Literature Review: Liver Fibrosis Biomarkers and Diagnosis Methods

This report provides a comprehensive literature review on liver fibrosis, encompassing its definition, causes, and progression through various stages. It delves into the role of biomarkers in diagnosis and prognosis, comparing and contrasting them with traditional methods like liver biopsy. The review explores the METAVIR scoring system, the common symptoms, and various treatment options. It examines the impact of conditions like non-alcoholic fatty liver disease, hepatitis B and C, and alcoholic liver disease on the development of fibrosis. The report also discusses the limitations of liver biopsy and the potential of biomarkers for early detection and management, incorporating relevant research from 2010 to 2018. The report also includes the different stages of liver fibrosis and what happens in each stage. Finally, the report concludes with a discussion on the use of biomarkers for prognosis and interpretation, offering a thorough overview of the current understanding of liver fibrosis.

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Literature Review:
1.0: Introduction:
Literature review can be explained as the segment of a dissertation or a thesis that
comprises of an exhaustive review of literatures that has already been done and closely relate
to the research topic (Aveyard 2014). This section would include an exhaustive review of
scholarly literatures that are aligned to the research objectives. Typically the scholarly
literatures included in the review were published in between 2010 to 2018. The rationale for
the inclusion of papers published over 9 years include a detailed overview about what has
already been done in the research area of interest.
1.1: Review of literatures:
Research studies mention that fibrosis includes the formation of a large amount of
scar tissue in the liver (Sumida et al. 2014). The condition arises when the liver repairs and
regenerates its damages cells. It should be noted in this context that a number of conditions
can damage the liver. Further, as stated by Zeybel and Idilman (2018), fibrosis does not
typically trigger any symptoms but excessive scarring can result in cirrhosis which can
worsen the intensity of the symptoms. Fibrosis can be detected on the basis of blood and
imaging tests, however on certain occasions liver biopsy can help in detecting fibrosis
(Fallatah 2014). The condition can be treated with the implementation of a number of
medical treatment.
Fibrosis manifests when the liver gets continuously damaged. It should be noted in
this context that a single event of injury does not lead to fibrosis. Liver fibrosis manifests
itself when the injury is repetitive and results in the formation of a scar tissue (Castera and
Pinzani 2010). In cases where the injury is repetitive and continuous the hepatic cells or the
liver cells attempt to recover the damaged tissue but the attempt to repair and recover the

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damaged tissue leads to the formation of a scarred tissue (Hernandez-Gea and Friedman
2011). Fibrosis is generally formed when a blockage is formed within the bile ducts
(Friedrich-Rust et al. 2008). The scar tissues that are formed replace the hepatic cells and do
not perform any important metabolic function. Also, scarring leads to distortion of the
internal structure of the liver. It should be crucially noted in this context that widespread and
controlled scarring and distortion lead to cirrhosis. In other words, it can be said that fibrosis
and cirrhosis are not specific disorder but are other primary causes that lead to liver damage
(Wallace et al. 2008). The scar tissues that are formed interfere with the blood flow to the
liver and limits the blood supply to the hepatic tissues (Friedrich-Rust et al. 2008). On
account of lack of appropriate blood supply, more scar tissues are formed and the condition
elevates the blood pressure in the hepatic portal vein that is responsible for carrying the blood
from the intestine to the liver. This condition is also known as portal hypertension. Research
studies suggest that the condition of Fibrosis can be reversed only if the condition is
diagnosed early and appropriate treatment regimen is followed so as to ensure recovery
(Zeybel and Idilman 2018; Castera and Pinzani 2010)).
The condition is triggered by a broad spectrum of drugs that continuously damage the
liver and cause liver fibrosis. These drugs mostly include Alcohol Amiodarone,
Chlorpromazine, Corticosteriods, Isoniazid, Methotrexate, Methyldopa, Oxyphenisatin and
Tolbutamide (Wallace et al. 2008). The mentioned drugs are mainly processed in the liver
and therefore can interfere with the normal functioning of the liver. In addition to this, a
number of other factors such as congenital disorders including congenital hepatic fibrosis and
Non-alcoholic fatty liver can also elevate the risk of suffering from Liver Fibrosis. Research
studies reveal that congenital hepatic fibrosis typically damage the kidneys, gallbladder and
the liver (Schuppan and Kim 2013; Tacke and Zimmermann 2014). The disorder is present at
birth and also leads to the manifestation of a number of symptoms. In case of the second most

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common disorder, or the Non-alcoholic fatty liver, the fat accumulates within the liver which
leads to the development of fibrosis (Lee et al. 2015). The disorder is more common in
people who suffer from metabolic syndrome. A number of other physiological problems can
enhance the probability of suffering from Liver fibrosis. Scholarly literature suggests that a
number of genetic metabolic disorders can increase the risk of suffering from Liver Fibrosis
(Tacke and Zimmermann 2014). Patients that suffer from Alpha-1 antitrypsin deficiency OR
Iron Overload hemochromatosis or Wilson disease are twice more likely to suffer from Liver
Fibrosis. These genetic disorders typically manipulate the manner in which nutrients are
broken down, metabolised or assimilated within the body (Puche et al. 2011). In cases where
the nutrients are not metabolized in a synchronised manner, there could be a possibility that
the substances would accumulated within soft tissue organs such as the liver which could lead
to scarring. Further, the evidence base also suggests that viral infections like chronic hepatitis
B or C can adversely affect the liver which could give rise to scarring of hepatic tissues (Shah
et al. 2009). Also, the risk of suffering from liver fibrosis increases in patients who suffers
from autoimmune disorders. These autoimmune disorders include problems such as Auto-
immune hepatitis Primary biliary, Cholangitis and Primary Sclerosing Cholangitis (Iwaisako
et al. 2012). On being affected with these autoimmune disorders, the body has a tendency to
act against its own immune system. This increases the probability of scarring the hepatic
tissues. In the mentioned autoimmune disorders, the bile duct is inflamed with scarring of
tissues and blockage. Further, liver fibrosis also manifests in cases where the hepatic blood
flow is interrupted. In case of Budd-Chiari syndrome, a blood clot interrupts the blood flow
out of the liver (Parkes et al. 2010). Further, in case of Heart failure or Portal Vein
thrombosis, the main vein that supplies blood to the liver is blocked by a blood clot. In case
of Veno-occlusive disease of the liver, the small veins of the liver are blocked by the
presence of blood clot and this leads top scarring of the hepatic tissues (Bejarano et al. 2009).

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It should be noted in this context that in conditions where the blood is unable to leave the
liver, the liver gets inflamed and the size of the liver enlarges. Also, due to lack of sufficient
blood supply, the hepatic cells die and are continuously replaced with the scar tissues. Also,
scarring can be caused due to Sinusoidal obstruction syndrome. The Sinusoidal obstruction
syndrome is caused by the accumulation of pyrrolizidine alkaloids (Cales et al. 2009). These
alkaloids are present in a number of herbal products which include supplements and herbal
tea extracts which are considered beneficial for the physical health of individuals (Mallet et
al. 2009).
The evidence base further enlist the most common causes to be alcohol abuse, viral
hepatitis C and Nonalcoholic fatty liver which lead to Liver fibrosis within the U.S
population base (Poynard et al. 2012). In this regard, it is important to note that Non-
alcoholic fatty liver in generally occur in individuals who are obese, are either pre-diabetic or
are diagnosed with Diabetes (Mallet et al. 2009). Further, increase in level of cholesterol or
lipid within the blood serve as high risk factors that lead to Liver Fibrosis.
According to Cales et al. (2009), it has been mentioned that scarring forms the first
stage of Liver fibrosis. If the scarring of the hepatic tissue is uncontrolled then liver Fibrosis
can assume a more serious forms which is also known as Liver Cirrhosis. It is important to
note in this context that research done on a number of animal trials have successfully proven
that the damaged liver has the capability to regenerate itself (Bejarano et al. 2009). However,
unfortunately, the same has not been researched in human models. As a matter of fact, the
research conducted on humans show that once there is scarring within the liver tissue, the
hepatic tissue do not reveal or regenerate at an accelerated pace (Parkes et al. 2010).
However, a number of lifestyle modifications can help in preventing the fibrosis from getting
worse and ensure proper symptom management. It is on the basis of staging that the
physician estimates the percentage of liver damage (Bejarano et al. 2009). It is important to

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acknowledge in this context that staging is subjective and every scale has its own set of
limitations. The most prevalent scoring system is the METAVIR scoring scale. The system
helps in predicting the degree at which the scarring of the tissues or fibrosis is spreading.
Physicians generally assign the score after performing the biopsy on a tissue sample. Also,
the activity grades range invariably in between the scores A0 to A3. A0 suggests no activity, A1
suggests mild activity, A2 suggests moderate activity and As suggests severe activity
(Iwaisako et al. 2012). The fibrosis stages are marked in between the range of F0 to F4. F0
suggests no fibrosis, while F1 suggests portal fibrosis without septa. F2 suggests portal fibrosis
with few septa, F3 suggests a number of septa without the indication of Cirrhosis and F4
suggests Cirrhosis (Mallet et al. 2009). Therefore, on the basis of grading discussed, a patient
that suffers from the most severe form of the disease would be scored A3, F4 METAVIR
score.
The scoring system propounded by Batts and Ludwig is one of the other scoring
system that marks Liver Fibrosis in a range of grade 1 to grade 4. Grade 4 marks the most
severe form of Liver Cirrhosis. Some of the most common symptoms of Liver Fibrosis
include, loss of appetite, distortion of thoughts, fluid accumulation within stomach or legs,
nausea, weight loss, weakness and Nausea. A research study conducted by Shah et al. (2009),
reported that almost 6% to 7% of the World population suffers from Liver Fibrosis but is not
aware of the same.
The most common treatment options comprise of implantation of pharmacological
interventions such as using ACE inhibitors like Lisinopril, Ramipril and Benazepril. In
addition to this treating with a Tocopherol or interferon-alpha and PPAR-alpha agonist can
also help in treating Liver Fibrosis (Puche et al. 2011).

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The introduction of the clinical discipline of Hepatology coincides with Menghini's
needle in the early 1950s. Liver biopsy was the only diagnostic method available in this
regard, and it really was a gold standard with regard to the identification of liver fibrosis.
From the start it was characterized by an extensive cooperative attempt between the doctor
and pathologist to introduce the so called one second needle biopsy of the liver (Bejarano et
al. 2009). Liver biopsy is the more accurate method to identify and detect fibrosis (to
determine the degree of severity) and to recognize the fibrosis-related disease. When the
diagnosis is uncertain, biopsy is often performed. Due to invasive nature of the liver biopsy
which can trigger complications, physicians can do blood tests first to determine the degree
of fibrosis and then conduct liver biopsy if only blood tests show a mild or serious amount of
fibrosis. Recent evidence suggests medical professionals use certain specific imaging tests
more and more as non-invasive biopsy options (Tacke and Zimmermann 2014). The use of
hepatic biopsy was a step forward with the implementation of scouring technologies. This
introduction meant that the evaluation of liver biopsy specimens which was beyond
characterization and, in many cases, the view of the pathologist had been made more
accurate. In general, it was intended to promote the implementation of scoring schemes in the
context of a worldwide contract to compare sample outcomes (Schuppan and Kim 2013). In
fact, liver biopsy is vulnerable to intra-observer and inter-observer variability and sampling
mistakes. Even a 25 mm lengthy liver biopsy, for example, has a 25 per cent fibrosis discord.
In addition, if the size of the specimen is sufficient, the experience of the pathologist
becomes even more important with respect to specialization, length and place of exercise
(Wallace et al. 2008).
The liver biopsy doesn't effectively mirror the fibrotic changes taking place
throughout the liver, as an efficiently formed biopsy contains 5 to 11 full portal tracts and
represents only 1/ 50000 liver volume (Hernandez-Gea and Friedman 2011). The hepatic

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fibrotic process is not linear and there have been different stages of fibrotic biopsies from
different regions. In 10 to 30 per cent of patients it was shown in several reports that cirrhosis
could be missed. Early and advanced end- stage cirrhosis cannot distinguish a liver biopsy
and cannot thus be used as an optimal prognostic predictor (Castera and Pinzani 2010). With
regard to the liver biopsy complications, pain incidences are reported to be 20 per cent, but
they grow to 84 per cent if they include a slightly uncomfortable sensation. The occurrence
was revealed to be 0.3 per cent -0.57 per cent and 0.01 per cent respectively of severe
complications and mortality. Operators who are trained by an experienced teacher should
conduct a biopsy to minimize complications and it is advisable to operate with an American
guide and use an aspirative type of biopsy needle (Castera and Pinzani 2010). In addition to
the fat deposits of the typical NASH (non -alcoholic steatohepatitis) in hepatocytes, the
pathological features of the NSAH include inflame cells (neutrophils and lymphocytes),
lobula infiltrations, hepatocytic degradation by balloning, Mallory - Denk bodies, fibrosis
pericellular, sinusoidal fibrosis. However, few patients with NASH demonstrate all these
typical results, and NASH diagnosis on the basis of them does not have embedded
requirements. Studies categorized NAFLD as 4 kinds: type 1, (only fat deposition), type
2, (fat exposure and parenchyma inflammatory cell infiltration), type 3, (fat accumulation and
hepatocytes ballon degeneration), and type 4, (type 3 requirements as well as Mallory -Denk
bodies and/ or fibrosis). Researchers noted that liver disease-related mortality in the type 1
plus type 2, but increased considerably to 11 per cent in type 3 plus type 4, were only 1.7 per
cent in the follow -up era of roughly eight years (Toyoda et al. 2011). From a predictive point
of view, they suggested defining the kinds 3 and 4 as NASH. Liver biopsies can be carried
out in ambulatory hospitals to decrease cost abroad, but patients with biopsy are hospitalized
in Japan for a few days. Liver biopsies, approximately valued at 10 million for all patients in
Japan, would not be very cost effective for all NAFLD patients. However, there have been no

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cost-benefit analyses to date. With respect to follow - up after liver biopsy, Toyoda et al.
(2011) noted that NAFLD patients have a very low follow-up frequency, compared with that
of viral hepatitis patients.
Several comprehensive Western country reviews have earlier discussed non - invasive
NASH or advanced fibrosis diagnostic techniques. Most of these articles however outlined a
straightforward list of non - invasive trials. Thus, in this research investigation, biomarkers or
scoring schemes with critical evaluations will be discussed as well as diagnostic algorithms
that can be applied even in clinical practice in NAFLD patients (Puche et al. 2011). NIMs
(Non- invasive Markers) help evaluate the stage of fibrosis in patients with no clear evidence
of liver biopsy, for example patients with CHB (chronic hepatitis B), persistent normal
fibrous alanine aminotransferase serum (ALT), patients with CHC (chronic hepatitis C) or
CHB who require further assessment of fibroid stage during or following treatment, and
patients with autoimmune hepatitis (AIH) who have experienced r-induced fibroid phases. In
order to use serum markers directly associated to the fibrogenic system, known as "direct
markers" (such as hyaluronic acid, TIMP1 or Tissue Inhibitor of Metalloproteinase 1),
patients with other chronic illnesses that are characterized by fibro- genesis or changing
extracellular in other bodies and structures should cautiously be ruled out. Even though
patient age has never fully researched the effect of direct serum markers, the restricted proof
available still shows that in a paediatric cohort the same direct markers are more sensitive and
particular than in the adult NAFLD (Non -alcoholic fatty liver disease) cohort (Shah et al.
2009). The mixed serum biomarker diagnostic significance for hepatic fibrosis was identified
in one research. 182 chronic hepatitis C infected patients from several Turkish facilities were
included in the research. There were two categories of patients: mild stage fibrosis (Metavir,
F0 - F1) or advanced stage fibrosis (Metavir, F2 - F4) (Puche et al. 2011). Two categories
included. Of the trials examined, the sensitivities in APRI, FIB-4 and Fibrotest for serious

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fibrosis were 69 per cent, 69 per cent and 75 per cent, respectively, with specificity of 60 per
cent and 71 per cent, respectively.
Liver fibrosis NIBMs (Non - invasive Biomarkers) are divided into two main
categories: Class 1 or direct biomarkers or fibrosis markers, or indirect biomarkers. The
immediate markers correspond directly with the fibrosis method, or are components of the
Hepatic stellate cells matrix generated during ECM turnover (Schuppan and Kim 2013). The
indirect markers, on the other hand, represent changes in the function of the liver and are
molecules emitted into the blood owing to swelling of the liver. Procollagen is a precursor of
collagen. The carboxy - terminal (Type 1 (PC1CP)) is cleaved with two distinct enzymes,
which produce collagen and the amino -terminal (Type III (PCIIINP). Collagen mature is
integrated in the ECM. Type IV collagen is a ECM element examined as a liver fibrosis
replacement marker. It has three distinct areas (a domain of the amino -terminal, a core helix
and a carboxy – terminal (Tacke and Zimmermann 2014). Collagen Type IV has been widely
researched in various etiological liver diseases. Hyaluronic acid (HA) is a element of the
EMC generated by hepatic stellate cells and a glycosaminoglycan. Laminine has been
generated by hepatic star cells as a non - collagen glycoprotein element of ECMs. It is placed
in the membrane of the liver cellar. Serum laminin concentrations, as described by distinct
writers, are raised beyond the ordinary upper limit (0.59 to 1.4 U / mL) or (9.74 to 2.46)
(Bejarano et al. 2009).

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(Source: Castera and Pinzani 2010)
(Source: Castera and Pinzani 2010)

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(Source: Castera and Pinzani 2010)