IN FIBRINOGEN LEVEL IN LIVER CIRRHOSIS
Arif, A Sattar Khan* and Arif Raza Khan**
Department of Biochemistry, Khyber Medical College, *Department of Chemistry, University of Peshawar and **Police Services Hospital, Peshawar, Pakistan
Background: Liver cirrhosis causes significant morbidity and
mortality in our country, however early diagnosis prevents complications and
carries good prognosis. Estimation of fibrinogen level may be helpful in
preventing bleeding tendencies. Methods:
Plasma fibrinogen level of 82 confirmed liver cirrhosis in 18–60 years age
admitted patients of Khyber Teaching Hospital were determined and compared with
normal controls, to establish it as a marker for diagnosis in cirrhosis liver
and prognosis. Fibrinogen level was determined by Fibriprest-2. Results: Significantly low levels in patients were recorded as
compared to controls. 40% cases showed low fibrinogen level, while nearly 44%
had normal levels. Conclusion:
Fibrinogen level was low in early and terminal cirrhosis and high in advancing
cirrhosis as compared to controls that showed normal levels.
WORDS: Cirrhosis, Liver, Fibrinogen.
role carried out by the liver in the production of different proteins involved
in the coagulation and fibrinolysis has been already demonstrated. Liver
diseases can cause both quantitative and qualitative abnormalities in the
clotting factors. Fibrinogen is synthesized at the level of the hepatic
microsomes1,2, and the existence of multiple coagulation defects,
including a thrombin time prolongation with normal or high fibrinogen levels has
also been frequently observed in patients with severe liver disease. In liver
cirrhosis there is diffuse fibrosis which destroys the liver lobules.
Regenerative nodules press on the liver substance leading to a vicious circle of
further necrosis and fibrosis2. Fibrinogen is a glycoprotein of
molecular weight approximately 340,000 daltons, present in the plasma at a
concentration in the range of 2–4 g/l. It is synthesized in the liver (1.7–5
gm/day), and by the megakaryocytes3. It is an acute phase reactant
and is often elevated in liver disorders especially in hepatoma and cirrhosis4.
the liver disease is advanced there is not only impaired synthesis of albumin
but also fibrinogen, prothrombin and coagulation factors V, VII, IX and X.
Although some of these changes may have serious consequences such as bleeding
diasthesis, they are significant for the most part as clinical clues to the
presence of advanced liver disease and cirrhosis. Liver diseases not only alter
the concentration of circulating fibrinogen, but also make it functionally
abnormal. As most coagulation proteins are synthesized by the liver, patients
with liver diseases often exhibit multiple coagulation defects. Normal or even
elevated levels of plasma fibrinogen is often observed in patients of severe
liver disease with liver damage. In several cases this abnormality has been
explained on the basis of increased antithrombin activity in the plasma probably
due to circulating fibrinogen/fibrin degradation products whose clearance by the
diseased liver is delayed5. However the phenomena can also be
explained by the abnormal fibrinogen synthesis displayed by the damaged liver.
This finding has been observed in liver cirrhosis and aggressive chronic
hepatitis6,7; as well as in hepatocellular carcinoma8,9.
hypothesis have been made to explain the pathogenesis of acquired
dysfibrinogenemia. The most frequently observed phenomenon is an alteration of
the glucide fraction with an elevation of sialic acid content, which would
explain the cause of this functional anomoly10. Although there is
disparity between the quantity of fibrinogen measured with functional and
immunological assays, most patients have moderate bleeding. However in some
cases dysfibrinogenemias induce a hyper coagulable state and increased risk of
defects including a thrombin time prolongation with abnormal fibrinogen level
have been observed in severe liver diseases, especially in cirrhosis liver by
previous research workers12. Acquired dysfibrinogenemias appear to be
a common problem than previously thought in patients of liver diseases like
carcinoma, cirrhosis, fibrinolysis and dissiminated intravascular coagulatoin (DIC).
DIC is inordinate activation of the coagulation system, leading to deposition of
microthrombi in small vessels and consumption of platelets, prothrombin,
fibrinogen, factors V, VIII
and XIII. This consumption results in
depletion of these factors, activation of fibrinolytic system and production of
fibrin degradation products. These products further interfere with normal
platelet formation and fibrin polymerization13. Recent studies
suggest that slow fibrin formation occurs as a result of structural changes
induced in the fibrinogen molecule itself. These relatively minor alterations in
structure cause a functional dysfibrinogenemia and abnormalities in the
objective of the present study is to establish plasma fibrinogen level as a
marker for diagnosis and prognosis of liver cirrhosis.
was a case control study. It was done from 9th June 1999 to 6th
December 1999. Forty (40) age, sex and socioeconomically matched controls having
no history of viral hepatitis and cirrhosis liver were selected from the family
members of the patients, staff of Khyber Teaching Hospital, Khyber Medical
College and Pakistan Medical Research Council (PMRC) Peshawar. Eighty-two (82)
Cirrhotic patients of age between 18–60 years both males and females belonging
to different socioeconomic classes were selected from the medical units of
Khyber Teaching Hospital Peshawar. Past history of all patients and controls
regarding blood transfusions, injections, jaundice, use of razors and history of
dental or surgical procedure or haemodialysis was recorded, and the patients
were clinically examined for signs of liver cirrhosis. Ultrasonography abdomen
was the preliminary investigation to detect cirrhosis liver, and diagnosis was
established by evidence of shrunken liver with coarse echotexture, features of
portal hypertension like spleenomegaly, portal vein diameter greater than 14 mm,
and presence of ascites. Ultrasound guided biopsy was done in selected cases
where there was no contraindication. Ascitic fluid if present was sent for
serology. Relevant biochemical tests were also done.
1.8 ml of blood was drawn from the antecubital vein of the subjects and was
immediately transferred to tubes containing 0.2 ml of an anticoagulant,
trisodium citrate 0.9 M (3.2 percent) for the determination of fibrinogen and
some other tests. Quantitative determination of fibrinogen was done by
Fibriprest-2, supplied by Diagnostic Stago France.
total of 40 controls (Group-A) and 82 patients (Group-B) suffering from
cirrhosis liver were investigated during the course of present study. There were
variations in fibrinogen level in the patients of liver cirrhosis (shown in
Table-1), however the level remained within normal range in controls (mean ±
SD, 3.02 ±
of total, 36 patients had normal fibrinogen level. In 21 patients it was above
normal (mean ±
SD, 11.90 ±
5.5) and in 25 patients fibrinogen level was below the normal range (mean ±
SD, 1.37 ±
0.08 g/l). The results showed that there was a highly significant difference in
plasma levels of fibrinogen (P<0.001)
in patients (Group B) when compared to controls (Group A). Fibrinogen level was
variable in different stages of cirrhosis liver (Table-2).
Fibrinogen Levels of Controls and Patients of
Mean ± SD
Controls (n= 40)
3.02 ± 0.05
3.50 ± 2.07
(Early and terminal stage)
1.37 ± 0.08
in normal range
(n= 36 )
2.76 ± 0.94
normal (n= 21)
11.90 ± 5.5*
* P< 0.001 (Highly Significant).
Normal plasma fibrinogen level= 2–4 g/L.
Out of total 25 patients in which the level of plasma fibrinogen was below the normal Range, 12 % (10) were in the early stage of the disease who had not developed complications of cirrhosis and 18 % (15) were in the terminal stage who had developed complications of the disease. Seventy percent of the patients (57) out of total were in an advanced stage of cirrhosis and they had developed either one or more complications of the disease (Table-2). In these patients who presented with advancing cirrhosis, fibrinogen level was normal in 36 patients and rose above normal in 21 (Table 1).
Plasma Fibrinogen Levels in Uncomplicated and Complicated Liver Cirrhosis
Fibrinogen in g/l
1.8 ± 0.90
3.5 ± 1.02
1.2 ± 2.48
existence of acquired dysfibrinogenemia in patients of liver cirrhosis is a
relatively frequent finding12. Most of the dysproteinemias described
in patients with liver disease have been due to quantitative abnormalities.
However the presence of quantitative abnormalities of plasma proteins in this
group of patients is now becoming increasingly recognized. In several patients
with cirrhosis liver and hepatoma an acquired abnormality of fibrin monomer
polymerization has been reported14.
abnormalities of fibrinogen or dysfibrinogenemias are initially differentiated
on the basis of abnormal clottability of fibrinogen by thrombin7. A
low fibrinogen level was recorded in 12% of our patients who were in early stage
of liver cirrhosis, and in 18% patients at terminal stage of the disease.
Massive destruction of liver hepatocytes results in poor production of plasma
proteins and fibrinogen leading to decrease in their level, and showing that the
occurrence of dysfibrinogenemia with low fibrinogen level may be a consequence
of liver damage rather than the manifestation of any single type of liver
disease6. Sallah and Bobzien are of the opinion that low
fibrinogen levels may occur in DIC and hyperfibrinolysis but levels less than
100 mg/dl are found only in fulminent hepatitis and severely decompansated
normal fibrinogen level recorded in our study may be due to compensation by the
normal liver as also inferred by Martinz et al.9 from their
study. The demonstration of a functional abnormality of the circulating
fibrinogen molecule does not necessarily mean that the molecule secreted by the
diseased liver is abnormal. It is conceivable that a normal fibrinogen is
secreted by the abnormal liver and it undergoes rapid alteration in circulation
due to abnormal plasma environment. In 50% cases of advanced cirrhosis and
nearly 100% of cases of fulminant hepatic failure the structure of fibrinogen is
abnormal, although the level may be normal. Abnormalities in fibrinogen
structure may impair fibrin polymerization and clot formation despite normal
fibrinogen level, as noted in the plasma of the patients in our study may occur
due to their impaired removal by the diseased liver. Most of the
asialoglycoproteins are rapidly removed from the circulation by the liver as a
result of binding of their terminal galactosyl residues to the hepatocyte
membrane. Impairment of this clearance mechanism might be responsible for the
finding of elevated levels of altered thyroxin binding proteins in the patients
with liver disease. The liver also appears to play a role in the removal of
altered coagulation factors. Abnormal removal of altered coagulation proteins by
the diseased liver may result in high fibrinogen balance in these patients.
occurrence of dysfibrinogenemias in our patients
suggests that abnormality may be a consequence of liver damage resulting in
abnormal fibrinogen level in these patients.
The estimation of fibrinogen level is an important diagnostic index permitting us to follow the dynamics of the disease and it may also be helpful in diagnosing the haemorrhagic tendencies before they are clinically manifested. Further investigations into the nature of these alterations in fibrinogen level may provide a basis for better understanding of the pathogenetic mechanism responsible for it in the patients of cirrhosis liver.
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