-negative).
Drug treatment with peginterferon alfa2a or adefovir dipivoxil should be initiated

only by an appropriately qualified
healthcare professional with expertise in
the management of viral hepatitis.
Recommendations:
adefovir dipivoxil
Adefovir dipivoxil is recommended as

an option if:
treatment with interferon alfa or

peginterferon alfa-2a has been
unsuccessful, or
a relapse occurs after successful initial
treatment, or
treatment with interferon alfa or
peginterferon alfa-2a is poorly tolerated
or contraindicated.
Recommendations:
adefovir dipivoxil
Adefovir dipivoxil should not normally be

given before treatment with lamivudine.
It may be used either alone or in
combination with lamivudine when:
treatment with lamivudine has resulted in

viral resistance, or
lamivudine resistance is likely to occur
rapidly, and development of lamivudine
resistance is likely to have an adverse
outcome.
Recommendations: entecavir
Entecavir is recommended as an option for

the treatment of people with chronic
HBeAg-positive or HBeAg-negative
hepatitisB in whom antiviral treatment is
indicated.
Recommendations: telbivudine
Telbivudine is not recommended for the

treatment of chronic hepatitis B.
People currently receiving telbivudine
should have the option to continue therapy
until they and their clinicians consider it
appropriate to stop.
Recommendations: tenofovir
Tenofovir disoproxil is recommended as an

option for the treatment of people with
chronic HBeAg-positive or HBeAg-negative
hepatitisB in whom antiviral treatment is
indicated.
This does NOT apply in patients who also
have Hep C, Hep D or HIV
For discussion
What is our local epidemiology?

How are we recording and acting upon
any use of telbivudine?
What data is available to measure use of
these drugs locally?
Current and
Future Treatment
of Chronic
John Scott, MD, MSc
Hepatitis
C
University of Washington
Case
43 yo Asian woman w/ chronic Hep C,

GT 1, HCV RNA level of 2 million IU/ml
ALT 53, INR 1.0, Albumin 4.1
Liver biopsy: grade 2 inflammation,
stage 2 fibrosis
HTN
What to do next?
Treat now or wait?
Outline
Epidemiology
Natural History
Current Therapy
-Efficacy
-Side effects
-Mechanism of action
-Kinetics
Future Therapy
Epidemiology
3.9-4.1 million Americans are HCV

Ab+
May be as high as 7 million
2.7-3.2 million are chronically

infected
Highest prevalence in 30-54 yo
Highest prevalence in African
Americans and Hispanics
CDC. MMWR 1998 47(RR19):1-38
Risk Factors for HCV
Injection drug use (60%)

Blood transfusion before 1992
Multiple sex partners
Iatrogenic (hemodialysis, re-use of
vials, etc)
Intranasal cocaine
Piercing, tattooing, scarification
Unknown (10%)
Evolution of therapy for

HCV
~1990s
mid-90s
What is Pegylation?
Covalent attachment of
polyethelene glycol to peptide
Increases hydrodynamic size
Prolonged circulation,
delayed renal clearance
PegIntron (12kd, Schering),
Pegasys (40kd, Roche)
Enzon pharmaceutical
Adenosine deaminase
Others: Neulasta (GCSF),
doxorubicin
Side Effects of
PegIFN/Ribavirin
Depression ranging
Interfer
from mild to suicidality

Irritability, aggressive
behavior
Worsening of mania
Fatigue
Insomnia
Myalgias, fever, flulike symptoms
Hair loss
Cytopenias
The importance of viral

kinetics
Kinetics and SVR
GT 1 (Pegasys + RVN)
Time
HCV RNA status
Wk 4
Neg
<2 log
<2 log
Any
Wk 12
Neg
Neg
>2 log
Any
Wk 24
Neg
Neg
Neg
Pos
SVR
91%
60%
43%
2%
Mechanism of Action:
Interferon
HCV
HCV virions
Interferon alfa
Assembly
IFN receptors
JAK
Viral RNA
HCV replicative
complex
PKR
STAT
IRF9
ADA
STAT1
ISG mRNA
ISGF3
ISRE
Adapted from
Hoofnagle J. NEJM 2006
OAS
OAS:
activates
antiviral
RNAses
PKR:
inactivat
es viral
Ribavirin Prevention of
Relapse
Treatment
Follow-up
% relapse (HCV RNA +)
50
Continue ribavirin > wk 24
40
Stop ribavirin at wk 24
30
* p<0.05
20
10
24
30
36
*
48
Weeks of treatment
52
(Bronowicki et al., Gastroenterology 2006;131:1040-8) slide courtesy of JM Pawlotsky
60
72
Ribavirins Antiviral
Mechanisms
Direct inhibition of HCV RNA-dependent

RNA polymerase ?
Depletion of intracellular GTP pools via

IMPDH inhibition ?
RNA mutagenesis leading to "error

catastrophe" ?
Ribavirin Antiviral
Mechanisms
O
N
H N
2
HO
HO
OH
25OAS
PKR
Mx
ADAR1
ISG20
ISG54
ISG56
Slide courtesy JM Pawlotsky
Future Therapies
Coming soon! (2011?)

Potent
Rapid antiviral resistance if used by
itself
More side effects
HCV Life Cycle: Key

Features
Multiple proteins mediate HCV entry:
CD81, Scavenger Receptor B1, Claudin 1, Occludin, Very

Low Density Lipoprotein Receptor
Input HCV RNA is translated, a polyprotein is formed,

and individual viral proteins are released from
polyprotein by cellular and viral proteases
HCV proteins associate with endoplasmic reticulum
membranes, the site of HCV replication
Virion assembly occurs at lipid droplets
HCV leaves the cell by hitching a ride on the
apolipoprotein B secretion pathway
HCV life cycle is intimately tied with lipid metabolism
HCV Variability
RNA virus, RDRP lacks proof-reading

function
Mutations arise during replication
are not corrected
Genotypes
genetically divergent HCV isolates that can

be grouped phylogenetically
Quasispecies
Highly related yet genetically distinct viruses
Drug Development
is NOT Easy
-one for every 1,000 drugs makes it into humans

-One in 5 receive FDA approval
HCV Drug Development

Phase of Development
Viral entry inhibitors
Preclinical
II
III
Hepatitis C immunoglobulin HCIg)

HCV-Ab 68 and Ab 65 (monoclonal Ab)
HCV RNA translation inhibitors
ISIS 14803 (antisense)

AVI 4065 (antisense)
Heptazyme (ribozyme)
VGX-410C (small molecule IRES inhibitor)
TT 033 (siRNA)
*
*
Posttranslational processing inhibitors

NS3-4A serine proteinase inhibitors
BILN 2061
ITMN 191
VX-950
SCH 503034
ACH-806/GS-9132
HCV replication inhibitors
NS5B polymerase inhibitors

MK-0608
HCV-796
R1626
JTK-003
NM-283
XTL 2125
Cyclophilin B inhibitors
DEBIO-025
NIM 811
NS5A inhibitors
A-831, A-689
Helicase inhibitors
QU663
Recombinant Ab fragments
Virus assembly and release inhibitors
UT-231B (iminosugar-glucosidase inhibitor)

Celgosivir (glucosidase inhibitor)
(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)
*
*
*
*
*
IV
HCV Lifecycle
HCV Lifecycle
NS3 Protease Targets
Serine proteinase
catalytic site
(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)
NS3 Protease Inhibitors

Having Reached Clinical
Development
Peptidomimetic inhibitors
BILN 2061 (Boehringer-Ingelheim)
Telaprevir (VX950, Vertex & Tibotec)
Boceprevir (SCH503034, Schering-Plough)
TMC 435350 (Tibotec)
ITMN-191 (InterMune)
MK-7009 (Merck)
BI 201335 (Boehringer-Ingelheim
HCV RNA Change from

Baseline (Log10 IU/mL)
VX-950 Alone or in Combination

with Pegasys: Mean Viral
Response
1
0
1
-2
3
4
5
5 6Time7(In8 91 1 1 1 1
6 B 1 2 3 4Study
Days)
01234
Baseline
Pegasys +
placebo
VX-950
VX-950 + Peg-IFN
Reesink H et al. EASL. April 26-30, 2006.

Vienna, Austria. Abstract 737.
Slide courtesy Roche Medical Affairs
Wild
type
Phenotypic
Characterization of
Telaprevir-Resistant
Variants
Highly sensitive clonal method

Detect 5% frequency of variants
Performed at days 4, 8, 12, 14
80 sequences/patient/time point
T54A V36A/M R155K/T 36/155 A156V/T
Low resistance
High resistance
Adapted from Kieffer T, et al. 200
Thanks!
Larry Corey,
MD
Chia Wang, MD
Dave Gretch,
MD, PhD
Erica Coppel
Erica Seddig
Hepatocellular
Carcinoma
Amr Khayat, MBBS
Hepatocellular carcinoma (HCC) is a primary

malignancy of the liver.
It is now the third leading cause of cancer deaths
worldwide, with over 500,000 people affected.
Hepatitis and excessive alcohol are the leading
causes of HCC.
(Hepatitis B or hepatitis C, 20%) or with cirrhosis
(about 80%).
HCC may present with right upper quadrant pain,
weight loss, jaundice, bloating from ascites, and
signs of decompensated liver disease.
Microscopically, there are four

cytological types:
fibrolamellar,
pseudoglandular (adenoid),
pleomorphic (giant cell) and
clear cell.
Local expansion, intrahepatic spread,

and distant metastases.
Serum AFP rise in 40-64%.

On CT, HCC can have three distinct patterns of
growth:
A single large tumor

Multiple tumors
Poorly defined tumor with an infiltrative growth pattern
Diagnostic Procedures
In patients with lesions less than 1 cm,

>>>> conservative management with close
follow-up and no biopsy is recommended.
In patients with 1- to 2-cmlesions, abiopsy
should be performed,.
Patients with lesions greater than 2 cm,
cirrhosis, characteristic imaging studies, and
elevated AFP values can be managed
without biopsy.
Patients with large tumors who are not
candidates for resection or transplantation ,
>>>>>> biopsy is frequently not indicated.
Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis,

staging, and treatment of hepatocellular carcinoma. Liver Transpl.
Feb 2004;10(2 Suppl 1):S115-20.
Important features that guide

treatment include:
Size
Spread (stage)
Involvement of liver vessels
Presence of a tumor capsule
Presence of extrahepatic
metastases
Vascularity of the tumor
AJCC/UICC Classification
System
Child-Pugh score
The Child-Pugh score is used to assess the

prognosis of chronic liver disease, mainly
cirrhosis. To determine treatment required
and the necessity of liver transplantation.
The score employs five clinical measures of liver
disease. Each measure is scored 1-3, with 3
indicating most severe derangement.
Chronic liver disease

is classified into
Child-Pugh class A to
C, employing the
added score from
Treatment/Management
Surgical resection
Liver transplantation
Percutaneous ablation
Radica
l
Alcohol injection
Potenti
ally
Transarterial embolization and
Curativ
chemoembolization
e
Chemotherapy.
Palliativ
e
There is no agreement on a common

treatment strategy for patients with
HCC worldwide, and several proposals
have been published.The three major
curative therapies, resection, liver
transplantation and percutaneous
treatments, compete as first-line
treatment option for small single HCC
in patients with well-preserved liver
function.
Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. The

Lancet 2003; 362: 190717.
Poon RT, Fan ST, Tsang FH, Wong J. Locoregional therapies for
hepatocellular carcinoma: a critical review from the surgeon's
perspective. Ann Surg 2002; 235: 46686.
Surgery: Resection and Transplantation
Surgery is the mainstay of HCC treatment and achieve the best outcomes in wellselected candidates.
Less than 5% patients resectable
Factors affecting resectability:
Size<5cm
number of tumors
involvement of major structures
hepatic function
no extra-hepatic spread
no portal hypertension
Requires experienced surgical and supporting team

5 year survival 60%-70%
3 year recurrence 45 - 60%
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.
Hepatology 1999; 30: 143440.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J
Med 1996; 334: 6939.
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for

early hepatocellular carcinoma: resection versus transplantation. Hepatology
1999; 30: 143440.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of
small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;
334: 6939.
Transplantation
Milan Criteria :
Single HCC 5 cm or
Up to three nodules 3 cm
No extra hepatic spread
About 10 % qualify for listing
The major drawback of transplantation is
The scarcity of donors.

The long waiting time.
While Waiting :
Adjuvant therapies whilst on the waiting list
are used in most centers to prevent tumor
progression.
Resection Vs
Transplantaion
138 pt with cirrhosis and HCC

85 LT and 53 Resection
Childs A and B
1, 3, 5-year
Survival
1, 3, 5-year
Disease free
Liver
Resection
Transplantat
ion
84, 74, 62 % 83, 57, 50 %
83, 72, 60 % 70, 44, 31 %
Liovet hepatology 1999
Percutaneous Treatments
For patients who cannot undergo resection.

Complete responses in more than 80% of tumors smaller
than 3 cm in diameter, but in 50% of tumors of 3-5 cm in
size.
5-year survival rates of 40%-60%. reported in patients
with small single tumors, commonly <2 cm in diameter.
Although these treatments provide good results, they are
unable to achieve response rates and outcomes
comparable with surgical treatments.
Transarterial Embolization and Chemoembolization is
recommended as first line non-curative therapy for nonsurgical patients with large/multifocal HCC who do not
have vascular invasion or extrahepatic spread.
Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous
ablation predicts survival in patients with hepatocellular carcinoma.
Hepatology 2004; 40: 135260.
Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular
carcinoma in patients with cirrhosis: long-term results of percutaneous
image-guided radiofrequency ablation. Radiology 2005; 234: 9617.
Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular
carcinoma by percutaneous tumor ablation methods: ethanol injection
therapy and radiofrequency ablation. Gastroenterology 2004; 127: S159
66.
Percutaneous Ethanol Injection
207 patients with cirrhosis +

HCC < 5 cm
100% Ethanol
Follow up was 25 months
No complications
4.3 sessions per patient
88% complete necrosis
1 ,2,3-year survival rates:
90,80,63%
Cancer 1992;69:925
Radiofrequency Ablation
BEFO
RE RF
AFT
ER
RF
Complet
e
Necrosis
Progres
sion
(3ys)
Survival
(3ys)
PEI
88 %
40,4%
57,6 %
RFA
96 %
15,3 %
71,1 %
Lin et al. 2004
Complet
e
Necrosi
s
Mean
No. of
Session
s
RFA
(52)
47
(90%)
PEI
(60)
48 (80
%)
Radiology 1999; 210:655
1,2
4,8
RFA : More expensive, more

complication, more seeding.
PEI: More Sessions, less effective in
Palliative Therapies
Primary treatment for unresectable HCC.

Embolization agents usually gelatin or microspheres
may be administered together with selective intra-arterial
chemotherapy mixed with lipiodol (chemoembolization).
Doxorubicin, mitomycin and cisplatin are the commonly
used antitumoral drugs.
Arterial embolization achieves partial responses in 1555% of patients, and significantly delays tumour
progression and vascular invasion.
# Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular

carcinoma. Gastroenterology 2004; 127: S17988.
# Llovet JM, Real MI, Montana X, et al. Arterial embolisation or
chemoembolisation versus symptomatic treatment in patients with
unresectable hepatocellular carcinoma: a randomised controlled trial.
Lancet 2002; 359: 17349.
# Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial
lipiodol chemoembolization for unresectable hepatocellular carcinoma.
Hepatology 2002; 35: 116471.
Transarterial Chemoembolization
Meta-analysis of 7 randomized
controlled trials
2 yr survival: 41% (19-63%)

Treatment response: 35% (16-61%)
Average no. of sessions: 1-4.5
Risks:
Infection
Tumor lysis syndrome
Hepatic failure
Llovel J He aloI2003"37:429
Systemic Treatments
A meta-analysis of seven RCTs comparing tamoxifen

vs. conservative management, comprising 898
patients, showed neither antitumoral effect nor
survival benefit of tamoxifen. Thus, this treatment is
discouraged in advanced HCC.
Systemic chemotherapy has been tested in nine RCT.
The most active agents in vitro and in vivo are
doxorubicin and cisplatin. Systemic doxorubicin has
been tested in more than 1000 patients within clinical
trials and provides partial responses in around 10% of
cases, without any evidence of survival advantages .
Llovet JM, Bruix J. Systematic review of randomized trials for

unresectable hepatocellular carcinoma: chemoembolization
improves survival. Hepatology 2003; 37: 42942.
# Fong Y, Kemeny N, Lawrence T. Cancer of the liver and biliary
tree. In: De Vita VT, Hellman S, Rosenberg S, eds. Cancer:
Principles and Practices of Oncology. Philadelphia, USA:
Lippincott Williams and Wilkins, 2001: 1162204.
# Palmer D, Hussain S, Johnson P. Systemic therapies for
hepatocellular carcinoma. Expert Opin Investig Drugs 2004; 13:
155568.
Chemotherapy
Palliative not Curative.

Regional (Intra-arterial) better that
systemic.
Resistant to many agents.
Follow-up
Despite optimal treatment, hepatocellular carcinoma

continues to have a high recurrence rate. majority of
which occur within 2 years.
Earlyrecurrence after resection is associated with a
dismal prognosis, reducing 5-year survival rates from
70% to 30%.
Common extrahepatic sites of metastatic
diseaseinclude lung, bone, CNS, and adrenal glands.
Factors that increase the likelihood of recurrence
include the presence of :
multiple foci of hepatocellular carcinoma,

liver capsule invasion,
tumor size (>5 cm).
Vascular invasion, both microscopic and macroscopic.
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver
disease and hepatocellular carcinoma. Gastroenterology. Feb 2004;126(2):460-8.
In general, a CT scan at 1 month

postresection.
Serum alpha-fetoprotein
measurements and repeat imaging
studies (eg, ultrasound, CT, MRI)
every 3-6 months.
After 2-3 years, safe to increase the
follow-up interval.
Summary
Early-stage hepatocellular carcinoma is typically clinically silent,

and HCC is often advanced at first manifestation.
Without treatment, the 5-year survival rate is less than 5%.
Complete surgical resection followed by hepatic transplantation
offers the best long-term survival, but few patients are eligible for
this therapy.
Radiofrequency ablation is the preferred method for managing
unresectable small HCCs that are few in number. More widespread
disease is treated with percutaneous therapies such as
chemoembolization.
Systemic administration of biologic and chemotherapeutic agents is
minimally successful in slowing the growth of HCC and typically is
used to control symptoms in patients with overwhelming disease.
A multidisciplinary approach that includes surgery, systemic
therapy, and radiation therapy and that is based on the cooperation
of radiation oncologists, interventional and diagnostic radiologists,
hepatologists, and pathologists offer the best chance of a cure or at
least a longer and more normal life.
Liver Tumors
Ayman Abdo
MD, AmBIM, FRCPC
Objective
1.
2.
Identify the most important

features of common benign liver
tumors
Know the risk factors, diagnosis,
and management of hepatocellular
carcinoma
Classification
Benign
Hemangioma
Focal nodular
hyperplasia
Adenoma
Liver cysts
Malignant
1.
Primary liver
cancers
Hepatocellular
carcinoma
Fibrolamellar
carcinoma
Hepatoblastoma
2. Metastases
Benign Liver
Lesions
1.
2.
3.
4.
Hemangioma
Focal nodular hyperplasia
Adenoma
Cysts
Hemangioma
Clinical Features
The commonest liver tumor

5% of autopsies
Usually single small
Well demarcated capsule
Hemangioma
Diagnosis and Management
Diagnosis
US: echogenic spot, well demarcated
CT: venous enhancement from periphery
to center
MRI: high intensity area
No need for FNA
Treatment
No need for treatment
CT/Hemangioma

(FNH)
Clinical Features
Benign nodule formation of normal
liver tissue
Central stellate scar
More common in young and middle
age women
No relation with sex hormones
May cause minimal pain

(FNH)
Diagnosis:
US: Nodule with varying echogenicity
CT: Hypervascular mass with central scar
MRI: iso or hypo intense
FNA: Normal hepatocytes and Kupffer
cells with central core.
Treatment:
No treatment necessary
Pregnancy and hormones OK
CT/FNH
Hepatic Adenoma
Clinical features
Benign neoplasm composed of normal

hepatocytes no portal tract, central
veins, or bile ducts
More common in women
Associated with contraceptive hormones
Usually asymptomatic but may have
RUQ pain
Mat presents with rupture, hemorrhage,
or malignant transformation (very rare)
Hepatic Adenoma

DX
US: filling defect
CT: Diffuse arterial enhancement
MRI: hypo or hyper intense lesion
FNA : may be needed
Tx
Stop hormones
Observe every 6m for 2 y
If no regression then surgical excision
Adenoma
Liver Cysts
May be single or multiple

May be part of polycystic kidney
disease
Patients often asymptomatic
No specific management required
Hydated cyst
Malignant Liver
Lesions
Malignant Liver Tumors

1.
2.
3.
4.
5.
Hepatocellular carcinoma (HCC)

Fibro-lamellar carcinoma of the
liver
Hepatoblastoma
Others
HCC: Incidence
The most common primary liver

cancer
The most common tumor in Saudi
men
Increasing in US and all the world
HCC: Risk Factors

The most important risk factor is
cirrhosis from any cause:
1. Hepatitis B (integrates in DNA)
2. Hepatitis C
3. Alcohol
4. Aflatoxin
5. Other
HCC: Clinical
Features
Wt loss and RUQ pain (most common)

Asymptomatic
Worsening of pre-existing chronic liver
dis
Acute liver failure
O/E:
Signs of cirrhosis
Hard enlarged RUQ mass
Liver bruit (rare)
HCC: Metastases
Rest of the liver

Portal vein
Lymph nodes
Lung
Bone
Brain
HCC: Systemic
Features
Hypercalcemia
Hypoglycemia
Hyperlipidemia
Hyperthyroidism
HCC: labs
Labs of liver cirrhosis
AFP (Alfa feto protein)

Is an HCC tumor marker
Values more than 100ng/ml are
highly suggestive of HCC
Elevation seen in more than 70% of
pt
HCC: Diagnosis
Clinical presentation
Elevated AFP
US
Triphasic CT scan: very early
arterial perfusion
MRI
Biopsy
US: HCC
CT: Venous Phase
CT: Arterial Phase
HCC: Prognosis
Tumor size
Extrahepatic spread
Underlying liver disease
Pt performance status
HCC: Liver
Transplantation
Best available treatment

Removes tumor and liver
Only if single tumor less than 5cm or
less than 3 tumors less than 3 cm
each
Recurrence rate is low
Not widely available
HCC: Resection
Feasible for small tumors with

preserved liver function (no jaundice
or portal HTN)
Recurrence rate is high
HCC: Local Ablation
For non resectable pt

For pt with advanced liver cirrhosis
Alcohol injection
Temporary measure only
Radio Frequency
Ablation
Ethanol Injection
HCC:
Chemoembolization
Inject chemotherapy selectively in

hepatic artery
Then inject an embolic agent
Only in pt with early cirrhosis
No role for systemic chemotherapy
Chemoembolization
Fibro-Lamellar
Carcinoma
Presents in young pt (5-35)

Not related to cirrhosis
AFP is normal
CT shows typical stellate scar with
radial septa showing persistant
enhancement
Secondary Liver
Metastases
The most common site for blood born

metastases
Common primaries : colon, breast, lung,
stomach, pancreases, and melanoma
Mild cholestatic picture (ALP, LDH) with
preserved liver function
Dx imaging or FNA
Treatment depends on the primary cancer
In some cases resection or
chemoembolization is possible
Summary
Benign
Hemangioma
Focal nodular
hyperplasia
Adenoma
Liver cysts
Malignant
1.
Primary liver
cancers
Hepatocellular
carcinoma
Fibrolamellar
carcinoma
Hepatoblastoma
2. Metastases

Bucuresti
Liver and Biliary Tract Disease

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Universitatea Titu Maiorescu

Motion and Activity

The Anatomy of the Liver

Figure 24.20 Liver Histology

Normal Liver - Microscopy

Largest solid organ in the body

There are eight liver segments.

production and release of circulating factors critical to the

the single most sensitive tests of liver function are measures of

synthesizes a wide variety of plasma proteins, the most

variety of acute-phase proteins and cytokines that have important

3-Bile and the Enterohepatic

Bile is a mixed micelle composed of bile

Traditional LFTs (Liver Functional Test)

Traditional LFTs (Liver Functional

Progression to cirrhosis over 20 years2

1-(Decompensated) Alcoholic liver disease

What further history would be needed?

How would you investigate this

Chronic HCV Infection

5%-25% over 20-30 years

What is your management plan?

Recommended Treatment 2008

Strader DB, et al. Hepatology. 2004;39:1147-1171.

What is autoimmune hepatitis?

Autoimmune hepatitis is a disease in which the

Autoantibodies against hepatocytes

How is autoimmune hepatitis

antinuclear antibody (ANA),

are all of use, as is finding an increased Immunoglobulin G level.

In complex cases a scoring system can be used to help determine if a

diagnosis of autoimmune hepatitis always

What causes autoimmune

What are the symptoms and

Liver biopsy histology at initial presentation showing peri-portal

How is autoimmune hepatitis

Treatment starts with a high dose of prednisone. When

long-term use of steroid can cause serious side effects

Primary Biliary Cirrhosi

PBC and PSC

Wilsons & 1AT Deficiency

CIRROSIS OF THE LIVER

A chronic, progressive disease of the liver

Extensive parenchymal cell

Etiology and Pathophysiology

Etiology and Pathophysiology

Etiology and Pathophysiology

Etiology and Pathophysiology

Etiology and Pathophysiology

Etiology and Pathophysiology

Liver function tests

Which method: blood sample or

Manifestations of Liver Cirrhosis

Jaundice or Scleral Icterus

Major Complications of Cirrhosis

CIRROSIS OF THE LIVER

1-Portal hypertension and esophageal varices

Diurnal sleep pattern pertubation

Peripheral Edema and Ascites

Normal pressure ranges from 7 to 10 mm Hg.

In portal hypertension, pressure exceeds 10 mm Hg, averaging

In extrahepatic portal vein thrombosis (without liver disease),

In cirrhosis, collateral vessels circumvent the liver and deliver