Cirrhosis: Pathology review

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Case Study0:00–1:13

At the family medicine clinic, a 52- year- old male immigrant from Africa, named Jamar, came in for a checkup for the first time in a decade.
On questioning, he admits to an extensive history of alcohol abuse. Physical examination reveals gynecomastia, palmar erythema and spider angiomata, as well as a palpable spleen.
Next, a 70- year- old Caucasian female, named Eleanor, with a history of chronic hepatitis C infection, is brought to the emergency department by paramedics due to altered mental status.
She is completely disoriented and unable to provide an adequate history. Neurologic examination also reveals asterixis.
Lab tests of both show increased aspartate aminotransferase, or AST, and alanine aminotransferase or ALT. There’s also decreased albumin and increased prothrombin time.
The difference is that Jamar has an AST level twice as high as ALT, in contrast with Eleanor, who has an ALT higher than AST.
Eleanor, in particular, also has high serum levels of ammonia. Both Jamar and Eleanor have cirrhosis.

Pathology1:13–2:34

This is when chronic inflammation damage the liver causing it to become fibrotic. Normally, the liver is highly regenerative but scar tissue can replace liver cells which prevents regeneration and when this goes on for too long, it reaches the point where the damage is no longer reversible.
If enough of the liver is replaced by scar tissue in advanced cirrhosis, a liver transplant might be needed. Now, if we zoom into a hepatic lobule, we can see that it’s made of sheets of hepatocytes with sinusoids between them.
The sinusoids are made of branches of the portal vein and hepatic artery, and together with the bile duct, the form the portal triad which runs towards the central vein.
Now, there’s a space around each sinusoid, called the perisinusoidal space which contains stellate cells. When the hepatocytes are injured, they cluster together and form regenerative nodules.
Here, they secrete paracrine factors that activate the stellate cells, which then proliferate, and start secreting transforming growth factor beta1, or TGF-beta.
This causes them to produce collagen. The collagen build up around the nodules and help form scar tissue, leading to fibrosis.
Okay, let’s look at some of the causes of cirrhosis. First off, there’s chronic viral hepatitis which is usually due to a hepatitis B or C infection that last for over 6 months.

Causes2:34–3:55

Next, there’s alcoholic liver disease caused by excessive alcohol consumption, and nonalcoholic fatty liver disease, or NAFLD, caused by metabolic syndrome which consists of hypertension, hyperglycemia, insulin resistance, and dyslipidemia.
Now, alcohol metabolism needs alcohol dehydrogenase and aldehyde dehydrogenase, which uses up NAD+. Beta oxidation in lipid metabolism also needs this coenzyme, so when they’re used up, lipids accumulate inside hepatocytes.
Next, free oxygen species are also created during alcohol metabolism, and this could also damage hepatocytes. In NAFLD, insulin resistance cause fat to build up in the hepatocytes, so both kinds of liver disease lead to steatosis, which is the infiltration of liver cells with fat, and steatohepatitis, which is when there’s fatty infiltration along with inflammation.
Now, steatosis and steatohepatitis are reversible, but when too much damage is done, they can lead to cirrhosis and this is nonreversible.
Then, there’s hemochromatosis, which is an autosomal recessive disorder caused by a mutation in the HFE gene that leads to increased iron absorption in the small intestine.

Hemochromatosis3:55–4:46

Another cause is frequent transfusions, like when a person has thalassemia. Excess iron gets deposited everywhere, but particularly in the liver, pancreas, heart, pituitary gland, joints, and skin.
On your exam, individuals will have a classic triad of cirrhosis, diabetes mellitus, and skin hyperpigmentation, the latter two are lumped together with the term bronze diabetes since the skin looks bronzed or tanned.
Treatment consists of reducing iron in the body with phlebotomy or with iron chelators like deferasirox, deferoxamine, and deferiprone.

Wilson Disease4:46–6:20

Wilson disease is another autosomal recessive disorder. This is caused by a mutation in hepatocyte copper-transporting ATPase which is needed to move copper from the liver into bile for excretion, and it’s also needed to synthesize ceruloplasmin, the copper storage and transport protein in the blood.
So the mutation leads to excessive copper buildup in the liver, and low ceruloplasmin level. Eventually, the copper overflows into the blood and deposits in the brain and eyes.
A typical case in your exam will present an individual with cirrhosis and neurological symptoms like dysarthria, dystonia, tremor, and parkinsonism or psychiatric symptoms like depression and personality changes.
And another high yield finding is Kayser- Fleischer ring, which is a dark ring around the iris due to copper deposits in the cornea.
Treatment include cheltators that bind to excess copper, like penicillamine or trientine. Next, there’s alpha-1 antitrypsin deficiency, which is an autosomal codominant disorder, where there’s insufficient alpha-1 antitrypsin.
This protein normally inactivate neutrophil elastase, but when there’s a deficiency, these elastase can damage the alveoli in the lungs, resulting in emphysema.
And in the liver, misfolded alpha-1 antitrypsin builds up, killing hepatocytes and leading to cirrhosis. So, a test question will often present a young person with cirrhosis and dyspnea without a history of smoking.
Next, there’s autoimmune hepatitis, where circulating antibodies attack liver cells. This is often associated with specific autoantibodies, such as antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver-kidney microsomal-1 antibodies.

Antitrypsin Deficiency6:20–6:21

Autoimmune Hepatitis6:21–6:40

Finally, cirrhosis can be caused by biliary diseases like primary sclerosing cholangitis and primary biliary cholangitis.

Biliary diseases6:40–8:14

Both disorders cause damage to the biliary system, leading to scarring of the bile ducts that prevent bile from draining.
The bile backs up into the liver, causing damage, and eventually cirrhosis. Key symptoms for both include jaundice, pruritus, dark urine, clay-colored stool, and hepatosplenomegaly.
Primary sclerosing cholangitis or PSC, is a progressive disease in which there’s inflammation, fibrosis, and strictures of the intra- and extra- hepatic parts of the biliary tree.
This is classically described as “onion- skin” fibrosis, because it looks a bit like an onion skin, with concentric rings of fibrosis around the bile duct.
It’s classically seen in middle- aged males with inflammatory bowel disease. It’s also linked to cholangiocarcinoma and cancer of the gallbladder.
Now, in primary biliary cholangitis, or PBC, the epithelial cells lining the intrahepatic biliary ducts are gradually destroyed, but the cause is unknown.
It’s possibly autoimmune in nature since it’s classically seen in middle- aged females with another autoimmune condition, like autoimmune thyroiditis or rheumatoid arthritis.
Since the liver plays a major role in cholesterol metabolism, PBC can lead to hypercholesterolemia. This can manifest as xanthelasmas which are cholesterol deposits that form skin nodules, typically around the eyes.

Complications8:14–14:00

Now, sometimes, the exam will try to test you on cirrhosis by presenting its complications. So, let’s start with portal hypertension.
So, as the central veins and sinusoids become compressed by scar tissue, their pressure starts to build up. Higher portal pressure means that fluid in blood vessels is more likely to get squeezed out into tissues and then leak into large open spaces like the peritoneal cavity.
That’s how cirrhosis leads to excess peritoneal fluid, also known as ascites. The classic patient with ascites will present with abdominal distention, as well as shifting dullness on percussion.
If abdominal distention is also accompanied by severe abdominal pain and fever or chills, this might be a sign of spontaneous bacterial peritonitis.
This is an infection of ascitic fluid by a pathogen, most commonly a gram negative one, like Escherichia coli, or Klebsiella pneumoniae, and, less commonly, gram positive, like Streptococcus pneumoniae.
It’s called spontaneous because there’s no obvious source of infection like a ruptured bowel. An important thing to bare in mind here is that in a paracentesis of the ascitic fluid, the cell count is over 250 neutrophils per millimeter square.
It has a very high mortality rate and is treated with a third generation cephalosporin, like cefotaxime. Okay, with portal hypertension blood has a harder time getting into the liver from the GI tract, so it backs up into the spleen, causing splenomegaly.
It also backs up into the portosystemic collateral veins on the anterior surface of the abdomen, causing caput medusae. In the lower rectum, this leads to hemorrhoids, and in the lower end of the esophagus it leads to esophageal varices.
In fact, the only sign of portal hypertension could be esophageal variceal bleeding, leading to hematemesis, or vomiting of blood, or melena, which is the passage of black, tarry stools.
The treatment for portal hypertension is transjugular intrahepatic portosystemic shunts, or TIPS. This creates a shunt between the portal vein and hepatic vein so blood from the intestines bypasses the liver and move into systemic circulation.
Two more complications of portal hypertension are hepatorenal syndrome and hepatopulmonary syndrome which describe failure of the liver and kidneys and failure of the liver and lungs.
Though not fully understood, they seem to occur because changes in portal flow trigger arterial and capillary vasodilation which reduces systemic vascular resistance and can damage the kidneys and lungs.
Now, other types of complications start to appear as functional liver tissue decreases. One of them is the inability to remove toxins, like ammonia, from the blood.
These toxins can build up and harm tissues like the brain, causing hepatic encephalopathy. Anything that increases ammonia production or reabsorption in the gut can be a trigger, like GI bleeding, constipation, or infections.
Decreased ammonia removal by the kidneys can also be a trigger, like when there’s renal failure. Finally, TIPS used to treat portal hypertension can also be a trigger since ammonium rich blood from the intestines bypasses the liver completely.
Hepatic encephalopathy presents with symptoms like insomnia or hypersomnia, mood changes, along with confusion, and even coma in some cases.
For your exams, remember that the telltale sign is asterixis, a flapping tremor of the hand that appears when the wrist is extended, like a bird that’s flapping its wings.
A typical lab finding is high levels of ammonia and it can be lowered using lactulose. This is a non-absorbable sugar that decreases absorption of ammonia in the intestines.
Rifaximin or neomycin can be also used, which are antibiotics that kill ammonia- producing bacteria in the intestines. Also, since the liver plays a big role in metabolizing estrogen into inactive metabolites, increased estrogen in the blood can also lead to complications, like testicular atrophy, decreased body hair and gynecomastia in male, as well as spider angiomas, which are swollen blood vessels just beneath the skin surface, and palmar erythema, which is redness of the hands.
And, since the liver conjugates bilirubin, increased unconjugated bilirubin builds up in the blood which leads to jaundice, or yellowing of the skin and sclera.
Another important job of the liver is producing albumin, so cirrhosis also causes low albumin levels in the blood, or hypoalbuminemia.
This causes peripheral edema, often seen in the lower limbs, since there’s less oncotic pressure in the blood vessels and the fluid leaks out.
The liver also helps in making clotting factors, so, on your tests, a cirrhotic patient could also present with easy bruising and excessive bleeding.
Eventually, since the liver is in a constant cycle of damage and repair, it raises the chances of genetic mutations, potentially leading to carcinogenesis or development of hepatocellular carcinoma.
This is the most common primary malignant liver tumor in adults. A high- yield fact is that it’s associated with high levels of alpha fetoprotein.
For diagnosis of cirrhosis, the “gold standard” is a liver biopsy. But, for your exams, there are many important findings that will act as clues to help identify the cause!

Diagnosis14:00–17:15

In cirrhosis, there’s usually indicators of liver cell damage, like elevated aspartate aminotransferase, or AST, and alanine aminotransferase, or ALT.
In most cases, ALT is higher than AST, except for alcoholic liver disease, where the ratio of AST to ALT is typically higher than 2:1.
For alcoholic liver disease, remember that the histology will show Mallory bodies which are damaged intermediate filaments that accumulates inside hepatocytes.
These are eosinophilic so they appear pink on H&E stain. In NAFLD, lipids build up inside hepatocytes, causing them to swell up, which is called “ballooning.” For hemochromatosis, look for high serum iron, ferritin, and transferrin, but low total iron binding capacity.
Next, a liver biopsy with Prussian blue stain that detects iron is traditionally used, but this has been replaced by MRI, which detects liver iron distribution without an invasive procedure.
In Wilson disease, look for Kayser- Fleischer ring with an ocular slit-lamp examination. Serum ceruloplasmin level is low, while serum and urine copper are elevated.
In alpha-1 antitrypsin deficiency a liver biopsy will reveal globules of misfolded alpha-1 antitrypsin protein inside the liver cells, and remember that these are Periodic Acid Schiff or PAS stain positive.
For your exams, remember that Primary sclerosing cholangitis is associated with elevated IgM antibody levels and perinuclear antineutrophil cytoplasmic antibodies, or p-ANCAs.
Perinuclear means they are specific antibodies that target antigens around the nucleus of neutrophils. Also, in a magnetic resonance cholangiopancreatography, or MRCP, the biliary ducts are beaded or have a “pruned tree” appearance, meaning that there are multiple strictures.
In contrast, primary biliary cholangitis has increased antimitochondrial antibodies, and a normal MRCP. Indicators of biliary injury, like elevated alkaline phosphatase or ALP and gamma- glutamyl transferase or GGT are hints for primary sclerosing cholangitis or primary biliary cholangitis.
Remember that ALP can be also elevated in bone disease, in contrast with GGT, which is specific for biliary diseases. Next, indicators of reduced liver function include decreased serum albumin levels, increased bilirubin levels and prothrombin time or INR.
These are the best indicators of the prognosis in a person with cirrhosis. Another common finding is also thrombocytopenia or low platelet count, especially if there’s splenomegaly.
Alright, time for a review! Cirrhosis is when there’s damage to the liver and healthy tissue is replaced with scar tissue.

Review17:15–18:18

Causes include chronic hepatitis B or hepatitis C infection, alcoholic liver disease, non alcoholic liver disease, genetic disorders, like hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, as well as autoimmune hepatitis and biliary disorders, like primary sclerosing cholangitis and primary biliary cholangitis.
Over time, complications develop. Portal hypertension can lead to ascites, splenomegaly, portosystemic collaterals, hepatorenal or hepatopulmonary syndrome.
Decreased liver function can lead to hepatic encephalopathy, increased estrogen, jaundice, edema and easy bruising. Diagnosis is done with a biopsy or through lab and imaging tests.
It’s important to identify and treat the cause of cirrhosis because the only treatment for advanced cirrhosis is a liver transplant.
Okay, but let’s not forget about our cases. Jamar had the typical presentation of cirrhosis, probably due to chronic alcohol consumption.

Summary18:18–19:24

This included signs of high estrogen levels, specifically gynecomastia, spider angiomata and palmar erythema, as well as splenomegaly, which is a sign of portal hypertension.
Meanwhile, Eleanor came in with altered mental status and asterixis, which alongside high ammonia levels, should remind us of hepatic encephalopathy.
This is a complication of cirrhosis, probably secondary to her chronic hepatitis C infection. In both of them, blood tests showed indicators of liver damage, meaning elevated AST and ALT, and decreased liver function, meaning decreased albumin and increased prothrombin time.
The fact that Jamar has a ratio of AST to ALT higher than 2 is indicative of alcoholic liver disease. And if a liver biopsy were to be done, it would show regenerative nodules with intermediate bands of fibrosis.
...And that’s cirrhosis pathology in a nutshell.