ontent Reviewers:

Rishi Desai, MD, MPH

Contributors:
Kaia Chessen, Tanner Marshall, MS, Will Wei, Anca-Elena Stefan
Cirrhosis is when chronic inflammation and liver damage causes the liver to become fibrotic and
develop scar tissue.
At a cellular level, the hepatocytes become impaired and this leads to hepatic dysfunction
and portal hypertension.
Cirrhosis is usually irreversible, so it’s usually called “end-stage” or “late-stage” liver damage,
and often requires a liver transplant. However, in some cases, early treatment can slow down and
even reverse the cirrhosis.
Compensated cirrhosis is when there are enough healthy cells to make up for the damaged ones,
but minor complications like hemorrhoids can still occur.
Decompensated cirrhosis is when healthy cells can no longer keep up with the workload, causing
major complications like hepatic encephalopathy, ascites, and esophageal and gastric variceal
hemorrhage.
In compensated cirrhosis, although there aren’t any major complications, there may still be some
symptoms such as loss of appetite, fatigue, and muscle cramps. There may also be easy bruising
and excessive bleeding because there aren’t enough clotting factors produced by the liver.
Cirrhosis can also impair estrogen metabolism, causing amenorrhea and irregular menstrual
bleeding in females, and low libido and gynecomastia in males.
On physical exam, there may be hepatomegaly - where the liver can feel firm and nodular, but
when there’s a lot of scarring, the liver may be small so that it can’t be felt at all.
Another sign is spider angiomas- or spider nevi- which are swollen blood vessels just beneath the
skin surface- on the truck, face and upper limbs.
Palmar erythema- which is redness of the hands- can sometimes be seen.
There can also be hypertrophic osteoarthropathy- which is when there’s nail clubbing and
periostitis- which is inflammation around the small hand joints.
Sometimes, there are Dupuytren contracture, which is when one or more fingers are
permanently flexed.
Portal hypertension can lead to splenomegaly, along with caput medusae- which are distended
and engorged paraumbilical veins on the surface of the abdomen.
Finally, there may be minor complications such as hemorrhoids identified on a digital exam.
In terms of diagnosing cirrhosis, lab work includes a CBC- which most commonly
shows thrombocytopenia- especially if there’s also splenomegaly, but can also show anemia and
leukopenia.
Markers of liver injury are AST, ALT, alkaline phosphatase, and GGT and they’re usually
elevated.
Total and conjugated bilirubin are usually normal in compensated cirrhosis.
Finally, markers of liver function like albumin can decrease as cirrhosis progresses, and PT,
PTT, and INR- can increase as cirrhosis progresses.
In addition, Fibrosure or Fibrotest is done using alpha-2-macroglobulin, haptoglobin, total
gamma globulin, apolipoprotein A1, GGT, and total bilirubin to generate a score that
estimates liver fibrosis.
An abdominal ultrasound shows surface nodularity and increased echogenicity and sometimes
there’s atrophy in the right lobe and hypertrophy of the left and caudate lobe.
If there’s portal hypertension, then the diameter of the portal vein is over 13 millimeters.
There’s also ultrasound-based elastography- which measures tissue elasticity. Normal liver
elasticity ranges from 2.6 to 6.2 kilopascals and when it’s above 7 kilopascals, that means that
there’s significant fibrosis and when it’s above 11 kilopascals, that means there’s cirrhosis.
A liver biopsy is the gold standard for diagnosing cirrhosis and also finding the cause, but it’s not
always done, especially when other findings strongly suggest cirrhosis. If it’s done, a liver
biopsy will often show bridging fibrosis and irregular nodules of regenerating hepatocytes.
Individuals with cirrhosis should avoid alcohol, medications that are hepatotoxic, such
as acetaminophen and also herbal and dietary supplements, that can damage the liver like
germander. Individuals should also be vaccinated for hepatitis A and B if they’re not already
immune. Doses of certain medications, like tramadol which is an opioid pain medications, may
need to be adjusted to prevent further harm to the liver.
Individuals with cirrhosis should be monitored every 3 to 6 months using a CBC, markers of
liver injury and markers of liver dysfunction.
In addition, an ultrasound should be done and alpha fetoprotein levels can also be checked to
monitor for possible tumors, since cirrhotic individuals are at increased risk for
developing hepatocellular carcinoma.
Okay, now, with decompensated cirrhosis, there are major complications which may be triggered
by things like acute infections, alcohol intoxication, constipation, or even bouts of dehydration.
Treatment for these complications starts with resolving the triggering event - like treating the
infection or abstaining from alcohol.
One major complication of decompensated cirrhosis is jaundice - which can happen because the
liver is unable to conjugate bilirubin. Lab findings would show total bilirubin levels over 2
milligrams per deciliter.
Another complication is hepatic encephalopathy- and this happens because the liver is unable to
effectively remove toxins- like ammonia- from the blood. These toxins can build up and get into
the brain causing symptoms like insomnia or hypersomnia. As toxins accumulate, there can be
mood changes, along with confusion and even coma in some cases.
On physical exam, there may be asterixis- a flapping tremor of the hand that appears when the
wrist is extended- like a bird that’s flapping its wings.
Lab findings show high levels of ammonia, and it can be lowered using lactulose given orally or
through an enema. Lactulose is a non-absorbable sugar that decreases absorption of ammonia in
the intestines and prevents constipation.
If the individual doesn’t improve in 48 hours, then oral Rifaximin is given. That’s an antibiotic
that kills ammonia-producing bacteria in the intestines and also has anti-inflammatory proprietes.
Individuals with recurrent hepatic encephalopathy can be given ongoing treatment with lactulose.
Now, although portal hypertension can seen in compensated cirrhosis - as things worsen, it can
lead to major complications that are seen in decompensated cirrhosis.
Portal hypertension can cause peripheral edema as well as a build up of excess fluid in
the peritoneal cavity - resulting in ascites.
Ascites can cause abdominal distention, as well as shifting dullness on percussion and a positive
fluid wave test.
Additional lab work for ascites includes electrolytes in order to identify any imbalances,
especially hyponatremia.
An abdominal ultrasound can confirm the diagnosis- usually the fluid in ascites appears
anechoic.
Next, a paracentesis is done to collect ascitic fluid. The ascitic fluid is typically crystal clear, and
bloody ascitic fluid suggests a tumor.
A cell count and differential is also done and with normal ascitic fluid there are below 250
neutrophils. In addition, total protein levels are below 3 grams per deciliter, saying that the fluid
is a transudate- while an exudate has more than 3 grams per deciliter of protein.
Next, the ascitic fluid is tested for albumin to calculate the Serum-to-ascites albumin gradient- or
SAAG. A SAAG above 1.1, means that portal hypertension is present.
Because salt helps retain water, treatment of moderate ascites includes sodium restriction to 2
grams per day.
In addition, a combination of diuretics like spironolactone- a potassium sparing diuretic-
and furosemide- a loop diuretic- is commonly used to get rid of excess fluid. Individuals without
peripheral edema typically lose about 0.5 kilograms daily, and individuals with peripheral edema
lose about 1 kilogram daily. As the ascites resolves, the diuretics are tapered and then stopped.
If an individual develops hepatic encephalopathy or has severe hyponatremia- with sodium levels
below 120 milliequivalents per liter, then diuretic treatment is stopped and serial paracentesis is
done to reduce the ascites.
In severe hyponatremia, fluid intake is restricted to less than the urine volume.
Treatment of severe ascites is done using large volume paracentesis- where up to 5 liters of fluid
is taken out of the abdomen at one time without causing hypovolemia. When more than 5 liters
of fluid is taken out, albumin is given afterwards.
A major complication of ascites is spontaneous bacterial peritonitis- or SBP- which is an
infection of the ascitic fluid. It can cause severe abdominal pain, fever, and an altered mental
status.
A paracentesis of the ascitic fluid is done- and the fluid looks turbid or cloudy, the cell count is
over 250 neutrophils per millimeter square and total protein is above 1 gram per deciliter, and the
SAAG is above 1.1.
In addition, the glucose is usually above 50 milligrams per deciliter- which distinguishes SBP
from a secondary bacterial peritonitis, where glucose is below 50 milligrams per deciliter and the
LDH is below 225 international units per liter.
Cultures and cgram stains are also sent.
With SBP, there’s a single pathogen found and the common are Escherichia coli, Klebsiella
pneumoniae, and Streptococcus pneumoniae, whereas with secondary bacterial peritonitis,
multiple pathogens are usually involved. Empiric antibiotics for SBP are IV Cefotaxime.
Another major complication of portal hypertension is variceal hemorrhage- specifically bleeding
from dilated veins in the esophagus and stomach.
Esophageal and stomach variceal veins are usually seen on an upper endoscopy which is usually
done within 12 hours of the bleeding. During that procedure variceal ligation or endoscopic
sclerotherapy can be done to help stop the bleeding. In addition, IV octreotide, which is
a somatostatin analogue, is used to help decrease portal blood flow.
If there’s massive bleeding or if endoscopic therapy fails to stop the bleeding, then balloon
tamponade is done using a Blakemore tube. This applies direct pressure on the esophagus.
If endoscopic approaches fail, a transjugular intrahepatic portosystemic shunt or TIPS procedure
can be done- which creates a path between the portal and systemic circulation in order to lower
the portal pressure.
In moderately ill individuals, IV ciprofloxacin is given for a week to prevent an infection, and in
severely-ill individuals, IV ceftriaxone is given instead.
Given the risk of bleeding, it’s important to spot varices early on, so in compensated cirrhosis -
an upper endoscopy is done every 2 to 3 years and in decompensated cirrhosis, it’s done every
year.
Individuals with varices should have endoscopic variceal ligation done, and those at high risk
like individuals with decompensated cirrhosis should get prophylactic beta-blockers-
like propranolol- which reduce portal vein pressures.
Individuals with a history of ascites, or SBP, or variceal hemorrhage, are given trimethoprim-
sulfamethoxazole as antibiotic prophylaxis.
Two more complications - hepatorenal syndrome and hepatopulmonary syndrome - describe
failure of the liver and kidneys and failure of the liver and lungs, respectively. They occur
because portal hypertension causes arterial and capillary vasodilation which reduces systemic
vascular resistance and can damage the kidneys and lungs.
Okay, now let’s switch gears and talk about hepatocellular carcinoma, which is a primary liver
tumor that often occurs in cirrhosis.
In some cases, there’s a paraneoplastic syndrome with symptoms like hypoglycemia- because the
tumor consumes a lot of glucose, diarrhea- caused by vasoactive peptides that
increase intestinal secretion, and hypercalcemia- due to secretion of parathyroid- like hormone.
Lab findings can include high levels of alpha fetoprotein and if there’s a paraneoplastic
syndrome, there can be hypoglycemia and high levels of calcium. If there’s diarrhea, there may
be hyponatremia or hypokalemia.
An ultrasound would show a hypoechoic mass in the liver and an abdominal CT-scan can help
stage the tumor using the Tumor-Node-Metastasis system.
Finally, a liver biopsy can be done and that typically shows broad trabeculae and pseudoglands.
Common sites of metastasis include the lungs, intra-abdominal lymph nodes and bone.
Depending on the location and spread of the tumor, a partial hepatectomy or a liver transplant
may be done.
If the tumor cannot be surgically removed, then ablation and embolization or chemoradiation can
be done.
If lymph nodes were invaded or if there’s metastasis, then medications like sorafenib or
lenvatinib can be used to slow tumor growth and relieve the symptoms.
Now, let’s talk about the underlying causes of cirrhosis. First off, there’s chronic viral
hepatitis which is usually due to a hepatitis B or C infection that lasts for over 6 months.
With chronic hepatitis B, HBsAg and anti-HBc antibodies are positive, and with chronic
hepatitis C, anti-HCV antibodies are positive and there are elevated levels of HCV RNA.
Next, there’s alcoholic liver disease caused by drinking over 30 grams of alcohol per day- or
more than 3 beers daily, and nonalcoholic fatty liver disease or NAFLD -which is associated
with metabolic syndrome- which includes obesity, arterial hypertension, insulin resistance, and
dyslipidemia. Both of these lead to steatosis- which is the infiltration of liver cells with fat, and
steatohepatitis- which is when there’s fatty infiltration along with inflammation.
When NAFLD causes steatohepatitis, it’s called non-alcoholic steatohepatitis or NASH.
With alcoholic liver disease, lab findings can show anemia and an elevated MCV- suggesting
vitamin B12 or folate deficiency due to alcohol toxicity. The ESR can be elevated and AST to
ALT ratio is above 2.
With NAFLD induced hepatic steatosis and NASH, other causes of hepatic steatosis need to be
ruled out, like alcoholic liver disease and viral hepatitis.
Next, an ultrasound is done and the liver typically appears hyperechoic with both alcoholic and
non-alcoholic liver disease.
On an abdominal CT-scan, the liver composition is compared to the spleen. A fatty liver has an
attenuation that is at least 10 Hounsfield units lower than the spleen.
On a liver biopsy, in steatosis, there’s fat accumulation, and in steatohepatitis there’s neutrophilic
infiltration.
Treatment relies on alcohol abstinence and with NAFLD it requires management of metabolic
syndrome.
Hemochromatosis is a hereditary disorder caused by a mutation in the HFE gene which lead to
increased iron absorption. The excess iron gets deposited in the liver,
heart, pancreas and pituitary.
In advanced stages, individuals have a classic triad of cirrhosis, diabetes mellitus and skin
pigmentation - the latter two are lumped together in the term bronze diabetes.
Lab findings include a serum transferrin above 45%, and disease confirmation is done
with genetic testing. T
reatment consists of reducing iron load with phlebotomies that remove up to 500 milliliters of
blood weekly for 50 weeks, and after that every 2 to 4 months.
Autoimmune hepatitis is a condition where circulating antibodies attack liver cells.
Lab findings include an elevated total gamma globulin level, especially IgG, antinuclear
antibodies or ANA, anti-smooth muscle antibodies, anti-liver-kidney microsomal-1 antibodies,
and antimitochondrial antibodies.
Autoimmune hepatitis is often associated with other autoimmune conditions, like autoimmune
thyroiditis.
Initial treatment is typically done with oral glucocorticoids like prednisone and once there’s
remission- meaning that liver injury markers normalise and there are no
symptoms- prednisone or azathioprine can be used for maintenance therapy.
Primary sclerosing cholangitis is a progressive disease in which there’s inflammation, fibrosis,
and strictures of the medium and large ducts in the intra- and extra- hepatic parts of the biliary
tree. Sometimes, there's an elevated total gamma globulin level, especially IgM. Perinuclear
antineutrophil cytoplasmic antibodies- or p-ANCA- can also be high.
Next, an ultrasound is done and this shows bile duct wall thickening and focal bile duct dilations.
Diagnosis is confirmed by MRCP where the biliary ducts are beaded or have a “pruned tree”
appearance, meaning that there are multiple strictures.
If an ERCP is done, then a biopsy can be performed that shows onion skin fibrosis due to
periductal fibrosis.
Treatment is done using ursodeoxycholic acid- which is a bile acid- that stimulates hepatobiliary
secretion and protects hepatocytes from being destroyed by bile acids. The only treatment
for primary sclerosing cholangitis is a liver transplant.
Primary biliary cholangitis sometimes called primary biliary cirrhosis, is an autoimmune
condition in which the epithelial cells lining the intrahepatic biliary ducts- are gradually
destroyed. There can be distinctive skin changes like hyperpigmentation as well as lesions like
xanthomas and rashes that show dermatographism- which means that it looks like someone has
written or drawn on the skin.
Lab findings include elevated cholesterol levels, antimitochondrial antibodies which are the key
findings, and sometimes antinuclear antibodies are also present.
An ultrasound or MRCP are done to rule out an extrahepatic obstruction.
If a liver biopsy is done, it shows inflammation, abnormal connective tissue, or fibrosis in
the portal and periportal areas.
Treatment is done using ursodeoxycholic acid. The only curative treatment is a liver transplant.
Wilson disease is a genetic disorder that leads to excessive copper deposition in the liver, eyes,
and brain.
Neurological symptoms include dysarthria, ataxia, dystonia, tremor, and parkinsonism. There
can also be psychiatric symptoms like depression and personality changes.
An ocular slit-lamp examination shows Kayser- Fleischer rings - which are dark rings around
the iris.
Lab findings includes ceruloplasmin levels below 20 milligrams per deciliter - that’s the protein
that transports copper. In addition, a 24 hour urine copper test shows over 100 micrograms of
copper in the urine.
Treatment includes avoiding foods with a high copper content like nuts, chocolate, and
mushrooms. Treatment includes cheltators that can bind to excess copper like D-Penicillamine
and Trientine.
Alpha-1 antitrypsin deficiency is a genetic disorder that affects the lungs and the liver. In the
lungs, there’s excess protease activity that results in destruction of elastin, resulting
in emphysema. In the liver, the abnormal alpha-1 antitrypsin protein accumulates and causes
inflammation.
Lab findings include alpha-1 antitrypsin levels below 11 micromol per liter.
Next, isoelectric focusing can be done- this separates molecules based on their isoelectric point
and can identify different alpha-1 antitrypsin variants. PCR can be used to identify the different
alpha-1-antitrypsin variants.
Pulmonary treatment is done with inhaled bronchodilators- such as Salmeterol, and prevention
relies on avoiding smoke exposure. There is no specific treatment for the liver disease.

Summary
Finally! As a quick recap, cirrhosis can be compensated- in which the individual is asymptomatic
or presents nonspecific symptoms. A work up includes a CBC- that can show thrombocytopenia,
anemia, leukopenia, markers of liver injury, like AST, ALT, alkaline phosphatase, GGT which
are elevated, and total and conjugated bilirubin which can be normal. Markers of liver function
like albumin- can decrease as cirrhosis progresses - while PT, PPT, and INR- can increase
as cirrhosis progresses. An ultrasound is done next, along with FibroSure, ultrasound-based
elastography or a liver biopsy- which is the gold standard for diagnosing cirrhosis.
With decompensated cirrhosis, major complications are present. First, there’s jaundice where
total bilirubin levels are over 2 milligrams per deciliter.
With hepatic encephalopathy, there’s asterixis and high levels of ammonia. Treatment relies on
eliminating precipitating factors, lactulose, and rifaximin.
Another complication is severe portal hypertension which often leads to ascites- that’s usually
treated with sodium restriction and diuretic therapy, SBP- that’s treated with IV cefotaxime,
and esophageal and gastric variceal hemorrhage- that’s treated with endoscopic variceal ligation
or endoscopic sclerotherapy or TIPS and prevented with propranolol, hepatorenal
syndrome and hepatopulmonary syndrome.
One complication of cirrhosis overall is hepatocellular carcinoma, which can be monitored with
an ultrasound every 3 to 6 months. A CT-scan is done to confirm the diagnosis and stage the
condition using TNM system. Treatment depends on the extent and location of the tumor.
Major takeaway

Cirrhosis

 of the 

liver

 can cause elevated circulating 

estrogens

, leading to features such as palmar erythema, 

gynecomastia

, spider angiomas, and 

testicular

atrophy

Main explanation

Cirrhotic

 patients are characterized by a variety of physical findings related to the decreased synthetic capacity of the 

liver  and progressive loss of liver

 functionality. This patient is characterized by several of the classic signs of 

alcoholic liver disease including , asterixis, confusion, caput medusae, palmar erythema, and lower extremity
edema. 

The palmar erythema in this patient is secondary to the hyperestrinism seen in patients with 

cirrhosis. Due to the loss of functional liver  tissue, this patient is unable to metabolize circulating 

estrogens through phase I  (hydroxylation) and phase II  (conjugation) pathways. With severe damage to the 

liver

, the metabolic capacity of this organ is diminished and there is increased circulating 

Estrogen  in the body. This increased estrogen  is responsible for several of the stigmata of 

Cirrhosis  including palmar erythema, spider angiomas,  gynecomastia , and 

Testicular atrophy  in men.

Cirrhosis of the liver

 is a leading cause of death in the Western world. Common mechanisms leading to death include 
liver
 failure, complications related to 
portal hypertension
, or 
hepatocellular carcinoma
. Classic signs of 
liver
 failure include elevated 
liver
 transaminases and bilirubin, elongated 
prothrombin time
, and 
thrombocytopenia
. Altered mental status may be observed resulting from 
hepatic encephalopathy
.

Cirrhosis
 causes coagulopathy through increased activity of 
tissue plasminogen activator
 (
tPA
), which is released by endothelial cells. Normally, 
tPA
 activity is counterbalanced by the release of plasminogen activator inhibitor type-1 (PAI-1).
However, patients with 
alcoholic cirrhosis
 exhibit increased 
tPA
 levels and decreased PAI-1 levels. Increased 
tPA
 activity can be seen in 30-60% of 
cirrhosis
 cases and leads to clot degradation as well as platelet deaggregation. Risk of uncontrolled 
bleeding
 is thus elevated.
ain explanation
Encephalopathy and 
ascites
 in the setting of chronic 
alcohol
 use are symptoms that are suggestive of a diagnosis of 
hepatic encephalopathy
 (HE) precipitated by gastrointestinal 
bleeding
 (positive fecal occult blood test) in the setting of long-standing 
liver
 
cirrhosis
.

HE occurs since 
liver
 dysfunction results in insufficient elimination and subsequent accumulation of metabolic products (e.g.
ammonia). As ammonia accumulates, it is able to cross the 
blood-brain-barrier
, resulting in astrocyte swelling, dysfunction, and impaired neurotransmitter synthesis. Anything that
increases ammonia production or reabsorption in the gut can trigger HE. These include gastrointestinal 
bleeding
, constipation, or infections.

HE presents with symptoms like 

insomnia
 or hypersomnia, mood changes, along with confusion, and even 
coma
 in some cases. Asterixis, a 
flapping tremor
 of the hand that appears when the 
wrist
 is extended, is commonly seen.

Treatment for hyperammonemia includes 

lactulose
, 
rifaximin
, and detection and correction of precipitating factors:

  

Lactulose

 is the first line treatment for overt 

hepatic encephalopathy

, and its mechanism of action involves lowering the 

colonic

pH

, which allows the conversion of intraluminal ammonia to ammonium ions (non-absorbable

form). As a result, use of 

lactulose

 reduces 

plasma

 ammonia levels.  

  

Antibiotics

 like 

rifaximin
 have also been shown to be effective in the treatment of 

hepatic encephalopathy

. It reduces 

plasma

 ammonia levels by altering GI flora and, in turn, reduces ammonia production intraluminally.