Pamantasan Ng Lungsod Ng Maynila

College of Medicine Department of Pathology

Hepatobiliary Tract and Pancreatic Pathology

PAYSON, RODRIGO JOSEPH S. / 2B / 2021-70118

Learning Objectives:
At the end of the section, the student shall be able to:
1. Cite important parts of the clinical history, physical examination, and diagnostic tests in the diagnosis
of the given cases.
2. Recognize the gross and microscopic features of the given cases.
3. Explain the pathology of the above conditions in relation to diseases of the liver, biliary tract and
pancreas.

Case 1
A 46-year-old woman presents to the emergency room with sudden onset of right upper
quadrant and epigastric pain that began 6 hours earlier. The pain is steady in colicky, worsened by eating,
and radiates to the right shoulder. Physical examination reveals inspiratory arrest with deep palpation of
the right upper quadrant. Relevant laboratory findings are as follows:
Total bilirubin: 2.5 mg/dL
BUN: 20 mg/dL
Cr: 1.00 mg/dL
AST: 77 U/L
ALT: 75 U/L

Guide questions:
1. Explain the pathophysiology of this condition?

Choledocholithiasis
(picture on the left)

From choledocho, which is the latin word for common bile duct, and lithiasis, which is the medical term
for stone. Choledocholithiasis occurs when a stone blocks the bile flow through the common bile duct.
Most often, gallstones form in the gallbladder and then migrate to the common bile duct, where they get
stuck. However, they can also form in the common bile duct itself, which is why choledocholithiasis can
still occur for people who have had their gallbladders removed. Gallstones occur when there’s an
imbalance in the composition of bile, which leads to sedimentation and formation into stone.
Choledocholithiasis may be asymptomatic if bile can flow past a partial obstruction. On the other hand,
when the obstruction is complete, bile can’t flow past it, causing distension and increased pressure as bile
accumulates behind the obstruction. As a result, individuals can develop right upper quadrant abdominal
pain. If left untreated, choledocholithiasis can lead to more serious complications, such as infection of the
biliary tract and acute biliary pancreatitis. People with gallstones can also be at a higher risk of
developing cholecystitis, which is the inflammation and infection of the gallbladder

Cholecystitis
(picture on the right)

Cholecystitis is inflammation of the gallbladder that occurs most commonly because of the presence
of stones in the gallbladder or an obstruction of the cystic duct by gallstones arising from the
gallbladder (cholelithiasis or choledocholithiasis). Uncomplicated cholecystitis has an excellent
prognosis; the development of complications such as gangrene or perforation renders the prognosis less
favorable.

Ninety percent of cases of cholecystitis involve stones in the gallbladder (ie, calculous cholecystitis), with
the other 10% of cases representing acalculous cholecystitis.

Acute calculous cholecystitis is caused by an obstruction of the cystic duct, leading to distention of
the gallbladder. As the gallbladder becomes distended, blood flow and lymphatic drainage are
compromised, leading to mucosal ischemia and necrosis. 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.

A study by Cullen et al demonstrated 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.The most common presenting
symptom of acute cholecystitis is upper abdominal pain. The following characteristics may be reported:

● Pain may radiate to the right shoulder or scapula

● Pain frequently begins in the epigastric region and then localizes to the right upper quadrant
(RUQ)
● Pain may initially be "colicky" (it is NOT a true colic) but almost always becomes constant
● Nausea and vomiting are generally present, and fever may be noted

Patients with acalculous cholecystitis may present with fever and sepsis alone, without the history of
pain.The physical examination may reveal the following:
 ● Fever, tachycardia, and signs of peritoneal irritation (eg, tenderness in the RUQ or
epigastric region, often with guarding or rebound)
● Palpable, tender gallbladder or fullness of the RUQ (30%-40% of patients)
● Jaundice (~15% of patients)

Cholelithiasis
There are two general classes of gallstones: cholesterol stones, containing more than 50% of crystalline
cholesterol monohydrate, and pigment stones composed predominantly of bilirubin calcium salts.

Pathogenesis of Cholesterol Stones

Cholesterol is rendered soluble in bile by aggregation with water-soluble bile salts and water-insoluble
lecithins, both of which act as detergents. When cholesterol concentrations exceed the solubilizing
capacity of bile (supersaturation), cholesterol can no longer remain dispersed and nucleates into
solid cholesterol monohydrate crystals. Four conditions appear to contribute to formation of cholesterol
gallstones
● supersaturation of bile with cholesterol
● hypomotility of the gallbladder
● accelerated cholesterol crystal nucleation
● hypersecretion of mucus in the gallbladder, which traps the nucleated crystals, leading to
accretion of more cholesterol and the appearance of macroscopic stones.

Pathogenesis of Pigment Stones

Pigment gallstones are complex mixtures of insoluble calcium salts of unconjugated bilirubin along
with inorganic calcium salts. Disorders that are associated with elevated levels of unconjugated
bilirubin in bile, such as chronic hemolytic anemias, severe ileal dysfunction or bypass, and bacterial
contamination of the biliary tree, increase the risk of developing pigment stones. Unconjugated
bilirubin is normally a minor component of bile, but it increases when infection of the biliary tract leads
to release of microbial β- glucuronidases, which hydrolyze bilirubin glucuronides.

Thus, infection of the biliary tract with Escherichia coli, Ascaris lumbricoides, or the liver fluke C.
sinensis, increases the likelihood of pigment stone formation. In hemolytic anemias the secretion of
conjugated bilirubin into the bile increases. About 1% of bilirubin glucuronides are deconjugated in the
biliary tree, and in the setting of chronically increased secretion of conjugated bilirubin, there is
sufficiently large amount of deconjugated bilirubin left to allow pigment stones to form.

Here is a summary for the pathophysiology of cholelithiasis causing Choledocholithiasis and

Cholecystitis

Image source: https://calgaryguide.ucalgary.ca/cholelithiasis/

 Figure 1. Cholelithiasis: formation of gallstones

2. What are the risk factors in developing this condition?

Risk factors for cholecystitis mirror those for cholelithiasis and include increasing age, female sex,
certain ethnic groups, obesity or rapid weight loss, drugs, and pregnancy. Although bile cultures are
positive for bacteria in 50%-75% of cases, bacterial proliferation may be a result of cholecystitis and not
the precipitating factor for it.

Table 1. Risk Factors for Gallstones

3. Discuss Charcot’s triad and Reynold’s pentad.

Choledocholithiasis can cause cholangitis, which is an infection of the bile ducts. The three typical
symptoms of cholangitis are known as Charcot's triad, consisting of right upper quadrant abdominal
pain, jaundice, and fever. The condition may progress rapidly to Reynold's pentad, which consists of
Charcot's triad with confusion and hypotension.
 Figure 2. Charcot’s triad and Reynold’s pentad

Case 2
A 65-year-old alcoholic male with known chronic liver disease evidenced by cirrhosis presents with
increasing weight loss and ascites. Physical examination reveals jaundice, gynecomastia, spider
angiomas, palmar erythema, shrunken scrotum, and hemorrhoids. CT scan shows a round
homogeneous and hypervascular mass in the right lobe of the liver.

Guide questions:
1. What risk factors are associated with this condition?

Hepatitis B & C
Chronic liver disease (CLD) is characterized by a six-month progressive decline in liver functions
such as clotting factor and other protein synthesis, detoxification of harmful metabolic products, and bile
excretion. Hepatitis B and C viruses, as well as certain medications, are common causes. The majority of
people have no symptoms, but some have vague symptoms like feeling ill, losing appetite, and fatigue.
Alcoholic liver disease
Drinking excessive amounts of alcohol, even for a few days, can cause fat to accumulate in the
liver. This is the first stage of ARLD and is known as alcoholic fatty liver disease. Although fatty liver
disease rarely causes symptoms, it is an important warning sign that a person is drinking excessively.
Cirrhosis is a stage of ARLD in which the liver is severely scarred. Even at this stage, there may be no
visible symptoms. Although the condition is usually irreversible, quitting drinking right away can prevent
further damage and significantly increase your life expectancy.

Cryptogenic cirrhosis
Cryptogenic cirrhosis is a condition that impairs liver function. Cryptogenic cirrhosis (CC) is the
end stage of a chronic liver disease in which its underlying etiology remains unknown after extensive
clinical, serological, and pathological evaluations have been performed. People with this condition
develop irreversible liver disease caused by scarring of the liver (cirrhosis), typically in mid- to late
adulthood.

Non-alcoholic Fatty Liver Disease (NAFLD/NASH)

NAFLD is linked to metabolic syndrome (obesity, hyperlipidemia, and diabetes mellitus). Some
of these patients developed cirrhosis as a result of nonalcoholic steatohepatitis. All metabolic syndrome
risk factors can aggravate the disease process.

Genetic Causes
The most common genetic causes of CPD are alpha-1 antitrypsin deficiency, hereditary
hemochromatosis, and Wilson's disease. The most common genetic cause of CPD in children is alpha-1
antitrypsin deficiency. Hereditary hemochromatosis is an inherited iron malabsorption disorder that runs
in families. Excess iron is absorbed through the gastrointestinal tract due to a mutation in the HFE gene,
which regulates iron absorption from the gut. As a result, total body iron levels rise abnormally (such as
ferritin and hemosiderin). This process results in the formation of hydroxyl radicals, which cause organ
fibrosis. Wilson's disease is an inherited autosomal recessive disorder that frequently results in copper
accumulation.

Autoimmune Causes
Autoimmune hepatitis is a rare disease in which autoantibodies destroy the liver parenchyma.
Cirrhosis is already present in the majority of patients with this disease. Women are more frequently
affected than men.

Primary biliary cirrhosis (PBC)

This is an autoimmune and progressive liver disease characterized by bile duct destruction,
inflammation, and scarring in the portal. It causes cholestatic jaundice and liver parenchymal fibrosis.
PBC is more common in women in their forties and fifties. PBC has elevated levels of alkaline
phosphatase.

Primary Sclerosing Cholangitis (PSC)

 It is frequently linked to ulcerative colitis. This condition is distinguished by a reduction in the
size of the intrahepatic and extrahepatic bile ducts as a result of inflammation and fibrosis.

Autoimmune hepatitis (AIH)

This is a chronic form of hepatitis that affects women more than men and is characterized by
elevated levels of autoantibodies such as antinuclear antibodies, anti-smooth muscle antibodies, and
hypergammaglobulinemia.

2. Explain the pathophysiology of the physical examination findings.

Figure 3. Pathogenesis and complications of Liver Cirrhosis

Increasing weight loss and ascites

Ascites is a common symptom of hepatic decompensation that directly impacts oral intake by limiting
physical capacity of the stomach, and indirectly by contributing to postprandial discomfort. Patients with
refractory ascites have a high prevalence of malnutrition and characteristically demonstrate the lowest
calorie intake of all patients with liver disease. In addition to the effect of ascites on gastric reserve,
depressed appetite and early satiety; repeated paracentesis causes significant nutrient losses. Not only
does the body expend considerable energy to heat a large body of ascitic fluid, but ascitic fluid has
considerable calorie content (in the form of proteins, carbohydrates and fats), and removal of this via
large-volume paracentesis results in calorie debt. Failure to replace this energy loss exacerbates the
catabolic state already seen in advanced cirrhosis. Infusion of serum albumin after paracentesis is
necessary to promote plasma volume expansion and prevent hyponatremia, though albumin replacement
after ascitic drainage has no effect on nutritional status or repletion of protein stores.

Jaundice
About 19–40% of patients with HCC present with jaundice at the time of diagnosis and usually occurs in
the advanced stages of the disease. It is caused by diffuse tumor infiltration of the liver parenchyma,
progressive liver failure, hepatic hilar invasion, severe cirrhosis or a combination of these factors.
Obstructive jaundice due to blockage of the bile duct blockage is uncommon in HCC, as only 1–12% of
patients present with this symptom. The prognosis of patients with jaundice is gloomy at best.

Gynecomastia
In liver disease there is an increased production of androstenedione by the adrenal glands, increased
aromatisation of androstenedione to estrogen, loss of clearance of adrenal androgens by the liver and a
rise in SHBG, resulting in gynaecomastia.

Based on other studies, cirrhosis, acting in concert with alcohol, produces feminization, such as
gynecomastia, alteration in body fat distribution and a female escutcheon. The main mechanism is that
both alcohol and acetaldehyde stimulate the adrenal cortex to increase the secretion of weak adrenal
androgens that serve as estrogen precursors. Alcoholic men with chronic liver disease have elevated
circulating estradiol and estrone levels from aromatization of androstenedione. Ethanol increases the
activity of aromatase, which converts androgens to estrogens.

Spider angiomas
Spider nevi or spider angiomas are seen in cirrhosis patients secondary to hyperestrogenemia. Liver
dysfunction leads to a sex hormone imbalance, causing increased estrogen to free testosterone ratio and
the formation of spider nevi. Palmar erythema is another skin finding that is seen in cirrhosis and is also
secondary to hyperestrogenemia. Jaundice is a yellowish discoloration of the skin and mucous
membranes seen when the serum bilirubin is greater than 3 mg/dL and in decompensated cirrhosis.

Palmar erythema
Liver cirrhosis is characterized by splanchnic and peripheral vasodilation, hyperdynamic circulation and
local differences in peripheral circulation between the upper and lower limbs as well as the torso, and
these hemodynamic differences predispose to the development of skin vascular abnormalities, including
spider veins, palmar erythema and warm hands.

Palmar erythema, also known as liver palms, is characterized by capillary dilatation in the skin of the
thenar eminence and fingertips and manifested by blanchable redness of the skin. This condition is caused
by elevated serum estrogen levels and changes in peripheral hemodynamics. Though palmar erythema
occurs in about two-thirds of patients with liver cirrhosis, it is non-specific and can also occur in patients
with rheumatoid arthritis, hyperthyroidism, diabetes, juvenile dermatomyositis and pregnancy.

Shrunken scrotum
Hepatic cirrhosis is associated with hypogonadism and signs of feminization irrespective of the direct
toxic effect of ethanol upon the testes. Testicular atrophy, low testosterone levels, decreased libido,
infertility, reduced secondary sex hair and gynecomastia are found in men with cirrhosis. Fifty percent of
patients with cirrhosis present reduced spermatogenesis and peritubular fibrosis.
The normal function of the hypothalamic–pituitary–gonadal axis is affected in liver diseases. The
pulsatile secretion of LH and the response to GnRH and clomiphene are reduced. As has already been
mentioned, in late stages of cirrhosis the patients present features of feminization, suggesting altered
levels of sex hormones. The clinical signs of hypogonadism are more pronounced in alcoholic patients
due to the direct effect of ethanol upon the testes. In cirrhotic patients, the estrogen/androgen ratio is
usually increased. The levels of testosterone and dihydroepian-drosterone are reduced, while the estradiol
levels are normal or slightly elevated. These alterations are dependent on the severity of the liver disease
and are more pronounced in patients with higher Child–Pugh score. Several other factors may contribute
to these hormonal changes in cirrhosis, including hepatic overproduction of SHBG, changed SHBG
isoforms with different steroid-binding affinities, elevated prolactin levels, direct suppression of Leydig
cell function by estrogens, increased estrogen receptors in the liver and cyclic variation in the severity of
the liver illness producing the hormonal changes of refeeding gynecomastia. It must be kept in mind that
the gynecomastia and impotence of cirrhotics are augmented by the chronic use of spironolactone, a
receptor antagonist of aldosterone and testosterone, which reduces the testosterone levels and slightly
increases the levels of estradiol.

Hemorrhoids
Hemorrhoidal disease is a common finding in cirrhotic patients (40–44%), as hemorrhoidal plexus is a
possible site of porto-systemic venous anastomosis. Liver cirrhosis leads to swollen and engorged veins
within the rectum called varicose veins. These may occur without constipation and may lead to bleeding
and other complications. Ascites or collection of excess fluids within the abdomen also leads to risk of
hemorrhoids. The swollen abdomen presses on the blood vessels, leading to hemorrhoids.

Round homogeneous and hypervascular mass in the right lobe of the liver
Most hepatocellular carcinomas occur in the setting of chronic liver disease with cirrhosis, while 15% to
20% arise in noncirrhotic livers. The most common underlying diseases are chronic viral hepatitis (B and
C), metabolic diseases such as hereditary hemochromatosis and α1-antitrypsin deficiency, and alcoholic
liver disease.

Nonalcoholic fatty liver disease also increases the risk of HCC, even in the absence of cirrhosis. Although
details are not clearly worked out, it is believed that the chronic injury, inflammation, and hepatocyte
regeneration that are seen in these disorders contribute to the acquisition of driver mutations that lead to
HCC development (described later). Part of the risk in Africa and Asia appears to be related to
contamination of crops by aflatoxin, a mycotoxin produced by Aspergillus species that acts
synergistically with alcohol and hepatitis B. The risk for HCC in cirrhosis related to other etiologies, like
Wilson disease and chronic biliary diseases, is somewhat lower but still elevated above the population
average. As with other cancers, HCC is associated with complementary sets of driver mutations that lead
to the acquisition of cancer hallmarks.

Among the most common are activating mutations in the β-catenin gene (40% of tumors), mutations in
the TERT (telomerase transcriptase) gene promoter that up-regulate telomerase activity (50% to60% of
tumors), and inactivating mutations in TP53 (up to 60% of tumors). One unusual histologic subtype that
often occurs in adolescents and young adults in the absence of preexisting liver disease, fibrolamellar
HCC, is strongly associated with a fusion gene that leads to aberrant activity of protein kinase A, an
enzyme that participates in a signaling pathway regulated by cAMP.

3. What modalities may be used to diagnose this condition? Discuss the expected findings.

A battery of special blood tests can frequently determine whether or not the liver is working properly.
These tests can also tell the difference between acute and chronic liver disorders, as well as hepatitis and
cholestasis.

The most commonly performed blood tests include the following:

Serum bilirubin test: This test determines the amount of bilirubin in the blood. The liver produces
bilirubin, which is excreted in the bile. Elevated bilirubin levels may indicate a bile flow obstruction or a
problem with bile processing by the liver.

Serum albumin test: This test is used to detect liver disease by measuring the level of albumin.

Serum alkaline phosphatase test: This test measures the amount of alkaline phosphatase in the blood.
Alkaline phosphatase is found in a variety of tissues, with the liver, biliary tract, and bone having the
highest concentrations. This test can be used to evaluate liver function and detect liver lesions that can
cause biliary obstruction, such as tumors or abscesses.

Serum aminotransferases (transaminases): This enzyme is released from damaged liver cells.

Prothrombin time (PTT) test: The prothrombin time test determines how long blood takes to clot.
Blood clotting necessitates vitamin K and a protein produced by the liver. Prolonged clotting may be
caused by liver disease or a lack of specific clotting factors.

Alanine transaminase (ALT) test: This test measures the amount of alanine aminotransferase released
into the bloodstream following acute liver cell damage. This test may be used to evaluate the treatment of
acute liver disease, such as hepatitis, and/or to assess liver function.

Aspartate transaminase (AST) test: This test assesses the amount of aspartate transaminase (an enzyme
found in the liver, kidneys, pancreas, heart, skeletal muscle, and red blood cells) released into the
bloodstream following liver or heart problems.

Gamma-glutamyl transpeptidase test: This test detects the presence of gamma-glutamyl transpeptidase
(an enzyme that is produced in the liver, pancreas, and biliary tract). This test is frequently used to
evaluate liver function, provide information on liver diseases, and detect alcohol ingestion.

Lactic dehydrogenase test: This test detects tissue damage and helps to diagnose liver disease. Lactic
dehydrogenase is a protein (also known as an isoenzyme) that is involved in the metabolic process of the
body.
5'-nucleotidase test: This test detects the presence of 5'- nucleotidase (an enzyme specific to the liver).
The level of 5'- nucleotidase is elevated in people with liver diseases, particularly those associated with
cholestasis (disruption in the formation of, or obstruction in the flow of bile).

Alpha-fetoprotein test: Fetal tissue and tumors both produce alpha-fetoprotein (a specific blood protein).
This test may be used to assess the efficacy of therapy in certain cancers, such as hepatomas.

Mitochondrial antibodies test: The presence of these antibodies can be indicative of primary biliary
cirrhosis, chronic active hepatitis, and other autoimmune disorders.

Liver biopsy. Small tissue samples are taken from the liver with a needle or during surgery. The samples
are checked under a microscope to find out the type of liver disease.

In chronic liver disease, Hepatocyte loss are transformed into dense fibrous septa. A collapse of the
underlying reticulin framework happens and there will be a deposition of collagen by myofibroblasts. It
give rise to diffuse scarring/cirrhosis. In gross evaluation, the liver is small due to loss of parenchyma. It
is soft and congested, and a yellowish to greenish bile-stained can be observed. In histologic findings,
confluent necrosis, a loss of parenchyma, and a large zones of destruction surrounding islands of
regenerating Hepatocytes maybe seen.

Your healthcare provider may want you to have imaging tests including:

CT scan (computed tomography). This is an imaging test that makes detailed images of the body using
X-rays and a computer. A CT scan provides information about the bones, muscles, fat, and organs.
MRI (magnetic resonance imaging). This test produces detailed images of organs and structures within
your body. It employs a magnetic field as well as radio wave energy pulses. A dye may be injected (shot)
into your vein. The dye enhances the visibility of the liver and other organs on the scan.

Ultrasound. This depicts your internal organs in action. It examines how blood flows through various
blood vessels. It creates images of blood vessels, tissues, and organs using high-frequency sound waves
and a computer.

An upper endoscopy may also be performed (EGD). A lighted flexible camera is inserted into your upper
digestive tract through your mouth to look for enlarged blood vessels that are at risk of bleeding due to
your cirrhosis. If you have fluid in your abdomen (ascites), you may require a low sodium diet, water pills
(diuretics), and needle removal of the fluid (paracentesis).

Case 3
A 50-year-old man presents to his doctor for complaining of weakness and loss of appetite. He admits to
extensive smoking, alcohol, and intravenous drug abuse. The now patient reports bleeding gums and
increased bruising. Physical examination reveals an overweight white male who has gynecomastia,
palmar erythema, and pitting edema of the lower extremities. Abdominal examination reveals shifting
dullness. Relevant laboratory findings are as follows:
WBC count: 2000/mm3
Hematocrit: 23%
Platelets: 80,000/mm3
Blood urea nitrogen (BUN): 40 mg/dL
Creatinine (Cr): 2.0 mg/dL
Albumin: 3.0 g/dL
Partial thromboplastin time (PTT): 35 seconds
Prothrombin time (PT): 12 seconds
Alanine aminotransferase (ALT): 75 U/L
Aspartate aminotransferase (AST): 120 U/L

Diagnosis: Liver cirrhosis (Clue includes elevated liver enzymes, AST and ALT which signifies
significant liver damage and dysfunction due to the architectural changes and distortion of hepatocytes).

Guide questions:
1. Based on the history, explain the pathophysiology of this patient’s condition.

Here are some salient features on what happens or changes that happens in a cirrhotic liver:
● Fibrosis describes encapsulation or 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 and host
factors.
● Cirrhosis is an advanced stage of liver fibrosis that is accompanied by distortion of the hepatic
vasculature. It is defined as the histological development of regenerative nodules surrounded by
fibrous bands in response to chronic liver injury, that leads to portal hypertension and end stage
liver disease.
● It leads to shunting of the portal and arterial blood supply directly into the hepatic outflow
(central veins), compromising exchange between hepatic sinusoids and the adjacent liver
parenchyma, i.e., hepatocytes. The hepatic sinusoids are lined by fenestrated endothelia which
 rest on a sheet of permeable connective tissue (the space of Disse) which contains hepatic stellate
cells (HSC) and some mononuclear cells. The other side of the space of Disse is lined by
hepatocytes which execute most of the known liver functions. In cirrhosis, the space of Disse is
filled with scar tissue and endothelial fenestrations are lost, a process termed sinusoidal
capillarization.
● In response to injury and loss, growth regulators induce hepatocellular hyperplasia (producing
regenerating nodules) and arterial growth (angiogenesis). Among the growth regulators are
cytokines and hepatic growth factors (eg, epithelial growth factor, hepatocyte growth factor,
transforming growth factor-alpha, tumor necrosis factor). Insulin, glucagon, and patterns of
intrahepatic blood flow determine how and where nodules develop.
● Angiogenesis produces new vessels within the fibrous sheath that surrounds nodules. These
vessels connect the hepatic artery and portal vein to hepatic venules, restoring the intrahepatic
circulatory pathways. Such interconnecting vessels provide relatively low-volume, high-pressure
venous drainage that cannot accommodate as much blood volume as normal. As a result, portal
vein pressure increases. Such distortions in blood flow contribute to portal hypertension, which
increases because the regenerating nodules compress hepatic venules.
● Histologically, cirrhosis is characterized by vascularized fibrotic septa that link portal tracts
with each other and with central veins, leading to hepatocyte islands that are surrounded by
fibrotic septa and which are devoid of a central vein.
● The major clinical consequences of cirrhosis are impaired hepatocyte (liver) function, an
increased intrahepatic resistance (portal hypertension) and the development of hepatocellular
carcinoma (HCC). The general circulatory abnormalities in cirrhosis (splanchnic vasodilation,
vasoconstriction and hypoperfusion of kidneys, water and salt retention, increased cardiac output)
are intimately linked to the hepatic vascular alterations and the resulting portal hypertension.
● Cirrhosis and its associated vascular distortion are traditionally considered to be irreversible but
recent data suggest that cirrhosis regression or even reversal is possible.
 Figure 4. A simplified pathophysiology map for liver cirrhosis. Notice that among the complications of
renal vasoconstriction is hepatorenal syndrome.

2. What is hepatorenal syndrome? Correlate with this patient’s presentation.

Hepatorenal syndrome is a type of kidney failure that happens in people with liver failure,
without any apparent cause for kidney dysfunction. The symptoms include a decrease in urine output and
an increase in urea and creatinine levels in the blood. While the exact cause is not fully understood, it is
thought to be linked to high blood pressure in the liver, which causes cells in the splanchnic vasculature to
produce more vasodilators like nitric oxide. This leads to a decrease in blood flow to the kidneys, which
activates the renin/angiotensin axis, causing further reduction in renal perfusion and glomerular filtration
rate, ultimately resulting in renal failure. Portal hypertension is high blood pressure in the portal vein
that runs through the liver. It causes the vein and its branches throughout your digestive system to widen.
Cirrhosis is its most common cause. Cirrhosis can also cause cirrhotic cardiomyopathy, which causes
abnormal widening of arteries in the body. Complex blood flow dynamics cause some vessels to narrow
when others widen. In the early phases of decompensated cirrhosis, renal perfusion is maintained within
the normal range because of increased synthesis of vasodilating factors (mainly prostaglandins). In the
later phases, renal perfusion cannot be maintained because the extreme arterial underfilling causes
maximum activation of vasoconstrictor systems together with decreased production of renal vasodilator
factors, and HRS develops. The splanchnic area escapes the effect of vasoconstrictors probably because
of the greatly increased local production of vasodilators.

This syndrome is evident in the case as the patient’s creatinine and BUN are both elevated.
Figure 5. International Ascites Club’s Diagnostic Criteria of Hepatorenal Syndrome
 Figure 6. Pathophysiology of Hepatorenal Syndrome

3. Why is gynecomastia, bleeding gums and low platelets found in this patient?

Hyperestrogenism in liver failure or liver cirrhosis occurs due to the inability of the liver to
properly metabolize estrogen, leading to an accumulation of the hormone in the body. The
pathophysiology behind this is multifactorial and involves several mechanisms. One of the key factors is
portal hypertension, which is an increase in blood pressure in the portal vein that carries blood from the
digestive organs to the liver. This leads to the formation of portosystemic shunts, which bypass the liver
and allow blood to flow directly from the digestive organs to the systemic circulation. As a result, the
liver is bypassed and cannot effectively metabolize estrogen and other hormones.

Another mechanism involved in hyperestrogenism in liver failure is the decreased production of

sex hormone-binding globulin (SHBG) by the liver. SHBG binds to estrogen and other sex hormones in
the blood, which reduces their bioavailability. In liver failure, the decreased production of SHBG leads to
increased levels of free estrogen in the blood, which can contribute to the development of hyperestrogenic
symptoms. Additionally, liver failure can lead to a decrease in the production of other hormones, such as
progesterone and androgens, which can alter the estrogen-to-androgen balance and contribute to
hyperestrogenism.

Thrombocytopenia, or low platelet count, was apparent to the patient as a consequence of a

decreased liver function due to degradation of the liver parenchyma secondary to cirrhosis. Since the liver
mainly produces thrombopoietin (TPO), which is a potent stimulus for platelet production, a damaged
liver has decreased synthetic function; hence a decrease in TPO to bring about megakaryopoiesis. Also,
coagulation factors which are also synthesized in the liver are depleted. Patients have bleeding tendencies
as manifested in the patient through bleeding gums.

Case 4
A 45-year-old HIV-positive alcoholic man presents to the emergency room with a 1-day history of nausea
and vomiting. He has severe epigastric pain which radiates to the back. Review of the patient’s medical
history reveals he is currently taking didanosine and azathioprine. Laboratory testing reveals an elevated
serum amylase level ten times higher than normal and a serum lipase level eight times higher than
normal.

Diagnosis: Acute Pancreatitis

Guide questions
1. What are the common causes of this condition?

Robbins:
Acute pancreatitis is characterized by reversible pancreatic parenchymal injury and inflammation and has
many causes, including toxic exposures (e.g., alcohol), pancreatic duct obstruction (e.g., biliary
calculi), inherited genetic defects, vascular injury, and infections.

Below are some of the etiologic factors in acute pancreatitis from Robbin’s Pathology:

● Due to autodigestion by inappropriately activated enzymes

 ● Trypsin activates digestive enzymes as well as prekallikrien, which activates clotting and
complement systems, amplifying small vessel thrombosis
● Obstruction from gallstones or alcohol associated concretions increases intraductal pressure,
causing enzyme rich interstitial fluid to accumulate, which causes fat necrosis, which attracts
neutrophils that release cytokines and cause interstitial edema, which impairs blood flow and
causes ischemia and acinar cell injury
● Acinar cell injury also caused by infections, drugs, trauma, shock, premature release of
proenzymes and lysosomal hydrolases
● Obstruction or alcohol cause proenzymes to be delivered in an intracellular compartment with
lysosomal hydrolases, which may activate them prematurely
● Alcohol may also reactivate chronic pancreatitis due to secretion of protein rich pancreatic fluid,
which causes deposition of inspissated protein plugs, causing obstruction of small pancreatic
ducts

2. What are components of Ranson criteria?

Figure 7. Ranson criteria

The Ranson’s criteria has a total of 11 prognostic signs that reflect on the severity of acute
pancreatitis. Five of these parameters are assessed upon hospital admission, whereas the rest are assessed
at 48 hours into admission. At admission, the measured parameters include age over 55 years, elevated
white blood cell count (WBC), hyperglycemia (i.e., elevated blood glucose), elevated lactate
dehydrogenase (LDH), and elevated serum aspartate transaminase (AST). At 48 hours, the criteria include
low hematocrit, elevated blood urea nitrogen (BUN), low serum calcium, hypoxemia (i.e., low blood
oxygen levels), markers of a low blood pH (i.e., metabolic acidosis), and fluid sequestration.

This scoring system aims to predict the severity of acute pancreatitis by determining if there are
any signs of dehydration (e.g., high BUN), inflammation (e.g., high WBC and LDH), or organ
dysfunction (e.g., hypoxemia) as well as the ability of the pancreas to regulate glucose levels (e.g.,
presence of hyperglycemia).

The presence of 1 to 3 of these aforementioned criteria indicates that severe pancreatitis is

unlikely, while the presence of more than 3 criteria indicates an increased risk of severe pancreatitis and
higher mortality.

Table 3. Ranson criteria

Ranson criteria are used to predict the severity and mortality of acute pancreatitis. Five
parameters are assessed on admission, and the other six are assessed at 48 hours post-admission. One
point is given for each positive parameter for a maximum score of 11. The modified criteria have a max
score of 10. Five parameters are assessed on admission and the other 5 at the 48-hour mark.

The criteria with 11 parameters are used to assess the severity of alcoholic pancreatitis. The 5
parameters on admission are age older than 55 years, WBC count greater than 16,000 cells/cmm, blood
glucose greater than 200 mg/dL (11 mmol/L), serum AST greater than 250 IU/L, and serum LDH greater
than 350 IU/L. At 48 hours, the remaining 6 parameters are: serum calcium less than 8.0 mg/dL (less than
2.0 mmol/L), hematocrit fall greater than 10%, PaO2 less than 60 mmHg, BUN increased by 5 mg/dL or
more (1.8 mmol/L or more) despite intravenous (IV) fluid hydration, base deficit greater than 4 mEq/L,
and sequestration of fluids greater than 6 L.

The modified Ranson criteria are used to assess gallstone pancreatitis. The five parameters on
admission are age older than 70 years, WBC greater than 18,000 cells/cmm, blood glucose greater than
220 mg/dL (greater than 12.2 mmol/L), serum AST greater than 250 IU/L, and serum LDH greater than
400 IU/L. At 48 hours, the remaining 5 parameters are serum calcium less than 8.0 mg/dL (less than 2.0
mmol/L), hematocrit fall greater than 10%, BUN increased by 2 or more mg/dL (0.7 or more mmol/L)
despite IV fluid hydration, base deficit greater than 5 mEq/L, and sequestration of fluids greater than 4 L.
Score Interpretation

0 to 2 points: Mortality 0% to 3%
3 to 4 points: 15%
5 to 6 points: 40%
7 to 11: nearly 100%

3. What are other conditions that may mimic the patient’s clinical presentation? Correlate your answer.

In many cases of abdominal pain, a lipase level three times the upper limit of normal allows for
the diagnosis of pancreatitis as the source of abdominal pain due to its high specificity. An abdominal
ultrasound helps to differentiate cholecystitis, whereas high suspicion of mesenteric ischemia warrants a
CT angiogram. In high-risk patients, the cardiac source should be concurrently ruled out as it can present
atypical epigastric pain. Though the pain of a progressing aortic dissection is more severe and tearing in
nature, it should be considered due to its particularly urgent nature.

As discussed in Robbin’s Pathology, abdominal pain is the cardinal manifestation of acute

pancreatitis. Characteristically the pain is constant, intense, and referred to the upper or mid back
and, occasionally, the left shoulder. The severity ranges from mild discomfort to incapacitating pain.
Anorexia, nausea, and vomiting are common. Elevated plasma levels of amylase and lipase support the
diagnosis of acute pancreatitis, as does the exclusion of other causes of abdominal pain.

Severe acute pancreatitis is a medical emergency. Patients usually present with an acute abdomen
and systemic findings caused by the release of toxic enzymes, cytokines, and other mediators into the
circulation. These activate a systemic inflammatory response, resulting in leukocytosis, disseminated
intravascular coagulation, edema, and acute respiratory distress syndrome. Shock, due to the systemic
inflammatory response syndrome, and acute renal tubular necrosis may occur.

Some of the conditions that may mimic Acute Pancreatitis are listed and categorized below:
A. Abdominal disorders
● Biliary colic, cholecystitis
When gallstone gets stuck in the bile ducts, it can cause pancreatic
enzymes to back up into the pancreas and cause gallstone pancreatitis. Although
this may initially manifest as colicky pain, this may also radiate to the midback
● Peptic ulcer disease
Rarely, peptic ulcers can penetrate the pancreas and cause pancreatitis,
which usually manifests with mild to severe pancreatitis with peripancreatic fluid
collections. However, this typically manifest as epigastric burning or aching pain.
Pain radiating to the back, similar to acute pancreatitis is suggestive posterior
penetrating gastric ulcer complicated by pancreatitis
● Gastroenteritis or Gastritis
Gastroenteritis also manifests with abdominal pain (and cramps), nausea,
and vomiting which are also manifested in this case.
 B. Cardiopulmonary disorder
● Myocardical Infarction
Myocardial infarction causes severe pain sometime manifesting in the
epigastric area and/or radiating to the left shoulder. This is something
accompanied by nausea and vomiting

C. Systemic disorders
● Diabetic ketoacidosis
DKA can also manifest with stomach pain, nausea, and vomiting
● Sickle cell disease
Sickle Cell Disease often cause vaso-occlusion, which can lead to acute
and chronic pain and tissue ischemia or infarction. If abdominal organs (liver,
gallbladder, spleen, kidneys, and pancreas) are affected, this may result to acute
abdominal pain with radiation based on the affected organ.

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