Approach to the Patient with
Liver Disease Chapter 301 Harrison 2012
Baghbanian M.
Gasteroentrologist
Sadughi hospital
1390/7/27
Diagnosis of liver disease is made by :
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Careful history
Physical examination
Laboratory tests
Radiologic examinations
Liver biopsy
– less for diagnosis than for grading and staging
Liver Structure and Function
• largest organ of the body
• 1–1.5 kg
• 1.5–2.5% of lean body mass.
• size and shape of the liver vary and match
the general body shape
The liver is located in ?
RUQ under the right lower rib cage against the
diaphragm and projects into the LUQ
The liver is held by ?
Ligamentous attachments to the diaphragm
 Peritoneum
 Great vessels
 Upper gastrointestinal organs
Liver blood supply?
Dual blood supply:
20% : hepatic artery(oxygen-rich)
from celiac artery
80% : portal vein (nutrient-rich )
from stomach, intestines, pancreas, and spleen
Liver cells?
The majority of cells :
– hepatocytes (2/3 of the mass of the liver)
The remaining cell are:
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Kupffer cells (reticuloendothelial system)
stellate (Ito or fat-storing) cells
endothelial cells and blood vessels
bile ductular cells
Liver structure?
In light microscopy:
Lobules with portal areas at the periphery and
central veins in the center of each lobule.
Portal areas?
Consist of :
 small veins
 Arteries
 bile ducts
 lymphatics
organized in a loose stroma of matrix and collagen.
Acini?
physiologic unit of the liver :
 helps to explain the morphologic patterns
and zonality of many vascular and biliary
diseases not explained by the lobular
arrangement.
Acini
 fenestrae in sinusoids→ free flow of plasma
but not cellular elements.
 plasma is in direct contact with hepatocytes
in the subendothelial space of Disse.
Acini
Blood flowing:
– zone 1 → zone 3 of the acinus
– portal veins → hepatic (central ) veins
Bile flowing:
 zone 3 → zone 1 of the acinus
Hepatocytes function?
1-synthesis of most proteins
– (albumin, coagulation factors)
2-production of bile
– (bile acids, cholesterol, phospholipids)
3-regulation of nutrients
– (glucose, glycogen, lipids, amino acids)
4-metabolism and conjugation of compounds for
excretion in bile or urine
– (bilirubin, drugs)
most commonly liver "function" tests
Serum bilirubin
– is a measure of hepatic conjugation and excretion
Albumin and prothrombin time
– are measures of protein synthesis.
hepatic dysfunction: Abnormalities of bilirubin,
albumin, and prothrombin time
liver disease patterns?
Hepatocellular diseases :
inflammation and necrosis
– (viral hepatitis or alcoholic liver disease)
Cholestatic diseases:
inhibition of bile flow
– (gallstone or malignancy , primary biliary cirrhosis)
Mixed pattern:
hepatocellular + cholestatic
– ( cholestatic forms of viral hepatitis and many drug-induced liver
diseases).
Liver disease patterns is important?
pattern of onset + prominence of symptoms
can rapidly suggest a diagnosis
symptoms of liver disease?
Fatigue
Itching
RUQ pain
Nausea
Poor appetite
Abdominal distention
GI bleeding
liver disease with no symptoms?
Many patients with liver disease are no
symptomatic
Manifestaion : abnormalities in liver tests
– As a part of a routine physical examination
– Or screening for blood donation
– Or for insurance or employment.
Diagnosis : HOW?
1- PATTERN of disease?
– (hepatocellular, cholestatic, or mixed injury)
2- Specific ETIOLOGIC ?
3- Grading ?
– (severity or activity of disease—active or inactive, and
mild, moderate, or severe)
4-Staging ?
– (whether acute or chronic; early or late; precirrhotic,
cirrhotic, or end-stage)
Clinical history
should focus on
symptoms of liver disease:
– their nature
– patterns of onset
– patterns of progression
— potential risk factors for liver disease.
Clinical history
Symptoms can also suggest the presence of:
 cirrhosis and end-stage liver disease
 complications of cirrhosis such as portal
hypertension.
Fatigue
The most common and most characteristic
symptom of liver disease.
 Typically after activity or exercise
Rarely present or severe in the morning after
adequate rest
afternoon versus morning
Nausea Vomiting
Nausea occurs with more severe liver disease
 May be provoked by odors of food or eating
fatty foods.
Vomiting can occur but is rarely persistent or
prominent.
Poor appetite with weight loss
Poor appetite with weight loss occurs
commonly in acute liver diseases but
is rare in chronic disease
Except advanced cirrhosis
Diarrhea
Diarrhea is uncommon in liver disease
Except with severe jaundice
– lack of bile acids can lead to steatorrhea
RUQ pain
RUQ pain occurs in many liver diseases and is
usually marked tenderness
The pain arises from stretching or irritation of
Glisson's capsule, which is rich in nerve
endings.
Severe RUQ pain
Is most typical of:
– Gallbladder disease
– Liver abscess
– Severe venoocclusive disease
Occasional accompaniment of acute hepatitis.
Itching
acute liver disease
– early in obstructive jaundice
– later in hepatocellular disease (acute hepatitis).
chronic liver diseases
– cholestatic disease (PSC and PBC) occur before the
onset of jaundice
– Itching can occur in any liver disease, particularly
cirrhosis
Jaundice
hallmark symptom of liver disease and perhaps
the most reliable marker of severity.
Patients usually report darkening of the urine
before scleral icterus.
Jaundice is rarely detectable in bilirubin level
<2.5 mg/dL.
severe Jaundice
With severe cholestasis :
 lightening of the color of the stools
steatorrhea
Jaundice without dark urine
Usually indicates indirect hyperbilirubinemia :
 Hemolytic anemia
 Genetic disorders of bilirubin conjugation
– Gilbert's syndrome : common and benign
– Crigler-Najjar syndrome:rare and severe
– Gilbert's syndrome affects 5% of the population;
jaundice is more : after fasting and stress.
Risk factors for liver disease
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Personal habits ( Alcohol use , Injection drug use)
Medications ( herbal , OCP, and over-the-counter)
Sexual activity
Exposure to jaundiced or other high-risk persons
Recent surgery
Remote or recent blood products transfusion
Occupation
Accidental exposure to blood or needlestick
Familial history of liver disease.
assessing the risk of viral hepatitis
Careful history of sexual activity include:
– the number of sexual partners
– for men, a history of sex with men.
Sexual exposure is :
common mode of spread of hepatitis B
rare for hepatitis C
Assessing the risk of viral hepatitis
A family history of hepatitis, liver disease, and
liver cancer is also important.
Maternal-infant transmission occurs with both
hepatitis B and C
Vertical spread of HBV can now be prevented by
passive and active immunization of the infant
at birth
Vertical spread of hepatitis C
Is uncommon
There are no reliable means of prevention
Transmission is more common in :
– HIV-co-infected mothers
– Prolonged and difficult delivery
– Early rupture of membranes
– Internal fetal monitoring
History of injection drug use
Even in the remote past, is important for
hepatitis B and C.
Injection drug use is now the single most
common risk factor for hepatitis C
Blood transfusion
Transfusion with blood products is no longer an
important risk factor for acute viral hepatitis
Before :
1992 is important risk factor for hepatitis C.
– HCV Ab didn’t checked
1986 is a risk factor for hepatitis B.
– anti-HBc didn’t checked
Risk factors for hepatitis A
Travel to an underdeveloped area of the world
Exposure to persons with jaundice
Exposure to young children in day-care centers
Eating shellfish(rare)
Risk factors for Hepatitis E
Is more common in Asia and Africa
Eating raw or undercooked pork or game (deer
and wild boars)
Tattooing and body piercing?
For hepatitis B and C are frequently mentioned
but are actually quite rare types of exposure
Alcohol
In the United States,70% of adults drink alcohol ,
but significant alcohol intake is less common
more than 2 drinks (22–30 g) per day in women
3 drinks (33–45 g) in men
a
A Alcoholic liver disease
drunk for 10 years
Family history
Familial causes of liver disease include:
– Wilson's disease
– Hemochromatosis
– Alfa 1 antitrypsin deficiency
– Familial intrahepatic cholestasis
– Benign recurrent intrahepatic cholestasis
– Alagille syndrome.
Wilson's disease
Severe liver disease in childhood or adolescence
with a family history of liver disease or
neuropsychiatric disturbance
investigation for Wilson's disease
Hemochromatosis
Liver disease in adulthood WITH:
– Family history of cirrhosis
– Diabetes
– Endocrine failure
investigation of iron status
Hemochromatosis
Adult patients with abnormal iron studies
genotyping of the HFE gene for the C282Y and
H63D mutations
Alfa1 ATD
A family history of emphysema + liver disease
investigation of 1AT levels
if low →Pi genotype
Physical examination
Complements rather than replaces the need for
other diagnostic approaches.
Is normal In many patients unless the disease is
acute or severe and advanced.
Can reveal signs that point to a specific diagnosis,
either in risk factors or diseases .
Physical examination
Typical physical findings in liver disease are:
Icterus
Hepatomegaly
Hepatic tenderness
Splenomegaly
Spider angiomata
Palmar erythema
Excoriations
Signs of advanced liver disease?
Muscle wasting
Ascites and edema
Dilated abdominal veins
Hepatic fetor
Asterixis
Mental confusion
Stupor and coma.
Bruising
Males with cirrhosis
Particularly when related to alcohol
signs of hyperestrogenemia
(gynecomastia, testicular atrophy, and loss of
male-pattern hair distribution )
Physical examination - Icterus
Sclera under natural light.
fair-skinned individuals : yellow skin may be obvious
dark-skinned individuals, the mucous membranes below
the tongue demonstrate jaundice.
Jaundice is rarely detectable if the serum bilirubin level is
< (2.5 mg/dL) but may remain detectable below this
level during recovery from jaundice (protein and tissue
binding of bilirubin).
Spider angiomata and palmar
erythema
occur in:
Acute liver disease
Chronic liver disease
Especially prominent in cirrhosis
Occur in normal individuals and are frequently
during pregnancy
Spider angiomata?
Superficial, tortuous arterioles
fill from the center outward.
only on the arms, face, upper torso
Pulsatile and difficult to detect in dark-skinned
individuals
Hepatomegaly
Is not a very reliable sign of liver disease
(variability of the size and shape)
Marked hepatomegaly is typical :
– Cirrhosis
– Venoocclusive disease
– Infiltrative disorders (amyloidosis, metastatic or
primary cancers of the liver,alcoholic hepatitis.)
Hepatomegaly
Careful assessment of the liver edge may also
demonstrate unusual:
– Firmness
– Irregularity of the surface
– Frank nodules
Splenomegaly
occurs in many medical conditions but can be a
significant physical finding in liver disease.
The availability of ultrasound (US) assessment of
the spleen allows for confirmation of the
physical finding.
Ascites
Ascites is best appreciated by attempts to detect
shifting dullness by careful percussion.
US examination will confirm the finding of
ascites in equivocal cases.
Edema ; causes?
Hypoalbuminemia
Venous insufficiency
Heart failure
Medications(NSAID)
Hepatic failure?
signs or symptoms of hepatic encephalopathy in
a person with severe acute or chronic liver
disease.
.
first signs of hepatic encephalopathy
?
change in sleep patterns and personality
irritability
mental dullness
In acute liver failure:
mania may be present
Physical findings Hepatic failure?
asterixis and flapping tremors of the body and
tongue.
Fetor hepaticus :
• slightly sweet, ammoniacal odor
• in patients with liver failure
• particularly portal-venous shunting of blood
Other causes of coma
Electrolyte imbalances
Sedative use
Renal failure
Respiratory failure
should be excluded in liver disease
Hepatic encephalopathy in acute
hepatitis
Is major criterion for:
• Diagnosis of fulminant hepatitis
• Indicates a poor prognosis.
Hepatic encephalopathy In chronic
liver disease
usually triggered by a medical complication :
– GIB
– Over diuresis
– Uremia and electrolyte imbalance
– Dehydration
– Infection
– Constipation
– Narcotic analgesics.
Hepatic encephalopathy examination?
Connect a series of 25 numbered circles rapidly
using a pencil.
– The normal range is 15–30 seconds
– delayed in patients with early encephalopathy.
 drawing abstract objects
 comparison of signature to previous.
Other signs of advanced liver disease
Umbilical hernia from ascites
Hydrothorax
Prominent veins over the abdomen
Caput medusa
• resulting from the recanulation of the umbilical vein.
hyperdynamic circulation
• Widened pulse pressure
Hyperdynamic circulation
cirrhosis
fluid and sodium retention
increased cardiac output
reduced peripheral resistance
hyperdynamic circulation
Widened pulse pressure
Hepatopulmonary syndrome?
In patients with long-standing cirrhosis and
portal hypertension
Defined by triad :
– liver disease
– hypoxemia
– pulmonary arteriovenous shunting.
Hepatopulmonary syndrome
examination?
Characterized by:
platypnea
orthodeoxia
– shortness of breath and oxygen desaturation that
occur paradoxically in upright position
pulse oximetry is reliable screening test
Skin disorders in liver disease
Hyperpigmentation in: chronic cholestatic diseases
(PBCand PSC)
Xanthelasma and tendon xanthomata as result of
retention of lipids and cholesterol.
Gray pigmentation occurs with hemochromatosis
Mucocutaneous vasculitis with palpable purpura :typical
of cryoglobulinemia of HCV but also occur in HBV.
Specific physical signs in liver disease
Kayser-Fleischer ring
• in Wilson's disease
• golden-brown copper in Descemet's membrane
at periphery of the cornea
• best seen by slit-lamp examination.
Dupuytren contracture , parotid enlargement
– suggestive of alcoholic liver disease
Laboratory Testing
Tests of liver injury:
– ALT , AST
– AlkP
– Bilirubin
Tests of liver function:
– Albumin
– Prothrombin time.
Further testing may be necessary:
Gama glutamyl transpeptidase (gGT)
– ALP elevations is due to liver disease?
Viral hepatitis serology
Markers of PBC (AMA)
Markers of sclerosing cholangitis (P-ANCA)
Markers of AIH(antinuclear, smooth-muscle,
liver-kidney microsomal Ab).
Diagnostic Imaging
US and CT:
– Have a high sensitivity for detecting biliary duct
dilatation
– First-line options in patient with obstructive
jaundice.
Imaging in Fatty liver
All three modalities can detect a fatty liver,
which appears bright
CT and MRI in fatty liver :
quantify liver fat
monitoring therapy
visualization of the biliary tree
MRCP offers several advantages over ERCP
 no need for contrast media or radiation
 images can be acquired faster
 less operator dependent
 no risk of pancreatitis.
MRCP:
is superior to US and CT for choledocholithias
 It is useful in congenital biliary abnormalities.
visualization of the biliary tree
ERCP:
 is more valuable in ampullary lesions and PSC
 allows for biopsy , direct visualization of the
ampulla and CBD, intraductal SONO.
 provides several therapeutic options in
obstructive jaundice (sphincterotomy, stone
extraction, and placement of nasobiliary
catheters and biliary stents.)
Hepatic vasculature imaging
Doppler US and MRI are used to assess:
– hepatic vasculature and hemodynamics
– monitor surgically or radiologically placed vascular
shunts such as transjugular intrahepatic
portosystemic shunts.
Diagnostic Imaging in hepatic masses
CT and MRI are indicated for the evaluation of :
– hepatic masses
– staging of liver tumors
– preoperative assessment
sensitivity is high
specificity remains a problem
two and sometimes three studies are needed
Diagnostic Imaging -elastography
Measure hepatic stiffness as a means of assessing
hepatic fibrosis
US and MR elastrography
– Detect hepatic fibrosis
– Obviate the need for liver biopsy
Elastography may be an appropriate means of
monitoring fibrosis and disease progression
Interventional radiologic techniques
-Biopsy of lesions
 radiofrequency ablation
Chemoembolization of cancer
Insertion of drains into hepatic abscesses
Measurement of portal pressure
 vascular shunts
Liver Biopsy
The criterion standard in the evaluation of liver
disease, particularly chronic liver diseases.
Is necessary for diagnosis sometimes
Is more useful in:
– Assessing the severity (grade and stage)
– Predicting prognosis
– Monitoring response to treatment
Liver Biopsy
The size of the liver biopsy length of 1.5–2 cm is
necessary for accurate assessment of fibrosis.
noninvasive means of assessing disease activity
( blood tests) and fibrosis (elastography ) may
replace liver biopsy in assessing stage and
grade of disease.
Liver Biopsy
Usually not needed in the diagnosis and
management of acute liver disease
exceptions that diagnosis remains unclear despite
thorough clinical and laboratory investigation.
Is helpful in the diagnosis of:
– Drug-induced liver disease
– acute alcoholic hepatitis.
Liver Biopsy
liver biopsy plays an important role in the
diagnosis of:
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Autoimmune hepatitis
Primary biliary cirrhosis
Nonalcoholic steatohepatitis
Alcoholic steatohepatitis
Wilson's disease (quantitative hepatic copper )
Strict diagnostic criteria have not been developed
for most liver diseases
Liver Biopsy
liver biopsy is an invasive procedure and not
without complications
→ should be used only when contribute to
management and therapeutic decisions
For patients with suspected liver
disease
1- initial testing for routine liver tests such as
bilirubin, albumin, ALT, AST, AlkP
2-These results will establish whether the
pattern of abnormalities is hepatic,
cholestatic, or mixed.
For patients with suspected liver
disease whether the disease is acute or chronic?
– If the disease is acute and if history, laboratory
tests, and imaging studies do not reveal a
diagnosis
liver biopsy establish the
diagnosis.
– If the disease is chronic
liver biopsy can
be helpful not only for diagnosis but also to grade
the activity and stage the progression of disease.
liver disease evaluation in
Immunocompromized patients
In patients with HIV infection or after bone marrow or
solid organ transplantation,
1- evaluation of opportunistic infections
(adenovirus, cytomegalovirus, coccidioidomycosis)
2- vascular and immunologic conditions (venoocclusive
disease, graft-versus-host disease).
Causes of chronic liver disease?
The most common Causes are :
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Chronic hepatitis C
Alcoholic liver disease
Nonalcoholic steatohepatitis
Chronic hepatitis B
Autoimmune hepatitis
Sclerosing cholangitis
Primary biliary cirrhosis
Hemochromatosis
Wilson's disease.
Grading
• Grading refers to an assessment of the
severity or activity of liver disease, whether
acute or chronic; active or inactive; and mild,
moderate, or severe.
• Liver biopsy is the most accurate means of
assessing severity, particularly in chronic liver
disease.
Serum aminotransferase levels
 Noninvasive means to follow disease activity,
But not always reliable in reflecting disease
severity.
Normal aminotransferase levels in
HBsAg(+) patients
Indicate:
– Inactive HBsAg carrier state or
– Mild chronic hepatitis B or
– Fluctuating disease activity
Serum testing for:
Hbe antigen
HBV DNA
(can help resolve these different patterns)
but these markers can also fluctuate and change over time.
Serum aminotransferase levels in
chronic hepatitis C
Similar to hepatitis B , serum aminotransferase
levels can be normal despite moderate activity
of hepatitis C disease.
•
Serum aminotransferase levels
in steatohepatitis
In alcoholic and nonalcoholic steatohepatitis:
– aminotransferase levels are quite unreliable in
reflecting severity.
In these conditions, liver biopsy is helpful in
guiding and recommending therapy
scales for grading activity in chronic
liver disease
The most common are:
– Histology activity index
– Ishak histology scale.
The amount of fibrosis is generally staged on:
– 0 to 4+ in Metavir scale
– 0 to 6+ scale in Ishak scale
Staging in chronic liver diseases
staging=amount of fibrosis
the most accurate method :Liver biopsy
Early stage
staging precirrhotic
Cirrhotic
Mild to moderate stages of hepatic fibrosis are
detectable only by liver biopsy.
importance of staging?
Prognosis
Guiding management of complications
Cirrhotic Patients are candidates for :
– Screening and surveillance for:
Esophageal varices
Hepatocellular carcinoma
Cirrhosis can be staged clinically?
Child-Pugh classification is reliable staging system :
(from 5–15)
5 and 6 → class A (compensated cirrhosis)
7–9 → indicating class B
10–15 → indicating class C .
This scoring system was initially devised to stratify
patients into risk groups prior to undergoing
portal decompressive surgery.
Child-Turcotte-Pugh Scoring
of Liver Disease Severity
Parameter
1 point 2 points
3 points
Bilirubin (uM)
<35
35-50
>50
Albumin (g/l)
>35
30-35
<30
Prothrombin (%) >76
76-63
<63
Encephalopathy
none
mild (gr. 1-2)
severe (gr. 3-4)
Ascites
none
moderate
severe, refractory
Class A = 1-6; Class B = 7-9; Class C = 10-15 points
importance of Child-Pugh score
 Reliable predictor of survival in liver diseases
 Predicts the likelihood of major complications of
cirrhosis such as bleeding from varices and
spontaneous bacterial peritonitis.
 Assess prognosis in cirrhosis
 Provide the standard criteria for listing liver
transplantation
Child-Pugh score of >7 (class B)
Decompensation of cirrhosis
listing liver transplantation.
M×odel for end-stage liver disease
(MELD score)
Assessing for liver transplantation:
MELD score
Child-Pugh system
Less center-to-center variation
More objective
Three noninvasive variables:
– INR
– serum bilirubin
– serum creatinine
PELD
(pediatric end-stage liver disease )
Children below the age of 12 years
Using :
– Bilirubin
– INR
– Serum albumin
– Age
– Nutritional status
Nonspecific Issues in Management of
Patients with Liver Disease
Alcohol use
Medications
Vaccination
Surveillance for complications of liver disease
Management of Alcohol use
Patients with Liver Disease
Alcohol use:
– Alcohol should be used sparingly, by patients with
liver disease.
– Abstinence should be encouraged for:
• all alcohol-related liver disease
• cirrhosis
• receiving interferon-based therapy for hepatitis B or C.
Vaccinations in Patients with Liver
Disease
All patients with liver disease should receive:
– HAV vaccine
Those with risk factors should receive;
– HBV vaccine
should also be encouraged:
– Influenza vaccine
– pneumococcal vaccine
Medications in Patients with Liver
Disease
Patients with liver disease should be careful using
any medications, other than the most necessary.
Drug-induced hepatotoxicity can:
– Mimic many forms of liver disease
– Exacerbate of chronic hepatitis and cirrhosis
Drugs should be suspected in which the cause of
exacerbation is unknown
surveillance for complications of
chronic liver disease
Variceal hemorrhage
upper endoscopy
Patients with cirrhosis: endoscopic obliteration
beta blocker
Hepatocellular carcinoma:
– Patients with cirrhosis
– US of the liver at 6- to 12-month intervals.
Healthy Liver
Hepatic Fibrosis
Cirrhosis
Liver Cancer
THE END
Macronodular cirrhosis
Micronodular cirrhosis
Visible signs
of advanced liver cirrhosis
Gynecomastia
Ascites
Caput Medusae
Umbilical hernia