Transcript Ascites - yeditepetip4

Acute Liver Failure
Doç.Dr.Atakan Yeşil
Yeditepe Unıversıty
Department of
Gastroenterology
How Do We Tell Someone Has Liver
Disease?
Clues that may lead to a suspicion of liver disease:
Nonspecific
More specific
(late findings)
Anorexia
Fatigue
Nausea
Vomiting
Mental confusion
Jaundice (“yellow eyes”)
Dark urine (“coca-cola” urine)
Abdominal swelling; ascites
Peripheral edema; leg swelling
Unfortunately none of these are specific markers of liver disease
and for many patients these are very late findings.
Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/disease
liver cell injury
bile flow/cholestasis
2. Quantitate degree of liver function/dysfunction
quantitative liver tests
3. Diagnose general type of liver disease
pattern of liver test abnormalities
4. Diagnosis of specific liver disease
disease-specific tests such as serology for
viral hepatitis
Tests of Liver Cell Injury/Death
Transaminases
Alanine amino transferase (ALT)
Aspartate amino transfersase (AST)
Transaminases are enzymes that catalyze the transfer of aamino groups from amino acids to a-keto acids.
These enzymes are important in gluconeogenesis.
ALT (alanine aminotransferase)
alanine
+
ketoglutarate
pyruvic acid
+
glutamate
AST (aspartate aminotransferase)
aspartate
+
ketoglutarate
oxaloacetic acid
+
glutamate
Transaminases:
AST(SGOT)
ALT(SGPT)
Many tissues
Liver only
Cytosol/mitochondria
Cytosol
Normal blood levels:
20-70 IU/liter (depending on method)
Some AST/ALT release occurs normally
Require pyridoxal 5’-phosphate as an essential cofactor
Release of AST/ALT from Liver Cells
during Acute Hepatocellular Injury
AST
ALT
Transaminases
Why do we used these enzymes to indicate liver damage?
1. Convenient to measure
2. Present in liver cells in large amounts
3. Direct release of enzymes into blood through
fenestrated endothelium allows rapid
“quantitative” assessment of ongoing
hepatocyte necrosis
4. Blood level roughly proportional to the number
of hepatocytes that died recently (hours-days)
Transaminases
Special considerations:
1. AST is also present in other tissues
(muscle, brain, kidney, intestine).
ALT is more specific for liver.
2. Even very mild liver abnormalities can cause
slightly elevated AST/ALT
- for example, mild fatty liver.
Transaminases
Problems with using transaminases to assess liver injury:
1. Only assess injury over the past 1-2 days as enzymes
are cleared efficiently from blood by RES
2. May not accurately assess hepatocyte death from
apoptosis
3. Magnitude of elevation does not necessarily correlate
with extent of liver function or dysfunction at the
present time or in the future.
AST and ALT = rate of destruction of hepatocytes
Liver function = number of functional hepatocytes left
Transaminases and Alcoholic Liver Disease: A
Twist
Pyridoxal 5’-phosphate (P5P) deficiency:

AST and ALT require P5P (vit. B-6) as an enzymatic
cofactor

Alcoholics are often deficient in P5P as their major
calorie source is alcohol

P5P deficiency results in lower synthesis of AST/ALT
(less in hepatocytes) and very low enzymatic activity
(ALT worse than AST)

Less AST/ALT released into blood and it isn’t
measured by lab assays
Transaminases and Alcoholic Liver Disease
Further: Mitochondrial AST and alcohol

Alcohol shifts mAST from mitochondria to plasma
membrane where it readily enters blood – thus AST
easier to remove from hepatocytes.
Therefore: AST>>ALT is released into blood
from damaged hepatocytes
AND
both AST/ALT enzymatic activities in blood
are lower than expected from the extent of liver
damage/dysfunction.
AST/ALT and Pyridoxal 5’ Phosphate
AST is Affected Less than ALT so AST>ALT
P5’P
Numerous active enzymes with P5’P
Few inactive enzymes without P5’P
Poorly measured by lab assays
Tests of Cholestasis/Reduced Bile Flow
Enzymes released as a
consequence of decreased
bile flow
Alkaline phosphatase
or
5’-nucleotidase
Leucine aminopeptidase
g-glutamyl transpeptidase
Accumulation in liver/blood
of substances normally
excreted in bile
Bilirubin
Bile salts
Alkaline Phosphatase:
Location at Canalicular (Apical) Membrane
Alkaline phosphatase
Origin of enzyme and mechanism of increase in
cholestatic liver disease:
1. Apical membrane of hepatocyte and bile duct cells
2. Very sensitive to any changes in bile flow,
obstruction of large or small bile ducts.
3. Amplified by bile acid retention
4. Easily released into blood as it is a GPI-anchored
protein solubilized from membrane by
detergents (bile acids)
Easily measured spectrophotometrically
Purpose: ? Detoxifies lipopolysaccharide (LPS) from bacteria
Release of GPI-Anchored Proteins From
Liver During Cholestasis
GPI-Anchored Proteins
Alkaline
Phosphatase
5’ Nucleotidase
GGTP
Hepatocyte
Bile canaliculus
Blood
Alkaline Phosphatase in Various Liver Diseases
1500
Degree of elevation of AP is highly variable
depending on duration and extent of
cholestasis and other unknown factors.
1000
500
Serum
Enzyme
Level
(IU/ml)
200
100
Long-standing
bile duct
obstruction
Acute bile
duct
obstruction
Mild early
partial
bile duct
obstruction
Hepatocellular
disease
Alkaline Phosphatase
Interpretation of elevated levels:
1. Cholestasis (especially in extrahepatic
obstruction
2. Infiltrative diseases (granulomas)
3. Neoplastic disease infiltrating liver
Sensitive test as will go up if only some small ducts are
obstructed and/or if there is only partial obstruction of
major ducts.
Disadvantages:
Not completely specific because of isoenzymes
in other organs (bone, intestine, placenta)
Ex: bone disease, intestinal obstruction, pregnancy.
Serum Bilirubin (Bile Acids)
Rationale:
Liver is virtually the only mechanism for excretion
Cholestasis from any cause results in “back-up”
of these compounds in blood
Interpretation:
Cholestasis: extrahepatic or intrahepatic
Disadvantages:
Does not distinguish hepatocellular disease,
in which hepatocytes don’t make bile,
from bile duct obstruction
Bilirubin
An organic anion
The byproduct of heme breakdown
In mammals bilirubin must be conjugated to
glucuronic acid and excreted in bile
Blood levels go up if any steps in production or
hepatocyte excretion are altered. However
obstruction at the level of bile ducts must be
complete or virtually complete for bilirubin
levels in blood to change
Hepatic Bilirubin Transport
SER
RBC
breakdown
in RES
UDP-glucuronide
+
Unconj BR
Conj
BR
Unconj
Bilirubin
Unconj BR
Bile
Canaliculus
Conj
BR
MRP-2:
Multispecific organic
anion transporter
Conj
BR
ATP
Blood
Hepatocyte
Conjugated bilirubin
Glutathione S-conjugates
other organic anions
Hepatic Bilirubin Transport and Mechanisms
of Hyperbilirubinemia
Gilbert's syndrome (mild)
Crigler-Najjar syndrome (severe)
SER
Hemolysis
Unconj
Bilirubin
Bile
Canaliculus
Unconj BR
Conj
BR
Multispecific organic
anion transporter
Conj
BR
ATP
Conjugated bilirubin
Glutathione S-conjugates
other organic anions
Blood
Hepatocyte
Dubin-Johnson syndrome
Rotor's syndrome
?estrogen/cyclosporin
Interpretation of Elevated Serum Bilirubin
Conjugated hyperbilirubinemia:
BR reached liver and was conjugated but not excreted in bile
1. Cholestasis/biliary obstruction (must be essentially complete)
2. Hepatocellular damage (collateral damage to all liver functions)
bile formation impaired >> conjugation impaired
3. Rare disorders of canalicular secretion of conjugated bilirubin
Unconjugated hyperbilirubinemia:
BR didn't reach liver efficiently or wasn't conjugated
1. Massive overproduction - acute hemolysis
2. Impaired conjugation
common:
Gilbert's syndrome (mild)
rare:
Crigler-Najjar syndrome (severe)
Further: Bilirubin Undergoes Non-Enzymatic Reaction
with Albumin
Why is Bili-Albumin of Clinical Interest?
• Not of interest during liver disease as this form of
bilirubin is measured as conjugated bilirubin.
• However, after resolution of cholestasis/liver disease,
bili-albumin is cleared like albumin
– Albumin half-life:
– Conj. bilirubin half-life:
–
several weeks
hours to days
• Thus resolution of jaundice is often SLOW compared
to improvement of other liver functions.
Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/disease
liver cell injury
bile flow/cholestasis
2. Quantitate degree of liver function/dysfunction
quantitative liver tests
3. Diagnose general type of liver disease
pattern of liver test abnormalities
4. Diagnosis of specific liver disease
disease-specific tests such as serology for
viral hepatitis
TESTS OF LIVER FUNCTION
Blood Level
Production
Albumin
Clotting factors
Blood Level
Bilirubin
Bile Acids
Elimination
Metabolism
14C-Aminopyrine
Metabolites
14CO
2
Albumin
• Rationale
– Liver is the sole source
• Interpretation of Decreased Level
– Decreased liver production
– Increased renal/GI loss (nephrotic syndrome; protein losing
enteropathy in inflammatory bowel disease
– Protein malnutrition
• Disadvantages
– Prolonged half-life
– No unique interpretation
Prothrombin Time
• Rationale
– Liver is sole source of vitamin K-dependent clotting factors,
including those critical for PT
– Factor VII has very short half-life (hours)
• Interpretation of Increased PT
– Hepatocyte protein synthesis impaired
– Vitamin K deficiency/Coumadin therapy
– Disseminated intravascular coagulopathy
• Advantages
– Rapidly reflects changes in liver function
Interpretation of Abnormal
Albumin/Prothrombin Time
Liver markedly diseased - reserve function gone
Albumin:
monitors slow changes in liver function
(months to years)
reflects long-term liver dysfunction
Protime:
monitors rapid changes in liver function
(hours to days/weeks)
reflects either short or long-term liver
dysfunction
Other Clues to Globally Impaired Liver Function
Bilirubin:
goes up with any disease that globally impairs
liver function (OR blocks bile flow)
Glucose:
hypoglycemia (late finding; indicates
very poor liver function)
BUN:
low BUN is a late and poorly specific finding
in liver dysfunction due to poor urea
synthesis
Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/disease
liver cell injury
bile flow/cholestasis
2. Quantitate degree of liver function/dysfunction
quantitative liver tests
3. Diagnose general type of liver disease
pattern of liver test abnormalities
4. Diagnosis of specific liver disease
disease-specific tests such as serology for
viral hepatitis
Interpretation of Liver Tests
A. Consider nonhepatic causes of abnormal liver tests
B. Examine the pattern of liver test abnormalities to
categorize liver disease:
1. cholestatic
versus
hepatocellular
2. acute
versus
chronic
3. decompensated
function
versus
mild functional
impairment
Patterns of Abnormal Liver Tests
Hepatocellular
Cholestasis
Major:
AST/ALT
Alkaline Phosphatase
Minor:
Bilirubin
PT/albumin
Bilirubin
AST/ALT
PT (Vit K deficiency)
Clues to Acute vs Chronic Liver Disease
Abnormalities of PT versus albumin
Known duration of abnormal liver tests
History of exposure to potential causative agents
Clinical signs of consequences of long-standing liver disease
Tempo of subsequent changes in AST/ALT, bilirubin, PT
chronic tends to change slowly
acute tends to change quickly
Clues to Severity of Liver Dysfunction
Prothrombin time
Albumin
(Bilirubin, glucose)
(Clinical signs of consequences
of severe liver dysfunction such
as hepatic encephalopathy)
Clues to severity
of liver damage
and, potentially, to
severity of liver
dysfunction may
come from the
temporal sequence
of changes in
readily available liver
tests.
For example, rapid
fall in AST/ALT
in severe hepatitis
may not be a good
sign.
Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/disease
liver cell injury
bile flow/cholestasis
2. Quantitate degree of liver function/dysfunction
quantitative liver tests
3. Diagnose general type of liver disease
pattern of liver test abnormalities
4. Diagnosis of specific liver disease
disease-specific tests such as serology for
viral hepatitis
These are discussed in future lectures
Patient #1:
• Presents with two days of fever,
abdominal pain, yellow skin,
nausea, vomiting.
• Labs demonstrate the following:
–
–
–
–
–
–
AST 3210
ALT 3060
Alk phos 249
TBili 6.2 (Direct 4.3)
Albumin 3.1
INR 1.2
What targets the hepatocyte?
• Toxins
– Alcohol
– Medications
• Tylenol
– Mushrooms
• Viral
– Hepatitis A/B/C
– EBV/HSV/CMV
• Ischemia
– Severe
hypotension
– Vasoconstrictio
n
– Sepsis
• Autoimmune
• Wilson’s
• Alpha-1
antitrypsin
Degree of elevation points
to etiology
• >1000 to 2000
– Ischemia
– Toxin
– Virus
• >500 to 1000
– Acute biliary obstruction
• <300
– Alcoholic liver disease, cirrhosis,
chronic obstruction
– AST/ALT>2 and each <300 suggests
EtOH or cirrhosis
• If >500, unlikely EtOH
Back to our patient
• Transaminases in the 1000s
– Suggests ischemia/toxin/viral
• IVDU
– Risk of acute Hep B or acute Hep C
• Cocaine
– Risk of ischemia
• Recent infection
– Doxycycline
Patient #2:
• 40 year-old overweight woman
presents with right UQ abd pain,
fever, chills. Previous episodes after
fatty meals.
• Laboratory Studies
–
–
–
–
–
–
AST 67
ALT 57
Alk Phos 293
TBili 4.1 (Direct 2)
Albumin 4
INR 1
Increased Bilirubin
• Sources
– Increased production
– Hemolysis, hematoma reabsorption
– Impaired uptake/conjugation
– Dubin-Johnson, Gilbert’s
– Impaired excretion
– Renal failure, biliary obstruction
• Conjugated=direct=processed by
liver
• Unconjugated=indirect=not
processed by liver
– Fractionation – helpful to assess for
unconjugated hyperbilirubinemia
• < 20% direct AND indirect >1.2
Biliary Obstruction
• Canicular cell injury
– Alkaline phosphatase
• Liver and bone major sources
• Increased synthesis and release in liver
disease
– Up to 3x normal in variety of liver
disease
– GGT
• Sensitive indicator of canicular cell injury
• Parallels alkaline phosphatase increase
when of liver origin
Causes of Biliary Obstruction
• Extrahepatic
– Choledocholithi
asis
– Malignancy
• Cholangiocarci
noma
• Pancreatic
cancer
• Gallbladder
cancer
• Ampullary
cancer
– Primary
sclerosing
• Intrahepatic
– TPN
– Sepsis
– Primary
sclerosing
cholangitis
– Primary biliary
cirrhosis
– Intrahepatic
mass
How would you like to
approach this patient?
• Finding the source of obstruction
– Ultrasound: good for extrahepatic cause
– CT/MRI/ERCP: for both intra or extrahepatic
cause
• In our patient?
Patient #3:
• 46 yo man with history of IVDU and longstanding alcohol use following up in clinic.
• Laboratory
–
–
–
–
–
AST 68
ALT 37
Alk phos 194
TBili 1.3
Albumin 2.9
Mixed Patterns of Elevated
Liver Function
• Chronic Liver disease
–
–
–
–
–
Hepatitis B, Hepatitis C
NASH
Alcoholic liver disease
Hemochromatosis
Autoimmune hepatitis
Patient#4:
• 72 yo man fell in bathroom. Found the
next day.
• Laboratory
–
–
–
–
–
AST 167
ALT 58
Alk phos 127
TBili 1.8
Albumin 3.9
What else do you want to
know?
• Where else is AST and ALT found?
• How can you look for evidence of muscle
injury?
Additional Laboratory
• CK 7260
• Myoglobin 23390
• UA – 2+ blood, microscopic no RBC
• Diagnosis?
Isolated or Predominant
Alk Phos
• Chronic Biliary Disease
– Primary biliary cirrhosis
– Primary sclerosing cholangitis
• Infiltrative disorder
–
–
–
–
Amyloid
Granulomatous diseases
Metastatic carcinoma
abscesses
Fulminant Hepatic Failure
• Rapid development of severe acute liver
injury with impaired synthetic function and
encephalopathy
– Previously had a normal liver or had wellcompensated liver disease
• 28 year old woman presents to
hospital with a two day history of
nausea, vomiting, and right upper
quadrant pain.
• She has been healthy and denies
any medication use.
• She recently traveled to Chinia. She
had a migraine atach and use
parastemol overdose daily for pain
relive.
• Vital signs are: 123/41, heart rate 109,
respiratory rate 24, and saturations 95%
on room air.
• She is has diffuse abdominal tenderness
and palpable liver edge with a scleral
icterus.
• What is the most likely cause of this
patient’s presentation?
• What are the common etiologies of
acute liver failure?
– Consider:
•
•
•
•
•
A – acetaminophen, hepatitis A, autoimmune
B – hepatitis B
C – cryptogenic, hepatitis C
D – hepatitis D
E – esoteric causes such as Wilson’s and
Budd-Chiari
• F – fatty infiltration such as fatty liver of
pregnancy and Reye
• Initial bloodwork comes back:
– ALT 3826, AST 4826, TBili 5,9, Alk Phos
83,INR 4.2, creatinine 1,2, pH 7.31
• What in the history gives us clues to the
cause?
–
–
–
–
Travel: hepatitis virus?
Over the drugs: acetaminophen?
Natural remedies: drug or toxin?
Childbearing age: fatty liver of pregnancy?
Elevated Liver Tests
• The pattern:hepatic or cholestatic
• AST/ALT>2 is suggestive for alcholic liver
diseases,almost< 400
• Hepatic +>1000:acute viral,toxic,ischemic
hepatitis
• Cholestatic:ALP,GGT
• LIVER FUNCTİON TESTS:Bilurubin,PT
and albumin reflect sentetic capacity of the
liver
• Obtaining further history, her family tells
you that she has been vaccinated against
hepatitis B because she is a lab tech, she
is not pregnant but do not know what
medications and remedies she takes.
• You take the history from the family
because the patient is rapidly becoming
unresponsive.
• What is the definition of fulminant
hepatic failure?
• What are the grades of
encephalopathy?
Acute liver failure (as fulminant hepatic failure,
acute hepatic necrosis, fulminant hepatic necrosis,fulmınan
hepatitis)
• Acute liver failure is characterized
by acute liver injury, hepatic
encephalopathy, and an elevated
prothrombin time/internationalnorma
lized ratio (INR).
• Whenever possible, patients with
acute liver failure should be
managed in an intensive care unit at
a facility capable of performing liver
transplantation (emergency)
• While the time course that
differentiates acute liver failure
from chronic liver failure varies
between reports, a commonly
used cut-off is an illness duration
of <26 weeks.
• Acute liver failure can be subcategorized
based upon how long the patient has been
ill and various cutoffs have been used.
• The last guidelines classify acute liver
failure as hyperacute (<7 days), acute (7 to
21 days), or subacute (>21 days and <26
weeks).
• In patients with hyperacute or acute liver
failure, cerebral edema is common,
whereas it is rare in subacute liver failure.
Renal failure and portal hypertension are
more frequently observed in patients with
subacute liver failure.
• These subcategories have been associated
with prognosis, but the associations reflect
the underlying causes, which are the true
determinants of prognosis.
• Hyperacute liver failure > Subacute liver
failure (better prognosis)
• The better prognosis is related to the fact
that these patients often
have acetaminophen toxicity or ischemic
hepatopathy, diagnoses associated with a
better prognosis than many of the
disorders that may result in subacute liver
failure, such as Wilson disease
Symptoms
•
•
•
•
•
•
•
•
Many of the initial symptoms in patients
with acute liver failure are nonspecific.
They include:
●Fatigue/malaise
●Lethargy
●Anorexia
●Nausea and/or vomiting
●Right upper quadrant pain
●Pruritus
●Jaundice
●Abdominal distension from ascites
physical examination findings
●Jaundice
●Vesicular skin lesions suggestive of
herpes simplex virus
●Fever in patients with herpes simplex
virus
●Right upper quadrant tenderness and
hepatomegaly
●Ascites
Laboratory test abnormalities
•
•
•
•
Laboratory test abnormalities typically
seen in patients with acute liver failure
include:
●Prolonged prothrombin time, resulting in
an INR ≥1.5 (this finding is part of the
definition of acute liver failure and thus
must be present)
●Elevated aminotransferase levels (often
markedly elevated)
●Elevated bilirubin level
●Low platelet
count (≤150,000/mm3, though
• Decreasing aminotransferase levels may
indicate spontaneous recovery but could also
signal worsening of the liver failure with loss of
hepatocyte mass.
• In patients who are improving, the bilirubin and
prothrombin time/INR will decline, whereas in
those with worsening liver failure, the bilirubin
and prothrombin time/INR will continue to rise.
• Because of the prognostic importance of the
prothrombin time/INR, it is recommended that
coagulation factors such as fresh frozen
plasma only be given for invasive procedures
or active bleeding.
• Other laboratory findings that may be seen in
patients with acute liver failure include
• ●Elevated serum creatinine and blood urea
nitrogen
• ●Elevated amylase and lipase
• ●Hypoglycemia
• ●Hypophosphatemia
• ●Hypomagnesemia
• ●Hypokalemia
• ●Acidosis or alkalosis
• ●Elevated ammonia level
• ●Elevated lactate dehydrogenase (LDH) level
Laboratory findings associated
with specific diagnoses
•
•
•
•
•
•
•
Acetaminophen: Very high aminotransferase levels (>3500
int. unit/L), low bilirubin, high INR
●Ischemic hepatic injury: Very high aminotransferase levels (25
to 250 times the upper limit of normal), elevated serum LDH
levels
●Hepatitis B: Aminotransferase levels of to 1000 to 2000
int. unit/L are common, alanine aminotransferase (ALT) level
that is higher than the aspartate aminotransferase (AST) level
●Wilson disease: Coombs-negative hemolytic anemia,
aminotransferase levels <2000 int. unit/L, AST to ALT ratio of
>2, normal or markedly subnormal alkaline phosphatase (<40
int. unit/L), alkaline phosphatase (int. unit/L) to total
bilirubin (mg/dL) ratio <4, rapidly progressive renal failure, low
uric acid levels
●Acute
fatty
liver
of
pregnancy/HELLP
syndrome:
Aminotransferase levels <1000 int. unit/L, elevated bilirubin, low
platelet count
●Herpes simplex virus: Markedly elevated transaminases,
leukopenia, low bilirubin
●Reye syndrome, valproate toxicity, or tetracycline toxicity:
Minor to moderate elevations in aminotransferase and bilirubin
levels
History
Patients and/or their families should be asked about:
•
•
•
•
•
•
•
•
•
●Timing of symptom onset (nausea, vomiting, jaundice, mental
status changes).
●History of alcohol use.
●History of prior episodes of jaundice.
●Medication use, including all medications used
●Risk factors for intentional drug overdose, such as a history of
depression or prior suicide attempts.
●Toxin exposure, including occupational toxin exposures or wild
mushroom ingestion.
●Risk factors for acute viral hepatitis, including travel to areas
endemic for hepatitis A or E, intravenous drug use, occupational
exposure, sexual exposure, chronic or inactive hepatitis B infection,
and immunosuppression.
●Risk factors for hepatic ischemia, including hypotension, cardiac
failure, a hypercoagulable disorder, oral contraceptive use, or
malignancy.
●Family history of liver disease, such as Wilson disease.
Physical examination
•
•
•
•
•
Physical examination findings may help identify a
cause of a patient's acute liver failure, but in many
cases the findings, such as jaundice or
hepatomegaly, are nonspecific. The physical
examination may also help identify complications of
acute liver failure, such as cerebral edema and
infection.
All patients should have a routine physical
examination, including a complete skin examination.
In addition, patients suspected of having Wilson
disease should undergo an ocular examination.
Physical examination findings that may point to a
specific cause of acute liver failure include:
●Vesicular skin lesions (herpes simplex virus)
●Kayser-Fleisher rings (Wilson disease)
●Features of preeclampsia, such as hypertension
(HELLP syndrome)
DIFFERENTIAL DIAGNOSIS
•
— The primary entity in the differential
diagnosis of acute liver failure is severe
acute hepatitis.
• Patients with severe acute hepatitis have
jaundice and coagulopathy but lack signs
of hepatic encephalopathy.
Distinguishing the two is important
because patients with severe acute
hepatitis generally have a good
prognosis, whereas those who
progress to acute liver failure have a
high mortality rate and often require
liver transplantation.
• Patients with severe acute alcoholic hepatitis may
present with liver failure that appears to have
developed over the course of weeks to months .
However, patients with alcoholic hepatitis typically
have a history of heavy drinking for many years
and are thus thought to have acute-on-chronic liver
failure.
• Differentiating alcoholic hepatitis from acute liver
failure is important because the two entities are
managed differently (eg, there is a role for
corticosteroids in the treatment of alcoholic
hepatitis, but not in acute liver failure).
• Alcoholic hepatitis should be considered in patients
with a history of heavy alcohol use or who have an
aspartate aminotransferase to alanine
aminotransferase ratio of approximately 2:1.
Neurologic examination
• The
presence
of
hepatic
encephalopathy is one of the
defining characteristics of acute
liver failure. Findings in patients
with hepatic encephalopathy are
variable, ranging from changes in
behavior
to
coma.
Hepatic
encephalopathy is graded from I
to IV.
• Patients with grade I
encephalopathy may have mild
asterixis, whereas pronounced
asterixis is typically seen in
patients with grade II or III
encephalopathy
• Asterixis is typically absent in
patients with grade IV
encephalopathy, who instead may
demonstrate decorticate or
decerebrate posturing.
Encephalopathy
•
•
•
•
major complication
precise mechanism remains unclear
Hypothesis: Ammonia production
Treatment toward reducing ammonia
production
• Watch out airway, prevent aspiration
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
• Cerebral edema may develop in
patients with acute liver failure leading
to increased intracranial pressure
• Cerebral edema is uncommon in
patients
with
grade
I
or
II
encephalopathy, but it is present in 25
to 35 percent of those with grade III
encephalopathy and in approximately
75 percent of those with grade IV
encephalopathy
• Pupillary changes are one sign of
increased intracranial pressure. The pupils
may progress from having a normal
response
(typical
with
grade
Iencephalopathy),
to
being
hyperresponsive
(grade
II
to
III
encephalopathy),
to
being
slowly
responsive (grade III to IV encephalopathy).
• As the coma worsens, the pupils may
become fixed and dilated (a sign typically
associated with brainstem herniation).
• After appropriate resuscitation and
treatment, the patient is more stable. The
family approaches you for more
information. They want to know whether
she is going to need liver transplant.
• What do you tell them and how do you
know?
Acetaminophen-induced disease
Arterial pH <7.3 (irrespective of the grade of encephalopathy)
OR
Grade III or IV encephalopathy AND
Prothrombin time >100 seconds AND
Serum creatinine >3.4mg/dL (301 µmol/L)
All other causes of fulminant hepatic failure
Prothrombin time >100 seconds (irrespective of the grade of encephalopathy)
OR
Any three of the following variables (irrespective of the grade of
encephalopathy)
1. Age <10 years or >40 years
2. Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug
reactions
3. Duration of jaundice before onset of encephalopathy >7 days
4. Prothrombin time >50 seconds
5. Serum bilirubin >18 mg/dL (308 µmol/L)
Treatment
• Monitor PT,pH,glucose level,liver
enzymes,cultures,fluıd balance
• Enteral feeding,dextrose infusıon,thiamine
• Prophlactic ab
• PPİ
• N-acetylcysteine for all causes,expeziaaly
acetimonhen toxicity
• Mechanical Ventilation
• Transport to transplantotoin as soon as
possible
Collaborative Care
Hepatic Encephalopathy
• 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
• Hepatic encephalopathy (HE) or
portosystemic encephalopathy (PSE) is a
reversible syndrome of impaired brain
function occurring in patients with
advanced liver failure
• However, HE is not a single clinical entity. It
may reflect either a reversible metabolic
encephalopathy, brain atrophy, brain edema,
or any combination of these conditions.
• The mechanisms causing brain dysfunction in
liver failure are still unknown. In advanced
coma, the effects of brain swelling, impaired
cerebral perfusion, and reversible impairment
of neurotransmitter systems cannot be
distinguished. Furthermore, these events
overlap, at least in models of acute liver
failure.
• Many patients have
elevated
ammonia
levels, but this is not
sensitive or specifik
for diagnosis…….
Ammonia is the best characterized neurotoxin that precipitates HE.
The gastrointestinal tract is the primary source of ammonia, which
enters the circulation via the portal vein.
Ammonia is produced by enterocytes from glutamine and by colonic
bacterial catabolism of nitrogenous sources, such as ingested protein
and secreted urea.
The intact liver clears almost all of the portal vein ammonia,
converting it into glutamine and preventing entry into the systemic
circulation. However, glutamine is metabolized in mitochondria
yielding glutamate and ammonia, and glutamine-derived ammonia
may interfere with mitochondrial function leading to astrocyte
dysfunction
•
•
•
•
The various hypotheses of the pathogenesis of hepatic
encephalopathy (HE) are not mutually exclusive. It seems likely that
many of the described abnormalities may be present at the same
time and may ultimately be responsible for the development of HE.
The synergistic action of ammonia with other toxins may account for
many of the abnormalities occurring in liver failure, such as the
changes in blood-to-brain transport of neurotransmitter precursors,
the metabolism of amino acid neurotransmitters, and cerebral
glucose oxidation.
These changes may lead to activation of inhibitory (GABA,
serotonin) and impairment of excitatory (glutamate, catecholamines)
neurotransmitter systems, resulting in enhanced neural inhibition.
Sepsis, neuroinflammation, and alterations in gut flora appear to be
additional factors in the development of altered brain function in
advanced liver disease.
•
•
•
•
•
Hepatic encephalopathy describes a spectrum of potentially
reversible neuropsychiatric abnormalities seen in patients
with liver dysfunction and/or portosystemic shunting.
Overt hepatic encephalopathy develops in 30 to 45 percent
of patients with cirrhosis and in 10 to 50 percent of patients
with transjugular intrahepatic portal-systemic shunts
The International Society for Hepatic Encephalopathy and
Nitrogen Metabolism consensus defines the onset of
disorientation or asterixis as the onset of overt hepatic
encephalopathy.
Some patients with hepatic encephalopathy have subtle
findings that may only be detected using specialized tests, a
condition known as minimal hepatic encephalopathy
Minimal hepatic encephalopathy is seen in up to 80 percent
of patients with cirrhosis
• In addition, it may be difficult to differentiate
mild (grade I) hepatic encephalopathy from
minimal
hepatic
encephalopathy.
The
International
Society
for
Hepatic
Encephalopathy and Nitrogen Metabolism
consensus suggests that the term "covert
hepatic encephalopathy" be used for both
minimal and mild (grade I) hepatic
encephalopathy, and that the term "overt
hepatic encephalopathy" be used for more
severe hepatic encephalopathy (grades II-IV).
• Hepatic encephalopathy is often easy to
detect in patients presenting with overt
neuropsychiatric symptoms.
• It may be more difficult to detect in
patients with chronic liver diseases who
have mild signs of altered brain function,
particularly if the underlying cause of the
liver disease may be associated with
neurologic manifestations (such as
alcoholic liver disease or Wilson's
disease).
•
•
•
•
Patients with grade I encephalopathy may have mild
asterixis, whereas pronounced asterixis is seen in patients
with grade II or III encephalopathy .
Asterixis is typically absent in patients with grade IV
encephalopathy, who instead may demonstrate decorticate
or decerebrate posturing.
However, this grading system does not take into account
patients with minimal hepatic encephalopathy who may
have very subtle signs and symptoms that may only be
detected using specialized psychometric tests].
In addition, it may be difficult to differentiate mild (grade I)
hepatic
encephalopathy
from
minimal
hepatic
encephalopathy. The International Society for Hepatic
Encephalopathy and Nitrogen Metabolism consensus
suggests that the term "covert hepatic encephalopathy" be
used for both minimal and mild (grade I) hepatic
encephalopathy, and that the term "overt hepatic
encephalopathy" be used for more severe hepatic
encephalopathy (grades II-IV).
• Hepatic encephalopathy is characterized by
cognitive deficits and impaired neuromuscular
Patients with minimal hepatic encephalopathy
have subtle cognitive deficits, often appear to
be asymptomatic, and may only be detected
with psychomotor or electrophysiologic testing.
• Patients with overt hepatic encephalopathy
have signs and symptoms that can be
detected clinically, without the use of
psychomotor testing (though psychomotor
testing may be helpful in evaluating patients
with mild encephalopathy).
Liver CIRRHOSIS
Doç.Dr.Atakan
Yeşil
Yeditepe
Unıversıty
Department of
Gastroenterology
• Consequence of chronic
liver disease characterized
by replacement of liver
tissue by fibrosis, scar
tissue and regenerative
nodules leading to
progressive loss of liver
function
• Hepatic fibrosis is a reversible wound
healing response characterized by
accumulution of extracelüler matrix made
up collagen fibrils.
• Cirrhosis is defined by global hepatic
fibrosis and reduced hepatic synthetic
function
etiology
•
•
•
•
Alcohol
Chronic hepatitis B
Chronic hepatitis C
Other:
Haemochromatosis
Non-alcoholic fatty liver disease
Primary biliary cirrhosis
Sclerosing cholangitis
Autoimmune hepatitis
Cystic fibrosis...
The answer is C.
• Unlike some other causes of cirrhosis,
pathologically it is characterized by small, fine
scarring and small regenerative nodules.
• Therefore, it sometimes is referred to as
micronodular cirrhosis. There is clear
evidence that excessive alcohol use in
the setting of chronic hepatitis C
strongly
increases
the
risk
of
development of cirrhosis; therefore,
screening and appropriate counseling
are essential.
• Ethanol results in proportionally greater
inhibition of ALT synthesis than AST
synthesis. Therefore, serum AST is
usually disproportionately elevated
relative to ALT, resulting in a ratio
greater than 2
• Hemochromatosis
is
a
common disorder of iron
storage
in
which
inappropriate increases in
intestinal iron absorption
result
in
excessive
deposition
in
multiple
organs but predominantly in
the liver.
• There are two forms: hereditary
hemochromatosis,
in
which
the
majority of cases are associated with
mutations of the HFE gene, and
secondary iron overload, which usually is
associated with iron-loading anemias such
as thalassemia and sideroblastic anemia.
• Serum ferritin testing and plasma iron
studies can be very suggestive of the
diagnosis, with the ferritin often >500
μg/L and transferrin saturation of 50 to
100%.
• However, these tests are not conclusive,
and further testing is still required for the
diagnosis.
• Although liver biopsy and evaluation for
iron deposition or a hepatic iron index
(μg/g dry weight)/56 × age > 2 is the
definitive diagnosis, genetic testing is
widely available today, and because of the
high prevalence of HFE gene mutations
associated
with
hereditary
hemochromatosis, it is recommended for
diagnostic evaluation.
• If the genetic testing is inconclusive, the
invasive liver biopsy evaluation may be
indicated.
• The presence of cirrhosis in an elderly woman with no
prior risk factors for viral or alcoholic cirrhosis should
raise the possibility of primary biliary cirrhosis (PBC).
• It is characterized by chronic inflammation and fibrous
obliteration of intrahepatic ductules. The cause is
unknown, but autoimmunity is assumed as there is an
association with other autoimmune disorders, such as
autoimmune thyroiditis, CREST syndrome, and the sicca
syndrome.
• The vast majority of patients with
symptomatic disease are women. AMA is
positive in over 90% of patients with PBC
and only rarely is positive in other
conditions. This makes it the most useful
initial test in the diagnosis of PBC.
• Since there are false-positives, if AMA is
positive, a liver biopsy is performed to
confirm the diagnosis.
Pathology
MICRONODULAR
CIRRHOSIS
• Uniform, small nodules
up to 3 mm in diameter
• Often caused by alcohol
damage
Pathology
MACRONODULAR CIRRHOSIS
• Large nodules
• Often seen following hepatitis B infection
• Cirrhosis with complicatons of encephalopathy, ascites
or variceal haemorrhage – DECOMPENSATED
CIRRHOSIS
• Cirrhosis without any of these complications –
COMPENSATED CIRRHOSIS
Manifestations of Liver Cirrhosis
Fig. 42-5
Clinical Manifestations
Early Manifestations
• Onset usually insidious
• GI disturbances:
–
–
–
–
Anorexia
Dyspepsia
Flatulence
N-V, change in bowel habits
Clinical Manifestations
Early Manifestations
•
•
•
•
Abdominal pain
Fever
Weight loss
Enlarged liver or spleen
Clinical Manifestations
Late Manifestations
• Two causative mechanisms
– Hepatocellular failure
– Portal hypertension
Clinical Manifestations
Jaundice
• Occurs because of insufficient
conjugation of bilirubin by the liver
cells, and local obstruction of
biliary ducts by scarring and
regenerating tissue
Clinical Manifestations
Jaundice
• Intermittent jaundice is characteristic
of biliary cirrhosis
• Late stages of cirrhosis the patient
will usually be jaundiced
Clinical Manifestations
Skin
• Spider angiomas (telangiectasia, spider nevi)
• Palmar erythema
Clinical Manifestations
Endocrine Disturbances
• Steroid hormones of the adrenal cortex (aldosterone),
testes, and ovaries are metabolized and inactivated
by the normal liver
Clinical Manifestations
Endocrine Disturbances
• Alteration in hair distribution
– Decreased amount of pubic hair
– Axillary and pectoral alopecia
Clinical Manifestations
Hematologic Disorders
• Bleeding tendencies as a result of decreased
production of hepatic clotting factors (II, VII, IX, and
X)
Clinical Manifestations
Hematologic Disorders
• Anemia, leukopenia, and thrombocytopenia are
believed to be result of hypersplenism
Clinical Manifestations
Peripheral Neuropathy
• Dietary deficiencies of thiamine, folic acid, and
vitamin B12
Complications
•
•
•
•
Portal hypertension and esophageal varices
Peripheral edema and ascites
Hepatic encephalopathy
Fetor hepaticus
• Complications
of
portal
hypertension begin to devolop
when portal pressure reahes
values>=12 mmHG normal<7
mmHg
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
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
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
Peripheral Edema and Ascites
• Ascites:
- Intraperitoneal accumulation of
watery fluid containing small
amounts of protein
ASCITES
• Presence of fluid in the
peritoneal cavity
• Therapy: diuretics
paracentesis
Complications
Peripheral Edema and Ascites
• Factors involved in the pathogenesis of ascites:
- Hypoalbuminemia
-  Levels of aldosterone
-  Portal hypertension
Complications
Hepatic Encephalopathy
• Liver damage causes blood to enter systemic
circulation without liver detoxification
Complications
Hepatic Encephalopathy
• Main pathogenic toxin is NH3 although other
etiological factors have been identified
• Frequently a terminal complication
Stage 4coma personality
1- Frank
23Mild
Drowsiness,
Somnolence
confusion,
, disorientation,
decreased
changes,
attention,
marked
intermittent
irritability,
confusion,
reversedspeech
disorientation
slurred
sleep pattern.
Complications
Fetor Hepaticus
• Musty, sweetish odor detected on the patient’s breath
• From accumulation of digested by-products
Development of Ascites
Fig. 42-
Diagnostic Studies
•
•
•
•
Liver function tests
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
• SAAG: serum ascites
albumin- ascitic ascites
albumin
• >1.1:portal hipertansiyon
• <1.1 exculuda cirrosis and
portal hypertension
• Ascitic total protein levels
greater than 3.5 and asitic
albumin levels greater than
2.5 suggest a cardiac cause
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)
•Patients with cirrhosis
should be screened for
varices every year with
UEG
Collaborative Care
Esophageal Varices
• Endoscopic sclerotherapy or ligation
• Balloon tamponade
• Surgical shunting procedures (e.g., portacaval shunt,
TIPS)
Collaborative Care
Hepatic Encephalopathy
• 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
• Hepatic encephalopathy (HE) or
portosystemic encephalopathy (PSE) is a
reversible syndrome of impaired brain
function occurring in patients with
advanced liver failure




Patients with grade I encephalopathy may have mild
asterixis, whereas pronounced asterixis is seen in patients
with grade II or III encephalopathy .
Asterixis is typically absent in patients with grade IV
encephalopathy, who instead may demonstrate
decorticate or decerebrate posturing.
However, this grading system does not take into account
patients with minimal hepatic encephalopathy who may
have very subtle signs and symptoms that may only be
detected using specialized psychometric tests].
In addition, it may be difficult to differentiate mild (grade I)
hepatic
encephalopathy
from
minimal
hepatic
encephalopathy. The International Society for Hepatic
Encephalopathy and Nitrogen Metabolism consensus
suggests that the term "covert hepatic encephalopathy"
be used for both minimal and mild (grade I) hepatic
encephalopathy, and that the term "overt hepatic
encephalopathy" be used for more severe hepatic
encephalopathy (grades II-IV).
• However, HE is not a single clinical entity.
It may reflect either a reversible metabolic
encephalopathy, brain atrophy, brain
edema, or any combination of these
conditions.
• The
mechanisms
causing
brain
dysfunction in liver failure are still
unknown. In advanced coma, the effects of
brain
swelling,
impaired
cerebral
perfusion, and reversible impairment of
neurotransmitter systems cannot be
distinguished. Furthermore, these events
overlap, at least in models of acute liver
failure.
•Many patients have
elevated
ammonia
levels, but this is not
sensitive or specifik
for diagnosis…….
•
The various hypotheses of the pathogenesis of
hepatic encephalopathy (HE) are not mutually
exclusive. It seems likely that many of the described
abnormalities may be present at the same time and
may ultimately be responsible for the development of
HE.
• The synergistic action of ammonia with other toxins
may account for many of the abnormalities occurring
in liver failure, such as the changes in blood-to-brain
transport of neurotransmitter precursors, the
metabolism of amino acid neurotransmitters, and
cerebral glucose oxidation.
• These changes may lead to activation of inhibitory
(GABA, serotonin) and impairment of excitatory
(glutamate,
catecholamines)
neurotransmitter
systems, resulting in enhanced neural inhibition.
• Sepsis, neuroinflammation, and alterations in gut
flora appear to be additional factors in the
development of altered brain function in advanced
liver disease.





Hepatic encephalopathy describes a spectrum of
potentially reversible neuropsychiatric abnormalities seen
in patients with liver dysfunction and/or portosystemic
shunting.
Overt hepatic encephalopathy develops in 30 to 45
percent of patients with cirrhosis and in 10 to 50 percent
of patients with transjugular intrahepatic portal-systemic
shunts
The International Society for Hepatic Encephalopathy and
Nitrogen Metabolism consensus defines the onset of
disorientation or asterixis as the onset of overt hepatic
encephalopathy.
Some patients with hepatic encephalopathy have subtle
findings that may only be detected using specialized tests,
a condition known as minimal hepatic encephalopathy
Minimal hepatic encephalopathy is seen in up to 80
percent of patients with cirrhosis
 In addition, it may be difficult to
differentiate mild (grade I) hepatic
encephalopathy from minimal hepatic
encephalopathy.
The
International
Society for Hepatic Encephalopathy and
Nitrogen
Metabolism
consensus
suggests that the term "covert hepatic
encephalopathy" be used for both
minimal and mild (grade I) hepatic
encephalopathy, and that the term "overt
hepatic encephalopathy" be used for
more severe hepatic encephalopathy
(grades II-IV).
• Hepatic encephalopathy is often easy to
detect in patients presenting with overt
neuropsychiatric symptoms.
• It may be more difficult to detect in
patients with chronic liver diseases who
have mild signs of altered brain function,
particularly if the underlying cause of the
liver disease may be associated with
neurologic manifestations (such as
alcoholic liver disease or Wilson's disease).
1.Lactulose:
• Thanks……