PATHOPHYSIOLOGY OF LIVER CIRRHOSIS

Infections
Hepatitis B Metabolic Non-alcoholic fatty Billary tract disease
Autoimmune
Alcohol Hepatitis C Hemochromatosis liver disease PSC
Hepatitis D Wilson disease hepatitis PBC
(NAFLD)

Injury to the hepatocytes

Signs and symptoms
Yellowing of the skin Complications
Ascites
(jaundice) Spontaneous bacterial peritonitis
Fatigue Fibrosis and scarring Gastroesophageal varices
Weakness Hepatic encephalopathy
Hepatorenal syndrome
Loss of appetite Hepatopulmonary syndrome
Itching Hepatocellular carcinoma
Easy bruising Cirrhosis

Compensated Decompensated
Cirrhosis Cirrhosis

Stage 1 Stage 2 Stage 3 Stage 4

Treatment
Preventing further damage to the
liver
Treating the complications of
cirrhosis,
Preventing liver cancer or
detecting it early, and
Liver transplantation.
Interpretation
The diagram presents the pathophysiology of the disease process of Liver
Cirrhosis. Cirrhosis is a late stage of scarring (fibrosis) of the liver caused by many
forms of liver diseases and conditions, such as hepatitis and chronic alcoholism,
heavy alcohol consumption may result in cirrhosis. Liver injury may be the result of
infectious, metabolic, autoimmune, vascular, hereditary, or chemical factors. The liver
has a limited number of cellular and tissue responses to injury. Hepatocyte
degeneration and intracellular accumulations, hepatocyte necrosis and apoptosis,
inflammation, regeneration, and ultimately fibrosis. Liver Cirrhosis etiologies include
Drugs and Toxins, Infections such as viral hepatitis, Metabolic, inherited (genetic)
disorders that result in the accumulation of toxic substances in the liver, which leads
to tissue damage and cirrhosis. Examples include the abnormal accumulation of iron
(hemochromatosis) or copper (Wilson disease). In hemochromatosis, patients inherit
a tendency to absorb an excessive amount of iron from food. Over time, iron
accumulation in different organs throughout the body causes cirrhosis, arthritis, heart
muscle damage leading to heart failure, and testicular dysfunction causing loss of
sexual drive. Autoimmune hepatitis is a liver disease caused by an abnormality of the
immune system. The abnormal immune activity in autoimmune hepatitis causes
progressive inflammation and destruction of liver cells (hepatocytes), leading
ultimately to cirrhosis. Nonalcoholic fatty liver disease (NAFLD) refers to a wide
spectrum of liver diseases that, like alcoholic liver disease, range from simple
steatosis to nonalcoholic steatohepatitis (NASH), to cirrhosis. NAFLD occurs in
individuals who do not consume excessive amounts of alcohol, yet in many respects,
the microscopic picture of NAFLD is similar to what can be seen in liver disease that
is due to excessive alcohol. NAFLD is associated with a condition called insulin
resistance, which, in turn, is associated with metabolic syndrome and diabetes
mellitus type 2. In PSC, the large bile ducts outside of the liver become inflamed,
narrowed, and obstructed. Obstruction to the flow of bile leads to infections of the bile
ducts and jaundice, eventually causing cirrhosis. The abnormal immunity in PBC
causes chronic inflammation and destruction of the small bile ducts within the liver.
Along with the gallbladder, the bile ducts make up the biliary tract. In PBC, the
destruction of the small bile ducts blocks the normal flow of bile into the intestine. As
the inflammation continues to destroy more of the bile ducts, it also spreads to
destroy nearby liver cells. As the destruction of the hepatocytes proceeds, scar tissue
(fibrosis) forms and spreads throughout the areas of destruction. The combined
effects of progressive inflammation, scarring, and the toxic effects of accumulating
waste products culminate in cirrhosis.
Parenchymal injury (acute or chronic) can lead to apoptosis and/or necrosis of
hepatocytes that cause phagocytosis of apoptotic cells and inflammation due to
necrosis leads to activation of Kuppfer cells (sinusoidal macrophages), endothelial
cells, platelets and leukocytes. Leukocytes lead to generation of lipid peroxides,
reactive oxygen species and a number of cytokines and stimulates regeneration of
adjacent hepatocytes (HGF) ultimately contributing to nodule formation. Promote
induction/expression of a variety of cytokines/chemokines and receptors on
neighboring quiescent hepatic cells and activate them. Fibrosis is the net deposition
of excess extracellular matrix (ECM) arising from an imbalance between hepatic
fibrogenesis and fibrinolysis leading to the replacement of injured tissue by a
collagenous scar. Liver fibrosis results from the perpetuation of the normal wound
healing response resulting in an abnormal continuation of fibrogenesis (connective
tissue production and deposition). Fibrosis progresses at variable rates depending on
the cause of liver disease, environmental factors, and host factors.
Liver Cirrhosis complications are Ascites, Spontaneous bacterial peritonitis,
Gastroesophageal varices, Hepatic encephalopathy, Hepatorenal syndrome,
Hepatopulmonary syndrome, and Hepatocellular carcinoma. Yellowing of the skin
(jaundice), Fatigue, Weakness, Loss of appetite, Itching, and Easy bruising are the
clinical manifestation of liver cirrhosis. There are 2 clinical stages of cirrhosis:
compensated and decompensated. For compensated cirrhosis patients, non-invasive
parameters all may be normal and liver biopsy would be required for diagnosis.
Patients with decompensated cirrhosis have had at least one complication including
ascites, jaundice, variceal haemorrhage, or hepatic encephalopathy, and overall they
have median survival times of 2 years.
There is no cure for cirrhosis. The damage already done to your liver is
permanent. However, depending on the underlying cause of your cirrhosis, there may
be actions you can take to keep your cirrhosis from getting worse. Preventing further
damage to the liver, treating the complications of cirrhosis, preventing liver cancer or
detecting it early, and liver transplantation are treatments to slow further damage to
your liver.
PATHOPHYSIOLOGY OF CHOLECYSTITIS

Gallstone blocks cystic Gallstones causing

duct, backing up bile into physical trauma to
the gall bladder gallbladder wall

Dull diffuse abdominal pain, may

Irritates visceral peritoneum, be felt more in RUQ, may
Irritation of gallbladder wall stimulates foregut autonomic radiate to the back and right
nerves shoulder

Increase gallbladder lumen

pressure, decrease blood
flow to gallbladder

Ischemia, gallbladder
necrosis, inflammation, Fever, nausea/vomiting,
Triggers cytokine release
loss of gallbladder tachycardic
structural integrity

Bacterial invasion to Irritation of parietal Persistent RUQ pain,

transmural inflammation of peritoneum, stimulates abdominal guarding and
gallbladder somatic nerves peritoneal signs
Positive Murphy’s sign

Over time, continued Inflamed vessels are more

inflammation of the permeable and leak fluid from Dehydration
gallbladder can cause the blood into the colon
complications

Gallbladder
gangrene Gallbladder
inflammation perforation
of the inflammation of the
gallbladder can gallbladder can cause
cause complications
complications
Interpretation

The pathogenesis of acute cholecystitis is primarily due to obstruction of biliary

outflow by a stone. Other rare causes may be stricture, kinking of the cystic duct,

intussusception of a polyp, torsion of the gallbladder, pressure of an overlying lymph

node on the cystic duct, or inspissated and concentrated bile. As the gallbladder

distends following the obstruction, the blood vessels in the gallbladder wall become

compressed, giving rise to a patch of gangrene on the fundus which can rupture and

produce bile peritonitis. In addition to these mechanical and vascular factors various

investigators have favored infection or chemical irritation as the cause of this disease.

Although the exact mechanism of acalculous cholecystitis is unclear, several

theories exist. Injury may be the result of retained concentrated bile, an extremely

noxious substance. In the presence of prolonged fasting, the gallbladder does not

receive a cholecystokinin (CCK) stimulus to empty; thus, the concentrated bile

remains stagnant in the lumen. The ability of endotoxins to cause necrosis,

hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with

an acute ischemic insult. Endotoxins also abolish the contractile response to CCK,

leading to gallbladder stasis.

PATHOPHYSIOLOGY OF CHOLELITHIASIS

Mechanical and chemical

Gallbladder contractions against Gallstone migration into biliary
irritation of the gallbladder’s
cystic duct opening tract
epithelial mucosa

Increase in intra- Blocks sphincter of

Acute inflammation Blocks the common
gallbladder oddi or the ampulla
of the gallbladder bile duct, preventing
pressure of water, obstructs normal bile flow
pancreatic duct

Backed up Cholestasis
pancreatic secretions
increase pressure on
Billary Colic acinar cells, injuring Infection of the biliary
them tree as duodenal
bacteria “ascend” up
the bile duct

Acute Cholecystitis Acinar cell injury auto-

activates pancreatic
proteases, which digest
pancreatic tissue Ascending
Cholangitis

Acute Pancreatitis
Interpretation

Gallstone formation occurs because certain substances in the bile are present in
concentrations that approach the limits of their solubility. When bile is concentrated in
the gallbladder, it can become supersaturated with these substances, which then
precipitate from the solution as microscopic crystals. The crystals are trapped in the
gallbladder mucus, producing gallbladder sludge. Over time, the crystals grow,
aggregate, and fuse to form macroscopic stones. Occlusion of the ducts by sludge
and/or stones produces complications of gallstone disease. The two main substances
involved in gallstone formation are cholesterol and calcium bilirubinate.
Bile salts in bile dissolve the unilamellar vesicles to form soluble aggregates called
mixed micelles. This happens mainly in the gallbladder, where bile is concentrated by
the reabsorption of electrolytes and water. Compared with vesicles (which can hold
up to 1 molecule of cholesterol for every molecule of lecithin), mixed micelles have a
lower carrying capacity for cholesterol (about 1 molecule of cholesterol for every 3
molecules of lecithin). If bile contains a relatively high proportion of cholesterol, to
begin with, then as bile is concentrated, progressive dissolution of vesicles may lead
to a state in which the cholesterol-carrying capacity of the micelles and residual
vesicles is exceeded. At this point, bile is supersaturated with cholesterol, and
cholesterol monohydrate crystals may form.
Thus, the main factors that determine whether cholesterol gallstones will form are
(1) the amount of cholesterol secreted by the liver cells, relative to lecithin and bile
salts, and (2) the degree of concentration and the extent of stasis of bile in the
gallbladder. Bilirubin, a yellow pigment derived from the breakdown of heme, is
actively secreted into bile by liver cells. Most of the bilirubin in bile is in the form of
glucuronide conjugates, which are water-soluble and stable, but a small proportion
consists of unconjugated bilirubin. Unconjugated bilirubin, like fatty acids, phosphate,
carbonate, and other anions, tends to form insoluble precipitates with calcium.
Calcium enters bile passively along with other electrolytes.
In situations of high heme turnover, such as chronic hemolysis or cirrhosis,
unconjugated bilirubin may be present in bile at higher than normal concentrations.
Calcium bilirubinate may then crystallize from the solution and eventually form
stones. Over time, various oxidations cause the bilirubin precipitates to take on a jet-
black color, and stones formed in this manner are termed black pigment gallstones.
 References

Cholelithiasis | Calgary Guide. (2015, May 25).

https://calgaryguide.ucalgary.ca/cholelithiasis/Mayo Clinic. (2018). Gallstones -
Diagnosis and treatment - Mayo Clinic. Mayoclinic.org.
https://www.mayoclinic.org/diseases-conditions/gallstones/diagnosis-
treatment/drc-20354220

Cirrhosis | McMaster Pathophysiology Review. (n.d.). Www.pathophys.org.

Retrieved February 22, 2022,
http://www.pathophys.org/cirrhosis/#Pathophysiology

Cleveland Clinic. (2019). Cirrhosis of the Liver | Cleveland Clinic. Cleveland Clinic.
https://my.clevelandclinic.org/health/diseases/15572-cirrhosis-of-the-liver

WebMD. (2004, July 9). Gallstones: What You Should Know. WebMD; WebMD.
https://www.webmd.com/digestive- disorders/gallstones

What Is Cirrhosis of the Liver? Treatment, Symptoms, Causes & Stages. (2021, February
10). MedicineNet.
https://www.medicinenet.com/cirrhosis/article.htm#what_is_sofosbuvir_and_velpat
asvir_what_is_sofosbuvir_and_velpatasvir_used_for