COMPLICATIONS OF LIVER

CIRRHOSIS
(Seminar paper)
Contents:

1. Introduction 3

2. Cirrhosis and its complications ...4

2.1. Development of complications ...4
2.2. Complications .4
2.2.1. Portal hypertension ...............4
2.2.2. Ascites ...5
2.2.3. Hepatorenal syndrome ..6
2.2.4. Spontaneous bacterial peritonitis ..7
2.2.5. Hepatic encephalopathy 7
2.2.6. Other complications ..8
2.2.7. Hepatocellular carcinoma 10

3. Conclusion .10

4. Summary 11

5. References ..12

2
INTRODUCTION

Cirrhosis is the result of long-term, continuous destruction to the liver and therefore represents
terminal, irreversible stage of liver damage. It may be due to many different causes such are
both hepatogenic and non hepatogenic viruses, metabolic diseases or toxic environment.
Cirrhosis can take many years to develop and can do so without any noticeable symptoms until
the damage to the liver is very serious. Usually, there is no such term as a liver cirrhosis
symptoms, but these symptoms that eventually occur in fact come from complications that
follow terminal liver destruction.[1] Early signs of cirrhosis would be non-specific and couldn't
point on the liver damage in any way. On the other hand, specific signs would come as a fact
that liver could no longer do its role in metabolism such are bilirubin excretion and synthetic,
catabolic or detox function as well as filtrating blood. Therefore, these include portal
hypertension and its consequences of gastroesophageal variceal hemorrhage, splenomegaly,
ascites, hepatic encephalopathy, spontaneous bacterial, peritonitis (SBP), hepatorenal syndrom
and epidermal or mucosa icterus. In the end, as a result of constant changes in liver tissue, a
hepatocellular carcinoma may occur.[2]

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CIRRHOSIS AND ITS COMPLICATIONS

1) DEVELOPMENT OF COMPLICATIONS

Cirrhosis is a condition that is defined histopathologically and has a variety of clinical

manifestations and complications, some of which can be life-threatening. Regardless of the
cause of cirrhosis, the pathologic features consist of the development of fibrosis to the point
that there is architectural distortion with the formation of regenerative nodules. This results in
a decrase in hepatocellular mass, and thus function, and an alteration of blood flow. The
induction of fibrosis occurs with activation of hepatic stellate cells, resulting in the formation
of increased amounts of collagen and other components of the extracellular matrix. The
complications of cirrhosis are basically the same regardless of the etiology. Patients who have
developed complications of their liver disease and have become decompensated should be
considered for liver transplantation. Many of the complications of cirrhosis will require specific
therapy.[2]

Causes of complications can be rougly divided into parts: one group of complications would
come as a result of liver failure and its functions itself while the other group would present the
effect of portal hypertension, so we could also say there are direct and indirect causes of
cirrhosis complications. Unfortunately, everything is not that simple and there is a much more
overlapping in pathogenesis of these conditions, which will be described in further text of this
paper.

2) COMPLICATIONS

1 PORTAL HYPERTENSION

Portal hypertension is an increase in the blood pressure within a system of veins called the
portal venous system. Veins coming from the stomach, intestine, spleen, and pancreas merge
into the portal vein, which then branches into smaller vessels and travels through the liver. If
the vessels in the liver are blocked due to liver damage, blood cannot flow properly through the
liver. As a result, high pressure in the portal system develops.[3] Portal hypertension is defined
as an blood pressure elevation in a portal system that goes over 5 mmHg, and with that value is
directly responsible for three other complications: varices and variceal hemorrhage,

4
hyperplenism and ascites. Complete pathophisiology begins with elevated pressure gradient but
it doesn't end there. Together with the increased pressure in portal systemlarge swollen veins in
many organs such as esophagus, stomach, rectum and umbilical area are developed, which are
called varices. The reason why it occurs is actually blood that cannot pass through the liver and
therefore must find a new pathaway in the organism in order it could continue to circulate
among the whole cardivascular system. In addition, the existence of varices itself is not the
problem itself, but actually the fact it may complicate by rupturing, causing variceal
hemorrhage inside the body organs and so the life-threatening situations.[2]

The most common position for varices are esophagus for about three centimetars above the
cardia, which may spread into the fundus of stomach which would than be followed by signs
of gastrointestinal bleeding marked by black, tarry stools or blood in the stools, or vomiting of
blood due to the spontaneous rupture and hemorrhage from varices.[3] Congestive splenomegaly
is common in patients with portal hypertension and appears for the same reason as varices.
Some patients will have fairly significant left-sided and left upper quadrant abdominal pain
related to an enlarged and engorged spleen. Splenomegaly itself usually requires no specific
treatment, although splenectomy can be successfully performed under very special
circumstances. On the other hand, some patients will develop hypersplenism which stands for
increased function of spleen and therefore may aquire hematologic disorders such as
thrombocytopenia and leukopenia.[2]

2 ASCITES

Ascites is the accumulation of fluid within the peritoneal cavity. Development of ascites
includes many mechanisms. One of them is portal hypertension, so ascites is considered as its
complication. There is an increase in intrahepatic resistance, causing increased portal pressure,
which in addition causes capillary leak in peritoneal cavity. The other reason is decreased liver
function which results in hypoalbuminemia, the lack of protein responsible for keeping blood
inside the intravascular pool, so its deficiency contributes accumulation of fluid in extravascular
system, or in this case, within the peritoneal cavity. The third reason for ascites is mechanism
of hepatorenal syndrom which will be described in addition.

5
The prognosis for patients with cirrhosis with ascites is poor, and some studies have shown that
<50% of patients survive 2 years after the onset of ascites. Thus, there should be consideration
for liver transplantation in patients with the onset of ascites.[2][4]

3 HEPATORENAL SYNDROME

The hepatorenal syndrome represents a functional form of a renal failure, that can occur as both
acute or chronic. The main characteristic is vasoconstriction in arterial cortical renal circulation
which appears as a defending mechanism due to systemic vasodilatation in portal hypertension.
It is very important to understand that, histologically, both kidneys are intact, and the failure is
just functional due to liver failure. In other words, with succesful transplant of the liver, function
of the kidneys would also go back as normal. The reason of renal vasoconstriction is probably
in the fact that it also participates in maintaining the blood pressure in its normal value, and that
is by constantly regulating what amount of sodium and water will be kept in organism in any
time. Therefore, if the blood pressure is low, which happens in portal hypertension simply
because the main protein that keeps water intravascular is in deficit, the kidneys will constantly
try to keep the pressure up by reapsorbing sodium and water back to organism, as well as
keeping vasoconstriction in arterial renal circulatioin, so that renal excretion at this point would
be very low, which is called oliguria, and is a symptom of a renal failure. On the other hand,
circulus vitiosus is made because the main protein, that is albumin, is lacking and there is
nothing else that could keep all this reapsorbed water intravascularly but it is simply just kept
in organism with loading the extravascular pool, making oedema, and that is ascites as the most
important. Also, there are two types of hepatorenal syndrome: type I, which is characterised by
progressive renal failure (acute), and the type II, that is developing more longer and is chronic.
In conclusion, a functional renal failure is made with the symptoms of a sodium and water
retention. Therapy includes substitute of albumin and hemodyalisis, but the only completely
helpful therapy is liver transplant.[2]

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4 SPONTANEOUS BACTERIAL PERITONITIS

Spontaneous bacterial peritonitis (SBP) is the development of a bacterial infection in the

peritoneum causing peritonitis, despite the absence of an obvious source for the infection.
Bacterial translocation is the presumed mechanism for development of SBP, with gut flora
traversing the intestine into mesenteric lymph nodes, leading to bacteremia and seeding of the
ascitic fluid. The most common organisms are Escherichia coli and other gut bacteria; however,
gram-positive bacteria, including Streptococcus viridans, Staphylococcus aureus, and
Enterococcus spp. can also be found. The diagnosis of SBP is made when the fluid sample has
an absolute neutrophil count >250/L. Patients with ascites may present with fever, altered
mental status, elevated white blood cell count, and abdominal pain or discomfort, or they may
present without any of these features. Therefore, it is necessary to have a high degree of clinical
suspicion, and peritoneal taps are important for making the diagnosis. Treatment is with a third-
generation cephalosporin. In patients with variceal hemorrhage, the frequency of SBP is
significantly increased, and prophylaxis against SBP is recommended when a patient presents
with upper GI bleeding.[2][5]

5 HEPATIC ENCEPHALOPATHY

Hepatic encephalopathy is a syndrome observed in patients with a liver failure, whether it is

acute, fulminant or chronic. It is defined as a variety of neuropsychiatric abnormalities in
patients with liver dysfunction, after brain disease is excluded. These abnormalities will come
as an alternations in mental status and cognitive functions. When talking about fulminant liver
failure, encephalopathy matches with a liver failure event and is actually a requirement for a
diagnosis of an injury, while in a chronic failure, and that is cirrhosis, it is not an only sign and
should be considered in a bigger picture, especially for a reason it is mostly followed by a
variety of non specific changes in mental status.[6]

The main theory for this event is there are gut derived neurotoxins such as ammonia as the
most important, which are usually removed by the liver because of its detox role in metabolism.

7
Ammonia is produced in the gastrointestinal tract by bacterial degradation of amines, amino
acids, purines, and urea. Two factors contribute to the hyperammonemia that is seen in cirrhosis.
First, there is a decrease in the mass of functioning hepatocytes, resulting in fewer opportunities
for ammonia to be detoxified by the above processes. Secondly, portosystemic shunting may
divert ammonia-containing blood away from the liver to the systemic circulation. With a
decreased liver function these neurotoxin remain in its toxic form and may gain entry into the
brain, causing morphologic abnormalities and therefore a symptomatic neuropsychiatric
abnormalities. Ammonia may have the most important role in this case, but there are other
identified molecules which could take place in pathogenesis of encephalopathy. Other
compounds and metabolites that may contribute to the development of encephalopathy include
certain false neurotransmitters and mercaptans, or simply, electolyte disbalans could take place
in a neuron malfunction.[2] The symptoms would vary from a minimal disabilities such as
reduced attention, through complete disorientation and coma. Also, complete changes in
behaviour could be seen, which would represent from lethargy or apathy, gross deficits in ability
to perform mental tasks, to trivial lack of awareness, shortened attention span, impaired addition
or subtraction, hypersomnia, insomnia, or inversion of sleep pattern, irritabillity or euphoria.[6]
The diagnosis of hepatic encephalopathy is clinical and requires an experienced clinician to
recognize and put together all of the various features.Treatment is mostly symptomatic and is
based on supportive substitute of water and electrolytes. Therefore, it includes hydration and
correction of electrolyte imbalance and furthermore, sometimes it is all that is necessary. In
addition, for correcting precipitating factors, lactulose is used, which would result in two or
three stools per day, and in that way, gut derived toxins would simply be excreted from
organism through the gastrointestinal system.[2]

6 OTHER

MALNUTRITION IN CIRRHOSIS
As it is mentioned, liver plays an important role in the regulation of protein and energy
metabolism. Because of that, it is not suprising that patients with liver failure are usually
malnourished. The reasons are usually multiplied, and make correlletions with poor dietary
intake, variations in gut absorption and finally, because the liver itself is responsible for protein
metabolism, including production of many important body protein, once again, malfunction

8
takes place which, in this case, results in protein deficit. It usually occurs as a increased body
catabolism, which is expressed through the muscle degradation and general body weakness.
The only treatment would be dietary supplementation.[2]

ABNORMALITIES IN COAGULATION
AND HEMATOLOGIC ABNORMALITIES

Coagulation abnormalities are a consequence of reductions in hepatic synthesis of coagulation

factors and include reduced synthesis of clotting factors and hyperfibrinolysis, as well as the
quantitative platelet deficits associated with hypersplenism. With liver malfunction there is
deficit of K vitamin coagulation factors, because these are the ones produced in liver. As a
consequence, prothrombin time is elevated, which is diagnostically important and manifests as
tendency to bleeding. On the other hand, due to hypersplenism, hematologic disorders may
occur which would present as a thrombocytopenia and anemia. Furthermore, the reasons for
anemia could also be an iron and folate deficiency from malnutrition. Treatment includes
dietary supplements.[2]

ENDOCRINE DYSFUNCTION

In people with cirrhosis, the elevated oestrogen levels are found. Usually, liver is the organ
responsible for catabolism and detox of many substances, and the oestrogen would be one of
them. With oestrogen being female body hormone, its elevated value will mostly be shown in
men. Considering the decrease in testosterone levels and increase in oestrogen levels with
decreasing liver function, the ratio of oestrogen to testosterone increases with declining liver
function. This leads to hypoandrogenization which is responsible for hypogonadism, and
therefore represents as a testicular atrophy, aspermia, sexual dysfunction and reduction of body
hair, beard growth and prostatic size. Also, hyperoestrogenization would manifest as a
feminization in men, with the signs of gynaecomastia, arterial spiders and female body
habitus.[7]

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7 HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly
in patients with underlying chronic liver disease and cirrhosis. Tumors progresses with local
expansion, intrahepatic spread, and distant metastases. It is believed that constant inflammation,
necrosis, fibrosis and ongoing regeneration, which primarly characterize the cirrhotic liver, are
also responsible for aquiring the carcinoma. The disease processes in its constant regeneration,
which results in malignant transformation. Also, it includes a variety of pathways, many of
which may be modified by external and environmental factors and eventually lead to genetic
changes that delay apoptosis and increase cellular proliferation. Whereas in the past, HCC
generally presented at an advanced stage with right-upper-quadrant pain, weight loss, and signs
of decompensated liver disease, it is now increasingly recognized at a much earlier stage as a
consequence of the routine screening of patients with known cirrhosis, using cross-sectional
imaging studies. Treatment includes operation, but just for small lesions. Other treatment would
be radiofrequency ablation and percutaneous ethanol injection.[8]

CONCLUSION

Liver cirrhosis presents as a terminal organ failure, and global prevalence of cirrhosis from
autopsy studies ranges from 4.5% to 9.5% of the general population.[9] From the moment of
affirming the diagnosis, the approach to treatment is taken very serious. In order to preserve the
quality of one people's life the substitute treatment is brought in as soon as possible. Still, it
must be considered as the only temporary solution while the only real treatment is liver
transplant. Also, considering the fact it is a last stage of liver failure, it must be clear there is no
specific medicine for treating the disease and getting it back in stages, as well as there is no
such device that would replace the liver function. With that in mind, it is also clear that all the
complications which come as a result of cirrhosis can't never be completely resolved with
anything but only liver transplant. There may be some supportive therapy in the beginning, but
it could only be treated and not cured. Furthermore, the importance of transplant lays in a fact
that it wouldn't only bring in the quality of life in a way it was before, but it also represents a
profilaxis from achieving much more serious complication in future life, and that is
hepatocellular carcinoma.

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SUMMARY

Cirrhosis represents terminal, irreversible stage of liver damage, which can be considered as a
clinical diagnosis. From a histological aspect, cirrhosis is a state of constant necrosis and
regeneration in a form of fibrosis, which results in permanent loss of hepatic mass, therefore
function. Loss of function leads to liver cirrhosis complications. Regardless of a cause, and
there are many, complications remain the same. Early signs are non-specific, and couldn't point
exclusivelly on a liver failure in any way. Specific signs, which are developed eventually, can
be result of a reduced blood flow through the cirrhotic liver and therefore its retention
retrogradely which is than presented as a portal hypertension, or can occur a result of a reduced
sintetic, catabolic and detox liver function. Portal hypertension is an increase in the blood
pressure within a system of veins called the portal venous system and is directly responsible for
three other complications: varices and variceal hemorrhage, congestive splenomegaly,
hyperplenism and ascites. Varices are developed as a need for alternative pathaway of
circulation past liver, but being very fragile hemorrhages in many organs can occur. Ascites
appear as an outcome of elevated blood pressure retrogradely from liver, decreased sintetic liver
function (hypoalbuminemia) and hepatorenal syndrome. Congestive splenomegaly is also a
result of elevated blood pressure in portal venous system. The hepatorenal syndrome presents
a functional form of a renal failure. The reason is in the fact that it also participates in
maintaining the blood pressure in its normal value, and that is by constantly regulating what
amount of sodium and water will be kept in organism in any time. With systemic vasodilatation,
renal absorption is high and excretion is low, which is manifested as oliguria and renal
failure.Spontaneous bacterial peritonitis (SBP) is the development of a bacterial infection in the
peritoneum causing peritonitis, despite the absence of an obvious source for the infection.Still,
it is probably caused by intestinal flora. Hepatic encephalopathy is a syndrome observed in
patients with a liver failure and is defined as a variety of neuropsychiatric abnormalities in
patients with liver dysfunction, after brain disease is excluded. The main theory for this event
is there are gut derived neurotoxins such as ammonia as the most important, which are usually
removed by the liver because of its detox role in metabolism. Other complications include
hematologic abnormalities due to its decreased sintetic function, resulting in thrombocytopenia
and coagulation disorder, as well as anemia. Furthermore, due to detox malfunction,
hyperoestrogenism is seen, especially in men, resulting in testicular atrophy and gynaecomastia.
In the end, if not treated, cirrhosis can lead to hepatocellular carcinoma. The only treatment for
cirrhosis is liver transplant.[1][2][5][6][7]

11
REFERENCES

1. British Live Trust; Cirrhosis of the Liver. Available at

https://www.britishlivertrust.org.uk/liver-information/liver-conditions/cirrhosis/.
Accessed April 22, 2017.
2. Kasper, Fauci, Hauser, Longo, Jameson, Loscalzo; Harrison's Principles of Internal
Medicine, Nineteenth Edition; The McGraw-Hill Education, 2015; 2710, 2714-2719
3. Web MD; Portal Hypertension. Available at
http://www.webmd.com/digestive-disorders/digestive-diseases-portal#1. Accessed
April 22, 2017.
4. E-medicine Health; Ascites. Available at
http://www.emedicinehealth.com/ascites/article_em.htm. Accessed April 22, 2017.
5. Medscape; Spontaneous Bacterial Peritonitis. Available at
http://emedicine.medscape.com/article/789105-overview. Accessed April 22, 2017.
6. Medscape; Hepatic Encephalopathy. Available at
http://emedicine.medscape.com/article/186101-overview#a3. Accessed April 23, 2017
7. International Journal of Pediatrics; Endocrine Manifestations of Cirrhotic and Liver
Disease. Available at http://ijp.mums.ac.ir/article_2454_387.html.
Accessed April 23, 2017
8. Medscape; Hepatocellular carcinoma. Available at
http://emedicine.medscape.com/article/197319-overview. Accessed April 23, 2017.
9. World Gastroenterology; Global Burden Of Liver Disease. Available at
http://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-
view-articles-collection/global-burden-of-liver-disease-a-true-burden-on-health-
sciences-and-economies. Accessed April 23, 2017.

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