CIRRHOSIS &

ABNORMAL LIVER
FUNCTION TESTS
Assoc Professor
Pathology Department, Al Nafees Medical College.
Islamabad
Dr Ahsan Kazmi
2
A chronic disease of the liver with wide
spread hepatic parenchymal injury and
hepatocyte destruction.
It may lead to anatomic and functional
abnormalities of blood vessels and bile
ducts
Definition
3
Clinical Features
Insidious development
Often produces no clinical manifestations
Common symptoms:
Anorexia,
nausea,
abdominal discomfort,
weakness, weight loss, and malaise
4
Clinical Features
Physical examination:
Enlargement of the liver and spleen due to
(Portal Hypertension) PHTN
Ascities
Peripheral edema,
Jaundice
Spider angiomas
GI bleeding
Palmer erythema
Right upper quadrant pain
Sign &
symptoms
of Liver
cirrhosis
SPIDER ANGIOMA, CIRRHOSIS
Clinical Features (CONTD)
Clinical features:
Silent
Anorexia, wt. loss, weakness, osteoporosis,
debility
Death caused by:
Hepatic failure
Complications of portal HTN
Hepato-cellular Ca (HCC)
ETIOLOGY
Alcoholic liver disease 60% to 70%
Viral hepatitis 10%
Non Alcoholic Steatotic Hepatitis (NASH)
Biliary diseases 5% to 10%
Primary hemochromatosis 5%
Wilson disease Rare

ETIOLOGY(contd)
1 -Antitrypsin deficiency- Rare
Cryptogenic cirrhosis 10% to 15%
Infrequent types of cirrhosis also include
cirrhosis developing in infants and children
with galactosemia and tyrosinosis
ETIOLOGY
Drug-induced cirrhosis, as with a-
methyldopa.
Severe fibrosis can occur in the setting of
cardiac disease (sometimes called "cardiac
cirrhosis," )
The most common causes are alcoholism
and viral hepatitis

Cirrhosis- Pathogenesis
WEST - One of Top 10 causes of death

End-stage of chronic liver disease is defined by
three
characteristics:
Fibrosis-
1. Bridging fibrous septae
2. Parenchymal nodules
3. Disruption of hepatic parenchymal
architecture
Cirrhosis- Pathogenesis (CONTD)
Parenchymal nodules
Proliferating hepatocytes encircled by
fibrosis, micronodules with diameters very
small (<3 mm,)
macronodules large (several centimeters)
Parenchymal injury and consequent fibrosis
are diffuse, extending throughout liver

Nodularity reflects balance between
regenerative activity and constrictive scarring

Cirrhosis- Pathogenesis (CONTD)
Vascular architecture reorganized with
Formation of abnormal interconnections
between vascular inflow and hepatic vein
outflow channels
Result in portal vein and arterial blood partially
bypassing functional hepatocyte mass

Pathogenesis
Fibrosis
Reversal thought to be rare
Liver contains abundant
metalloproteinases and collagenases
capable of degrading extracellular matrix

Common
Clinical/Pathophysiological
Events
Portal Hypertension WHY? WHERE?
Ascites WHY?
(Heart/Renal?)
Splenomegaly WHY?
Hepatomegaly? WHY?

Common
Clinical/Pathophysiological
Events
Jaundice WHY?
Anemia WHY?
Estrogenic effects WHY?
Coagulopathies (II, VII, IX, X) WHY?
Encephalopathy WHY?

18
Background
Two major syndromes result
Portal hypertension
Hepatic insufficiency.
peripheral and splanchnic vasodilatation with
the resulting hyperdynamic circulatory state
19
Background
Cirrhosis can remain compensated for many
years before the development of a
decompensating event.
Decompensated cirrhosis is marked by the
development of any of the following
complications:
Jaundice Hemorrhage
Ascites Encephalopathy
No specific therapy Except liver transplantation
20
Background
Other complications occur as a consequence of
PHTN and the hyperdynamic circulation.
Gastroesophageal varices result from PHTN,
although hyperdynamic circulation contributes

Ascites results from sinusoidal HTN and sodium
retention, which is 2ndry to vasodilatation and
activation of neurohumoral systems
21
Background
The hepatorenal syndrome results from
severe peripheral vasodilatation that leads to
renal vasoconstriction.
Hepatic encephalopathy is a consequence of
shunting of blood through portosystemic
collaterals (due to PHTN), brain edema
(cerebral vasodilatation), and hepatic
insufficiency.


23
Portal Hypertension
Portal vein collects blood from GI tract,
pancreas and spleen to the liver

Contains oxygen, nutrients and
bacterial waste

Portal Hypertension
A pathway for detoxification and
metabolism of absorbed substance.

Fibrosis and nodular regeneration of liver
with distortion of hepatic veins is the
main cause of intrahepatic resistance

25
Portal Hypertension
Persistent PHTN lead to
Changes in blood and lymphatic flow
hyperfiltration and ascites
collateral circulation the risk for
esophageal and gastric varices
Hepatic encephalopathy and
hepatorenal syndrome
Stellate cell activation in Liver Fibrosis
Cirrhosis Macro/Micronodules

Massom Trichrome Stain for
Fibrosis
Cirrhosis
Focal Confluent Necrosis
Focal Lytic Necrosis
FIBROSIS
CIRRHOSIS
34
Lab Findings
Bilirubin > 2mg/dl to 40 mg/dl

AST, ALT, Alkaline phosphatase
Aid in early diagnosis, prognosis, and
response to treatment
ALkPo > 3 times normal indicate
billiray disease
35
Lab Findings
Albumin
(non-specific protein) & Factor V and VII
(specific proteins) can provide
information on the functional capacity of
the liver
Low albumin < 3 that does not respond
to therapy is bad prognosis

36
Lab Findings
PT
Prolongation due to impaired synthesis of
vitamin K dependant clotting factors
No response to VIT K is poor prognosis
BUN
< 5 due to inadequate protein intake and
depressed hepatic capacity for urea
synthesis
Biopsy
Confirm the presence of cirrhosis

BLIND MANs LIVER
Blind Mans Diagnosis
N
O
FIBROUS
TISSUE
BETWEEN
PORTAL
AREAS
IRREGULAR NODULES SEPARATED BY PORTAL-to-PORTAL FIBROUS BANDS
TRICHROME
CIRRHOSIS, TRICHROME STAIN
CIRRHOSIS, TRICHROME STAIN
Intracellular =
DAMAGE
AST/ALT/LDH


Membrane =
OBSTRUCTION
AlkPhos/GGTP/5N
Remember
DEFference
BetWeen:
CIRRHOSIS
&
LIVER FAILURE

?????
Laboratory Evaluation of Liver
Disease
Liver Function Tests
LO
Functions of Liver
Tests for Liver functions
LFT
Test Category Serum Measurement

Hepatocyte integrity

Cytosolic hepatocellular enzymes
Serum aspartate aminotransferase (AST) *
Serum alanine aminotransferase (ALT) *
Serum lactate dehydrogenase (LDH) *





Biliary excretory function

Substances normally secreted in bile

Serum bilirubin
Total: unconjugated plus conjugated *
Direct: conjugated only *
Delta: covalently linked to albumin *
Urine bilirubin *

Serum bile acids *

Plasma membrane enzymes

(from damage to bile canaliculus)
Serum alkaline phosphatase *
Serum -glutamyl transpeptidase *
Serum 5'-nucleotidase *


Test Category

Hepatocyte function

Proteins secreted into the blood
Serum albumin -decrease
Prothrombin time *
(factors V, VII, X, prothrombin, fibrinogen)
Hepatocyte metabolism
Serum ammonia *
Aminopyrine breath test


Specific tests for specific liver diseases

Albumin
Measures amount of albumin in blood
Formed within liver & comprises 60% of total
protein in blood
Maintains colloidal osmotic pressure &
transports blood constituents
Measure of both hepatic function and
nutritional state
Normal: 3.5 5 g/dL
Albumin
: dehydration
: malnutrition, pregnancy,
liver disease, protein-losing enteropathies,
protein-losing nephropathies,
3
rd
space losses, overhydration,
capillary permeability,
inflammatory disease, familial idiopathic
dysproteinemia

Total Protein
Measures total protein in blood
Combination of prealbumin, albumin & globulins
Normal: 6.4 8.3 g/dL
ALP
Measures serum ALP concentration
Detect & monitor liver and bone disease
Normal: 30 -120 units/L
: 1 cirrhosis, intrahepatic/extrahepatic biliary
obstruction, 1/metastic liver tumor,
hyperparathyroidism, Paget disease, normal
growing bones in children, bone mets, RA, MI,
sarcoidosis, healing fracture, normal pregnancy,
intestinal ischemia or infarction
: hypophosphatemia, malnutrition, milk-alkali
syndrome, pernicious anemia, scurvy
ALT
Found predominantly in liver
Injury/disease to parenchyma release into blood
ID & monitor hepatocellular diseases of liver
If jaundiced, implicates liver rather than RBC hemolysis
Normal: 4 36 international units/L @ 37C
ALT
Sig : hepatitis, hepatic necrosis, hepatic
ischemia
Mod : cirrhosis, cholestasis, hepatic
tumor, hepatotoxic drugs, obstructive
jaundice, severe burns, trauma to striated
muscle
Mild : myositis, pancreatitis, MI,
infectious mono, shock

AST
Found in highly metabolic tissue (cardiac &
skeletal muscle, liver cells)
Disease/injury lysing of cells & release into blood
Elevation proportional to # of cells injured
Used for evaluation of suspected coronary artery
disease or hepatocellular disease
Normal: 0 35 units/L
: heart diseases, liver diseases, skeletal
muscle diseases
: acute renal disease, beriberi, DKA,
pregnancy, chronic renal dialysis
Bilirubin
Measures level of total bilirubin in blood
End product of RBC metabolism (RBCs Hgb
Heme (+ globin) Biliverdin Bilirubin
(unconjugated/indirect) Bilirubin (conjugated/direct)
Component of bile
Consists of conjugated (direct) & unconjugated
(indirect) bilirubin
Used to evaluate liver function; hemolytic anemia
workup in adults & jaundice in newborns
Jaundice occurs when total bilirubin > 2.5 mg/dL
Normal: 0.3 1 mg/dL
Critical: > 12 mg/dL
Unconjugated bilirubin
Measures level of indirect bilirubin in blood
Normal: 0.2 0.8 mg/dL
: erythroblastosis fetalis, transfusion rxn,
sickle cell anemia, hemolytic jaundice,
hemolytic anemia, pernicious anemia, large-
volume blood transfusion, large hematoma
resolution, hepatitis, cirrhosis, sepsis, neonatal
hyperbilirubinemia, Crigler-Najjar syndrome,
Gilbert syndrome

Conjugated bilirubin
Measures level of direct bilirubin in blood
Produced by conjugating glucuronide w/
unconjugated/indirect bilirubin in liver
Normal: 0.1 0.3 mg/dL
: gallstones,
extrahepatic duct obstruction,
extensive liver mets,
cholestasis from drugs,
Dubin-Johnson syndrome, Rotor syndrome

Viral Markers
HBsAg presence indicates acute HBV infection.

Anti-HBs not detectable during acute, presence indicates
immunity to HBV or previou vaccination for HBV.

HBcAg Presence indicates acute HBV Infection, and
signifies that patient is currently infective

Anti-HBc Presence indicates acute or chronic HBV infection.
acute or chronic depends on whether IgM present
or IgG

HBeAg Present during acute infection

Anti-HBe usually not tested but are present during acute
or chronic infection, indicate low transmissibility



Viral Markers
Serologic Markers in HVA Infection
Out come of HBV Infection
HBV Acute and Chronic Infection
Out Come of HCV Infection
Serologic Markers of HCV In Acute and
chronic Relapsing Infection
HBV and HDV Infection
Viral Markers
HBsAg presence indicates acute HBV infection.

Anti-HBs not detectable during acute, presence indicates
immunity to HBV or previou vaccination for HBV.

HBcAg Presence indicates acute HBV Infection, and
signifies that patient is currently infective

Anti-HBc Presence indicates acute or chronic HBV infection.
acute or chronic depends on whether IgM present
or IgG

HBeAg Present during acute infection

Anti-HBe usually not tested but are present during acute
or chronic infection, indicate low transmissibility

Viral markers
Anti-HAV Indicates acute infection

Anti-HCV Indicates acute or chronic
infection

Anti-HEV Indicates acute infection


Viral markers
Window Phase:
Period of several wks when HBsAg has
disappeared but HBsAb not yet detectable
At this time HBcAb always positive use to make
diagnosis
Persistence of HbsAg beyond 6months indicate
chronic infection /carrier