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CHAPTER SIX
PATHOLOGY OF THE HEPATO-BILIARY SYSTEM & EXOCRINE
PANCREAS
Objectives:
Upon completion of this course, you should be able to:
Describe the normal anatomy of the liver.
Discuss the pathophysiology, and diagnosis of specific pathologic conditions that
affect the liver, including cirrhosis, hepatitis, carcinoma, Wilson's disease, alpha 1-
antitrypsin deficiency, and intrahepatic biliary dysplasia.
Recognize complications of liver decompensation, including, portal hypertension,
esophageal varices, hepatic encephalopathy, and ascites.
State measures to prevent food-borne and blood-borne hepatitis.
Understand the etiology, risk factors, pathogenesis, morphology, clinical features, and
outcome of pancreatic inflammation and neoplasms.
List causes and common types of gall stones. Briefly describe the complications
Describe the pathology and complications of acute and chronic cholecystitis
THE LIVER
The dominant primary diseases of the liver are
1. Viral hepatitis
2. Alcoholic liver disease (in the Western world; rare in Iraq)
3. Hepatocellular carcinoma
HEPATIC FAILURE
This is the gravest consequence of liver disease. It should be noted that 80% of hepatic
functional capacity must be damaged before failure ensues. In many cases decompensation
arises as a result of intercurrent diseases that place further burden on an already sick liver;
these include
1. Gastrointestinal bleeding
2. Systemic infection
3. Electrolyte disturbances
4. Severe stress such as major surgery or heart failure.
The morphologic alterations that cause liver failure fall into three categories:
1. Massive hepatic necrosis; most often drug-induced, as from paracetamol overdose, halothane
& antituberculous drugs (rifampin, isoniazid). Hepatitis A & hepatitis B infection, and other causes
(including unknown) account for about one-third of the cases. Hepatitis C infection does not cause
massive hepatic necrosis.
2.
Chronic liver disease, which is the most common road to hepatic failure and is the endpoint of
persistent chronic hepatitis ending in cirrhosis.
3. Hepatic dysfunction without overt necrosis: hepatocytes may be viable but unable to
perform normal metabolic function, as with Reye syndrome, tetracycline toxicity, and acute fatty
liver of pregnancy.
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Regardless of cause, the clinical signs of hepatic failure are much the same. Jaundice is an
almost always present. Hypoalbuminemia, which predisposes to peripheral edema, and
hyperammonemia, which may play a role in cerebral dysfunction, are extremely worrying
developments. Fetor hepaticus (a characteristic musty body odor) occurs occasionally.
Impaired estrogen metabolism and consequent hyperestrogenemia are thought to be the
causes of
a. palmar erythema and spider angiomas of the skin
b. hypogonadism and gynecomastia in males
Hepatic failure is life-threatening because with severely impaired liver function, patients are
highly susceptible to failure of multiple organ systems. Thus, respiratory failure with
pneumonia and sepsis combine with renal failure to claim the lives of many patients. A
coagulopathy develops due to impaired hepatic synthesis of blood clotting factors. The
resultant bleeding tendency can lead to massive gastrointestinal bleeding as well as petechiae
elsewhere (see also esophageal varices). Intestinal absorption of blood places a metabolic
load on the liver, which worsens the extent of hepatic failure. The outlook of full-blown
hepatic failure is grave: A rapid downhill course is usual, & without liver transplantation,
death occurs within weeks to a few months in about 80% of cases .
Two particular complications signal the gravest stages of hepatic failure
1. Hepatic encephalopathy, which is manifested disturbances of consciousness with rigidity,
hyperreflexia, and tremor. It is regarded as a disorder of neurotransmission in the central
nervous system and neuromuscular system and appears to be associated with elevated blood
ammonia levels, which impair neuronal function and promote generalized brain edema.
2. Hepatorenal syndrome refers to the appearance of renal failure in patients with severe
chronic liver disease, in whom there are no intrinsic morphologic or functional causes for the
renal failure. Sodium retention, impaired water excretion, and decreased renal perfusion and
glomerular filtration rate are the main renal functional abnormalities. There is oliguria
associated with rising blood urea nitrogen and creatinine. The prognosis is poor, with a
median survival of only 2 weeks in the rapid-onset form and 6 months with the insidious-
onset form.
CIRRHOSIS
Cirrhosis is the end-stage of chronic liver disease & is defined by three characteristics:
1.
Bridging fibrous septae in the form of delicate or broad bands of fibrosis that link portal tracts
with one another and portal tracts with centrilobular veins.
2. Parenchymal nodules containing regenerating hepatocytes encircled by fibrosis, with
diameters varying from very small micronodules to large macronodules.
3. Disruption of the architecture of the entire liver
Classification of cirrhosis
The only satisfactory classification of cirrhosis is based on the underlying etiology. The
descriptive terms "micronodular" and "macronodular" should not be used as primary
classifications. Many forms of cirrhosis are initially micronodular (nodules < 3 mm), but
there is a tendency for nodules to increase in size; thus converting it to mixed (micro- &
macronodular) & eventually to macronodular form (nodules > 3mm).
The etiology of cirrhosis varies both geographically and socially. The following are
established causes of cirrhosis:
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1. Alcoholic liver disease (70% in Western countries)
2. Viral hepatitis (a very common cause in our country)
3. Biliary diseases
4. Primary hemochromatosis
5. Wilson disease
6. α1-Antitrypsin deficiency
7. Cryptogenic cirrhosis
Infrequent types of cirrhosis also include those cmplicating galactosemia and tyrosinosis in
infants and children, and drug-induced cirrhosis, as with α-methyldopa (aldomet). After all
the categories of cirrhosis of known causation have been excluded, a substantial number of
cases remain (15%) & is referred to as cryptogenic cirrhosis. It is possible that many of these
cases are due to undiagnosed nonalcoholic fatty liver disease. Once cirrhosis is established,
it is usually impossible to establish an etiologic diagnosis on morphologic grounds alone.
Pathogenesis of cirrhosis
The central pathogenetic processes in cirrhosis are progressive fibrosis and reorganization of
the vascular microarchitecture of the liver. In cirrhosis, types I and III collagen are deposited
in the lobule, creating delicate or broad septal tracts. New vascular channels in the septae
connect the vascular structures in the portal region (hepatic arteries and portal veins) and
terminal hepatic veins (centrilobulat & larger veins), shunting blood around the parenchyma.
Continued deposition of collagen in the space of Disse is accompanied by the loss of
fenestrations in the sinusoidal endothelial cells. As a result hepatocellular secretion of
proteins (e.g., albumin, clotting factors, and lipoproteins) is greatly impaired.
The major source of excess collagen in cirrhosis is the perisinusoidal stellate cells, which lie
in the space of Disse. Although normally functioning as vitamin A fat-storing cells, during
the development of cirrhosis they become activated. It is predominantly the cytokines
secreted by activated Kupffer cells and other inflammatory cells that stimulate perisinusoidal
stellate cells to divide and to produce large amounts of extracellular matrix.
Throughout the process of liver cell damage and fibrosis, remaining hepatocytes are
stimulated to regenerate and proliferate as spherical regenerative nodules within the confines
of the fibrous septae. The net outcome is a fibrotic, nodular liver in which delivery of blood
to hepatocytes is severely impaired, as is the ability of hepatocytes to secrete substances into
plasma. Disruption of the interface between the parenchyma and portal tracts obliterates
biliary channels as well. Thus, the cirrhotic patient may develop jaundice and even hepatic
failure, despite having a liver of normal mass.
In cirrhosis death is usually due to one or more of the following
1. Progressive liver failure
2. Portal hypertension related complications
3. The development of hepatocellular carcinoma.
PORTAL HYPERTENSION
Increased resistance to portal blood flow may develop in a variety of circumstances, which
can be divided into prehepatic, intrahepatic, and posthepatic causes.
Prehepatic conditions include
1. Portal vein thrombosis & narrowing
2. Massive splenomegaly through shunting excessive blood into the splenic vein.
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Posthepatic causes are
1. Severe right-sided heart failure
2. Constrictive pericarditis
3. Hepatic vein outflow obstruction.
Intrahepatic causes:
1. Cirrhosis is the dominant cause accounting for most cases of portal hypertension.
2. Schistosomiasis
3. Massive fatty change
4. Diffuse fibrosing granulomatous disease such as sarcoidosis and miliary tuberculosis
5. Diseases affecting the portal microcirculation, exemplified by nodular regenerative
hyperplasia
Portal hypertension in cirrhosis results from increased resistance to portal flow at the level of
the sinusoids, and compression of terminal hepatic veins by perivenular scarring and
expansile parenchymal nodules. Anastomoses between the arterial and portal systems in the
fibrous septa also contribute to portal hypertension by imposing arterial pressure on the low-
pressure hepatic venous system.
The four major consequences of portal hypertension in the setting of cirrhosis are
1. Ascites
2. The formation of portosystemic venous shunts leading to esophageal varices &
hemorrhoids
3. Congestive splenomegaly
4. Hepatic encephalopathy
Ascites refers to the collection of excess fluid in the peritoneal cavity. It usually becomes
clinically detectable when at least 500 mL has accumulated, but many liters may collect and
cause massive abdominal distention. It is generally a serous fluid having less than 3 gm/dL
of protein (largely albumin) as well as the same concentrations of solutes such as glucose,
sodium, and potassium as in the blood. Influx of neutrophils suggests secondary infection,
whereas red cells point to possible disseminated intra-abdominal cancer. With long-standing
ascites, seepage of peritoneal fluid through transdiaphragmatic lymphatics may produce
hydrothorax, more often on the right side.
The pathogenesis of ascites
This is complex, involving the following mechanisms:
1. Sinusoidal hypertension, altering Starling's forces and driving fluid into the space of
Disse, which is then removed by hepatic lymphatics; this movement of fluid is also promoted
by hypoalbuminemia
.
2. Percolation of hepatic lymph into the peritoneal cavity: normal thoracic duct lymph flow
approximates 800 to 1000 mL/day. With cirrhosis, hepatic lymphatic flow may approach 20 L/day,
exceeding thoracic duct capacity.
3. Intestinal fluid leakage: portal hypertension also causes increased perfusion pressure in
intestinal capillaries. This promotes movement of additional fluid out of intestinal capillaries into the
abdomen.
4. Renal retention of sodium and water due to secondary hyperaldosteronism
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INFLAMMATORY & INFECTIOUS DISORDERS
The liver is almost always involved in blood-borne infections such as bacterial (pyogenic
abscesses, miliary tuberculosis, salmonelloses), parasitic (malaria, amebiasis), fungal
(candidiasis), & viral (infectious mononucleosis, cytomegalovirus & herpes virus). Never the
less Viral hepatitis is the leading primary liver infection.
VIRAL HEPATITIS
Unless otherwise specified, the term viral hepatitis is reserved for “infection of the liver
caused by a group of hepatotropic viruses” i.e. having a particular affinity for the liver.
This group comprises
1. Hepatitis A virus (HAV)
2. Hepatitis B virus (HBV)
3. Hepatitis C virus (HCV)
4. Hepatitis D virus (HDV)
5. Hepatitis E virus (HEV)
Hepatitis A Virus (HAV)
Acute viral hepatitis A (infectious hepatitis) is a benign, self-limited disease with an
average incubation period of 4 weeks. HAV does not cause chronic hepatitis or a carrier
state and only rarely causes fulminant hepatitis. Nevertheless, most viral hepatitis epidemics
are attributed to HAV. In children, where most cases occur, the disease tends to be mild or
asymptomatic. HAV spreads by ingestion of contaminated water and foods. The viremia is
short-lived, thus, blood-borne transmission of occurs rarely; therefore, donated blood is not
screened for this virus.
HAV is a small, RNA virus. It reaches the liver from the intestinal tract after ingestion,
replicates in hepatocytes, and is shed in the bile and feces. It appears that the liver cell injury
is not directly related to the virus but results from T cell-mediated damage of infected
hepatocytes. Detection of anti-HAV IgM antibody is the best diagnostic marker for the
disease.
Hepatitis B Virus (HBV) this can produce
1. Acute viral hepatitis B with recovery and clearance of the virus
2. Chronic viral hepatitis B, which is either
a. Non-progressive or
b. Progressive ending in cirrhosis
3. Fulminant hepatitis with massive liver necrosis
4. An asymptomatic carrier state.
Chronic viral hepatitis B is an important precursor of hepatocellular carcinoma. Liver
disease caused by HBV is a real worldwide problem, with an estimated carrier rate of 400
million. HBV remains in blood during the last stages of a long incubation period (4-26
weeks) and during active episodes of both acute and chronic hepatitis. It is also present in all
physiologic and pathologic body fluids, with the exception of stool. Whereas blood and body
fluids are the primary vehicles of transmission, virus may also be spread by contact with
body secretions such as semen, saliva, sweat, tears, breast milk, and pathologic effusions. In
endemic regions, vertical transmission from mother to child during birth constitutes the main
mode of transmission. HBV infection in adults is mostly cleared, but vertical transmission
produces a high rate of chronic infection.
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HBV is a DNA virus & its replication does not require integration of the virus in the host
DNA, however, integrated HBV is frequently found in cells. After exposure to the virus,
there is a long incubation period (average 16 weeks), which may be followed by acute
disease lasting weeks to months. The natural course of acute disease can be followed by
serum markers. HBsAg appears before the onset of symptoms, peaks during overt disease,
and then declines to undetectable levels in 3 to 6 months. Anti-HBs persists for life,
conferring protection; this is the basis for current vaccination policy using noninfectious
HBsAg. HBeAg appears in serum shortly after HBsAg to signify active viral replication.
Persistence of HBeAg is an important indicator of
1. Continued viral replication
2. Infectivity
3. Probable progression to chronic hepatitis
IgM anti-HBc (c for core Ag) is detectable with the onset of elevated serum aminotransferase
levels and thus indicative of hepatocyte destruction. Later this IgM is replaced by IgG anti-
HBc.
The host immune response to the virus is the main determinant of the outcome of the
infection. A strong response by virus-specific CD4+ and CD8+ interferon γ-producing cells
are associated with the resolution of acute infection. HBV, (like HAV) does not seem to
cause direct hepatocyte injury as many chronic carriers have virions in their hepatocytes
without any evidence of cell injury. Hepatocyte injury and damage seem to be mediated by
CD8+ cytotoxic T cells of the virus-infected hepatocytes.
Hepatitis C Virus (HCV) is another major cause of liver disease. The worldwide carrier rate
is estimated at 175 million persons. A decrease in the incidence has resulted from the marked
reduction in transfusion-associated hepatitis C (as a result of screening procedures). The
major route of transmission is through blood inoculation, with low rates of sexual and
vertical transmissions. HCV infection has a much higher rate (than HBV) of progression to
chronic liver disease and eventual cirrhosis. It is a single-stranded RNA virus. Based on the
genetic sequence, HCV is subclassified into six genotypes. An infected person may carry
many HCV variants. This variability seriously hinders efforts to develop an HCV vaccine.
The incubation period for hepatitis C has a mean of 6 to 12 weeks. The clinical course of
acute viral hepatitis C is usually asymptomatic and is easily missed. Strong immune
responses involving CD4+ and CD8+ cells are associated with self-limited HCV infections,
but it is not known why only a minority of individuals is capable of clearing HCV infection.
Persistent infection is the hallmark of HCV; in 80% of such cases it complicates subclinical
acute infection. Cirrhosis develops in 20% of such patients. Fulminant hepatitis is rare.
Hepatitis D Virus (HDV) (Hepatitis delta virus) is a unique RNA virus in that it is
replication defective, causing infection only when it is encapsulated by HBsAg i.e. HDV is
absolutely dependent on HBV co-infection for multiplication. Delta hepatitis arises in two
settings:
1. Acute coinfection after exposure to serum containing both HDV and HBV and
2. Superinfection of a chronic carrier of HBV with a new inoculum of HDV. In the first case,
most coinfected individuals can clear the viruses and recover completely. The course is
different in superinfected individuals in that most cases show acceleration of hepatitis,
progressing to more severe chronic hepatitis. Infection by HDV is worldwide, with the
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highest prevalence rates (40%) in Africa & the Middle East. IgM anti-HDV antibody is the
most reliable indicator of recent HDV exposure, but its appearance is transient.
Hepatitis E Virus (HEV)
HEV hepatitis is a single-stranded RNA virus that is fecally transmitted. HEV is endemic in
India (where it was first documented). Epidemics have been reported from Asia and Africa.
HEV is not associated with chronic liver disease or persistent viremia. A characteristic
feature of the infection is the high mortality rate among pregnant women, approaching 20%.
A specific antigen (HEV Ag) can be identified in the cytoplasm of hepatocytes during active
infection. Virus can be detected in stools, and anti-HEV IgG and IgM antibodies are
detectable in serum.
Clinical Features and Outcomes of Viral Hepatitis
A number of clinical syndromes may develop after exposure to hepatitis viruses:
1. Asymptomatic infection (serologic evidence only)
3. Acute hepatitis (anicteric or icteric)
3. Chronic hepatitis (with or without progression to cirrhosis)
4. Chronic carrier state (asymptomatic)
5. Fulminant hepatitis (submassive to massive hepatic necrosis with acute liver failure)
With rare exceptions, HAV, HCV, and HEV do not generate a carrier state, and HAV and
HEV infections do not progress to chronic hepatitis. Viral persistence and development of
chronic disease is much more common after HCV infection than HBV infection. Because
other infectious or noninfectious causes (such as drugs and toxins), can lead to essentially
identical syndromes, serologic studies are decisive for the diagnosis of viral hepatitis and
identification of virus types.
Asymptomatic Infection:
The patients are identified only on the basis of minimally elevated serum aminotransferases
or the presence of antiviral antibodies.
Acute viral hepatitis
Any one of the hepatotropic viruses can cause acute viral hepatitis. Acute infections are
easily detected for HBV infections but only rarely diagnosed for HCV. A hepatitis virus
etiology is suggested by elevated serum aminotransferase levels. As jaundice appears (icteric
phase), symptoms begin to fade away. To begin with there is predominantly conjugated
hyperbilirubinemia but later hepatocellular injury interferes with bilirubin conjugation, thus,
unconjugated hyperbilirubinemia can also occur. An icteric phase is usual especially in
adults infected with HAV, but is absent in about 50% of the cases infected with HBV and in
most cases of HCV infection. Within weeks, the jaundice and most systemic symptoms clear
as convalescence begins.
Chronic Hepatitis is defined as “the presence of clinical, biochemical, or serologic
evidence of continuing hepatic disease for more than 6 months, with histological
documentation of inflammation and necrosis.”
Although chronic hepatitis is mostly caused by hepatitis viruses, there are other causes of
this condition, these include
Drugs (isoniazide, α-methyldopa, methotrexate),
Auto-immune damage (autoimmune hepatitis)
Wilson disease, α
1
-antitrypsin deficiency, chronic alcoholism.
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Causes of death in chronic hepatitis are related to the complicating cirrhosis e.g. liver
failure, hepatic encephalopathy, massive hematemesis from esophageal varices, and
hepatocellular carcinoma.
The Carrier State
With hepatotropic viruses, carriers are those who harbor one of the viruses & may have
nonprogressive liver damage, but are essentially free of symptoms. They constitute
reservoirs of infection. HBV infection early in life, particularly through vertical transmission
during childbirth, produces a carrier state in 90% to 95% of the cases. In contrast, less than
10% of HBV infections acquired in adulthood yield a carrier state. Individuals with impaired
immunity are particularly likely to become carriers. HCV can induce a carrier state, which is
estimated to affect 0.2% to 0.6% of the general population.
Fulminant Hepatitis
A very small proportion of patients with acute viral hepatitis A, B, or E may develop acute
liver failure, resulting from massive hepatic necrosis. Cases with a more prolonged course of
several weeks or months are usually referred to as subacute hepatic necrosis; livers of these
individuals show both massive necrosis and regenerative hyperplasia. It should be
remembered that drugs and chemicals can also cause massive hepatic necrosis.
Pathological features of viral heaptitis
The morphologic changes in acute and chronic viral hepatitis are shared among the
hepatotropic viruses and can be mimicked by drug reactions.
Acute viral hepatitis (Fig. 6-1)
The normal radial array of the lobules is lost.
There is diffuse ballooning degeneration of hepatocytes; the cells are swollen with clear,
wispy cytoplasm.
Hepatocytes necrosis assume one of 3 morphologic types
1. Cytolysis i.e. dissolution of the hepatocytes. The necrotic cells vanish (cell dropped
out). This is detected indirectly as macrophage aggregation
2. Apoptosis i.e. hepatocytes shrink, become intensely eosinophilic, and have fragmented
nuclei. Apoptotic cells are phagocytosed within hours by macrophages and hence may be
difficult to find despite extensive apoptosis.
3. Confluent necrosis of hepatocytes, seen in severe cases & may lead to bridging necrosis
that extends through portal-portal, central-central, or portal-central areas. (Fig. 6-2)
Hepatocyte regeneration as evidenced by irregularly thickened plates with occasional
rosettes & and multinucleation.
Inflammation is usually a prominent feature of acute hepatitis. The portal tracts are
infiltrated predominantly by lymphocytes. The inflammatory infiltrate may spill over into
the parenchyma to cause necrosis of periportal hepatocytes (interface hepatitis) and may
also infiltrate the sinusoids.
Hypertrophy & hyperplasia of Kuppfer cells
Cholestasis may be present, both intracellular (brown pigmentation of hepatocytes) &
canalicular (bile plugs in canaliculi).
HBV infection, acute or chronic, may produce two distinctive features of the infected
hepatocytes.
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a. Ground-glass" hepatocytes: a finely granular, eosinophilic cytoplasm due to massive
quantities of HBsAg (as seen by electron microscopy).
b. Sanded nuclei, resulting from abundant intranuclear HBcAg.
Chronic hepatitis (Fig. 6-3)
The changes are of variable severity, ranging from very mild to severe.
Hepatocyte necrosis may occur in all forms of chronic hepatitis.
The inflammatory component consists mainly of lymphocytes, macrophages, and
occasional plasma cells. In the mildest forms, significant inflammation is limited to portal
tracts. Lymphoid aggregates in the portal tract are often seen in HCV infection.
The liver architecture is usually well preserved
Continued periportal necrosis (interface hepatitis) and bridging necrosis are forerunners
of progressive liver damage.
The hallmark of serious liver damage is the deposition of fibrous tissue. At first, at the
portal tracts, but with time periportal fibrosis occurs. This is followed by bridging fibrosis
that links fibrous septa between lobules.
Continued loss of hepatocytes with fibrosis results in cirrhosis, with fibrous septa and
hepatocyte regenerative nodules. This pattern of cirrhosis is characterized by irregularly
sized nodules separated by variable but mostly broad bands of fibrosis. The nodules are
typically greater than 0.3 cm in diameter; accordingly, the cirrhosis is by definition
macronodular.
Autoimmune Hepatitis is microscopically indistinguishable from chronic viral hepatitis but
is associated with a set of immunologic abnormalities. This disease may run an indolent or
severe course. Salient features include:
Female predominance
Absence of viral infection serologic markers
Immunological abnormalities
a. Elevated serum IgG (>2.5 g/dl)
b. High titers of autoantibodies (80% of cases)
c. Presence of other autoimmune diseases (in 2/3 of the patients), including rheumatoid
arthritis, thyroiditis, Sjögren syndrome, and ulcerative colitis.
Pathogenesis
Most patients have a variety of auto-antibodies such as antinuclear, anti-smooth muscle, liver
kidney microsomal antibody, etc. The best characterized among these antibodies are smooth
muscle antibodies directed against cytoskeletal proteins that include actin, and troponin, and
liver kidney microsomal antibodies. The main effectors of cell damage are believed to be
CD4+ helper cells. Response to immunosuppressive therapy is usually dramatic. The overall
risk of cirrhosis, the main cause of death, is 5%.
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PYOGENIC LIVER ABSCESSES
In developing countries most liver abscesses result from parasitic infections, such as amebic,
echinococcal, etc. In the Western world, bacterial abscesses are more common, representing
a complication of an infection elsewhere. Gram-negative bacteria such as E. coli and
Klebsiella sp. are the usual offenders. The organisms reach the liver through one of the
following pathways:
1. Ascending cholangitis
2. Vascular seeding, predominantly portal i.e. from the GIT
3. Direct invasion from a nearby focus
4. A penetrating injury.
Debilitating disease with immune deficiency is a common background e.g. extreme old age,
immunosuppression, or chemotherapy.
Gross features
Pyogenic abscesses may be solitary or multiple, ranging from very small to massive
lesions.
Bacteremic spread through the arterial or portal system tends to produce multiple small
abscesses, whereas direct extension and trauma usually cause solitary large abscesses.
(Fig. 6-4 A)
Microscopic features
These are identical to pyogenic abscesses elsewhere.
Liver abscesses are associated with fever and right upper quadrant pain and tender
hepatomegaly. Jaundice is often the result of extrahepatic biliary obstruction. Surgical
drainage is often necessary.
AMEBIC LIVER ABSCESS is usually single, mostly right sided, & close to liver dome,
but tends to be multicentric in immunocompromised patients. Adults are mostly affected but
can develop in infants & children.
Gross features (Fig. 6-4 B)
The necrotic center contains odorless, pasty, chocolate brown fluid.
Microscopic
Most of the lesion consists of necrotic debris. There few if any neutrophils.
This centre is surrounded by fibrin, macrophages, lymphocytes & a few fibroblasts with
clusters of amebic trophozoites (up to 60 microns with small eccentric nucleus and
cytoplasmic vacuoles that may contain red blood cells; resemble histiocytes).
Complications
1. Bacterial superinfection
2. Extension or perforation into the following
1. Pleuro-pulmonary structures
2. Subphrenic space
3. Peritoneal cavity, and pericardial sac, bile ducts
6. Kidney, mediastinum, chest wall, abdominal wall, and flank.
Diagnosis: serology is 90% sensitive
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HYDATID DISEASE OF THE LIVER
Three quarters of infected individuals develop one or more hepatic cysts, which grow slowly.
The typical hydatid cyst is spherical and may measure up to more than 30 cm in diameter.
The majority occur in the right lobe, but they may be multiple, involving all lobes. A
characteristic gross feature is the presence of the soft, whitish laminate membrane. (Fig. 6-4
C) Histologic examination of the cyst wall shows an outer fibrous layer; a midlle onionskin
like laminated membrane, and an inner germinal layer. Calcification in the latter layer
signifies that the cyst is dead. The adjacent liver parenchyma often shows pressure atrophy
and a portal infiltrate in which eosinophils may be prominent. The viable cyst is filled with
colorless fluid, which contains daughter cysts and brood capsules with scolices.
Communication with the biliary tract and superimposed infection are frequent. Rupture of
the cysts into the peritoneal cavity may result in a fatal anaphylactic reaction or in the
formation of innumerable small granulomas grossly resembling peritoneal tuberculosis.
Identification of fragments of germinal membrane or scolices in their center points to the
diagnosis. Hepatic echinococcus cysts can also rupture inside the gallbladder or through the
diaphragm into the pleural space and lung.
The laboratory diagnosis can usually be made by hydatid serology and confirmed or
established by ultrasound or computed tomography.
ALCOHOLIC LIVER DISEASE
Excessive ethanol consumption is a common cause of chronic liver disease in Western
countries and accounts for up to 50% of deaths due to cirrhosis.
Chronic heavy drinkers are predisposed to 3 distinctive forms of alcoholic liver disease;
these may overlap. (Fig. 6-5)
1. Hepatic steatosis (almost all heavy drinkers)
2. Alcoholic hepatitis (30%)
3. Cirrhosis (15%)
Pathological features
Hepatic Steatosis (Fatty Liver):
Gross features
The liver is large (up to 4 or even 6 kg), soft, yellow, and greasy. (Fig. 6-6 A)
Microscopic features (Fig. 6-6 B)
Initially small lipid droplets accumulate in hepatocytes (microvesicular steatosis)
Persistent chronic intake of alcohol is associated with lipid accumulates in a large single
vacuole that compresses and displaces the nucleus to the periphery of the hepatocyte
(macrovesicular steatosis).
The affected hepatocytes are centrilobular, but in severe cases the entire lobule is affected.
With continued alcohol intake fibrous tissue develops around the central veins and extends
into the adjacent sinusoids. Until fibrosis appears, the fatty change is completely reversible
if there is abstention from further intake of alcohol
Alcoholic Hepatitis
Gross features
The liver is mottled red & yellow-green (bile stained).
It may increase in size.
Visible nodules and fibrosis signify progression to cirrhosis.
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Microscopic features (Fig. 6-7)
Alcoholic hepatitis is characterized by
1. Ballooning degeneration and necrosis of hepatocytes
2. Mallory Bodies: these appear as pinkish, tangled filaments within the cytoplasm of
degenerating hepatocytes
3. Neutrophil Infiltrations that permeate the lobule and accumulate around degenerating
hepatocytes.
4. Fibrosis is characteristically sinusoidal and perivenular
5. Cholestasis and hemosiderin deposition in hepatocytes and Kupffer cells
Alcoholic Cirrhosis: is the final, irreversible form of alcoholic liver disease.
Gross features (Fig. 6-8)
Initially, the liver is yellow, fatty, enlarged, (usually over 2 kg) , & finely (micro-) nodular
externally and on section.
Over several years it becomes brown, shrunken (weighing less than 1 kg) with variably
sized small and large nodules that create a "hobnail" appearance externally.
Microscopic features
Initially there are delicate fibrous septa that extend from central veins through the
sinusoids to the portal tracts and from portal tracts to portal tracts.
Regenerative activity of entrapped hepatocytes generates in the early stages uniform small
nodules (< 0.3 cm in diameter). This is by definition a micronodular cirrhosis. The
nodules eventually become larger & more prominent and are engulfed by ever wider bands
of fibrous tissue, and the liver is converted into a mixed micronodular and macronodular
cirrhosis.
Bile stasis often develops.
The induction of cytochrome P-450 by alcohol leads to enhanced transformation of other
drugs to toxic metabolites e.g. accelerated metabolism of paracetamol into highly toxic
metabolites that increase the risk of liver injury even with therapeutic doses of this
commonly used analgesic. Concurrent viral hepatitis, particularly hepatitis C is a major
accelerator of liver disease in alcoholics. In chronic alcoholics, alcohol may become a major
caloric source in the diet, displacing other nutrients and leading to malnutrition and vitamin
deficiencies (e.g., thiamine and vitamin B
12
). This is accentuated by impaired digestive
function, primarily related to chronic gastric and intestinal mucosal damage, and pancreatitis.
With alcoholic cirrhosis, the immediate causes of death are
1. Hepatic failure
2. Massive gastrointestinal hemorrhage
3. Intercurrent infection
4. Hepatorenal syndrome and
5. Hepatocellular carcinoma (5%
of cases).
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DRUG-INDUCED LIVER DISEASE
The liver is a major drug metabolizing and detoxifying organ in the body, thus, it is
subjected to injury from a wide range of therapeutic and environmental chemicals. Injury
may result from
1. Direct toxicity
2. Hepatic conversion of a foreign chemical to an active toxin
3. Immune damage, usually initiated by the drug or its metabolites acting as a hapten to
convert a cellular protein into an immunogen.
Exposure to a toxin or therapeutic agent should always be included in the differential
diagnosis of any form of liver disease. Drug reactions may be classified as predictable
(intrinsic) reactions or unpredictable (idiosyncratic) ones. Predictable drug reactions are dose
dependent & thus may occur in anyone who accumulates a sufficient dose. Unpredictable
reactions are idiosyncratic & depend on the host's ability to mount an immune response to
the antigenic stimulus.
Drug-induced chronic hepatitis is clinically and histologically indistinguishable from
chronic viral hepatitis or autoimmune hepatitis, and hence serologic markers of viral
infection are critical for making the distinction. Examples of predictable drug reactions are
associated with paracetamol, tetracycline, antineoplastic drugs, carbon tetrachloride, and
alcohol. Examples of drugs that can cause idiosyncratic reactions include chlorpromazine,
halothane anesthetic, sulfonamides, α-methyldopa, and allopurinol.
Drugs that may cause acute liver failure due to massive hepatic necrosis include
1. Paracetamol (the most common cause)
2. Halothane,
3. AntiTB drugs (rifampin, isoniazide),
4. Industrial chemicals such as carbon tetrachloride
5. Mushroom poisoning.
Gross features of massive hepatic necrosis (Fig. 6-9 A)
The entire liver may be involved, (or only random areas are affected).
With such extensive loss of hepatic substance, the liver shrinks to 500 gm and becomes a
floppy, red or bile-stained, soft organ covered by a wrinkled, redundant capsule.
Microscopic features (Fig. 6-9 B)
Complete necrosis of hepatocytes in contiguous lobules leaves only a collapsed reticulin
framework and preserved portal tracts.
If the patient survives for more than a week, regeneration of surviving hepatocytes occurs.
With massive destruction of confluent lobules, regeneration is disorderly, yielding nodular
masses of liver cells surrounded by bands of scarring (macronodular cirrhosis).
METABOLIC LIVER DISEASE
Under this heading come the following entities
1. Nonalcoholic fatty liver disease
2. Hemochromatosis,
3. Wilson disease, and
4. α
1
-antitrypsin deficiency.
14
Nonalcoholic Fatty Liver Disease (NAFLD) may present as steatosis (fatty liver),
nonalcoholic steatohepatitis (NASH) or cirrhosis. The latter is similar to alcoholic hepatitis.
NAFLD is associated with
1. Insulin resistance including Type 2 diabetes, is the most common associated condition
2. Obesity
3. Dyslipidemia (hypertriglyceridemia, low HDLP cholesterol, high LDLP cholesterol).
The presence of type 2 diabetes and obesity are the best predictors of severe fibrosis and
disease progression. Insulin resistance results in the accumulation of triglycerides in
hepatocytes. Fat-laden hepatocytes are highly sensitive to lipid peroxidation products
generated by oxidative stress, which can damage mitochondrial and plasma membranes,
causing apoptosis. Most persons with steatosis are asymptomatic; patients with NASH or
may also be asymptomatic, or present with symptoms of chronic liver disease. Liver biopsy
is required for diagnosis. Fortunately, the frequency of progression from steatosis to NASH,
and from NASH to cirrhosis seems to be low.
Hereditary hemochromatosis
The most common form of this genetic disease is an autosomal recessive variant of adult
onset caused by mutations in the HFE gene. Iron accumulates over the lifetime of the
affected individual from excessive intestinal absorption. Total iron accumulation may exceed
50 gm (N: 2-6g), over one-third of which accumulates in the liver (N: 0.5 g).
Fully developed cases of hereditary hemochromatosis show
1. Cirrhosis (all patients)
2. Diabetes mellitus (75%)
3. Skin pigmentation (75%).
Iron accumulations from known sources of excess iron are called secondary iron overload or
(secondary hemochromatosis), the most important of these are
1. Multiple transfusions
2. Ineffective erythropoiesis (as in β-thalassemia and sideroblastic anemia)
3. Increased iron intake (Bantu siderosis).
Chronic liver diseases can also cause iron accumulation in the liver e.g. alcoholic liver
disease.
Pathogenesis
In hereditary hemochromatosis there is a dysregulation of intestinal absorption of dietary
iron. This leads to net iron accumulation of up to 1.0 gm/year. It appears that HFE gene
regulates the levels of hepcidin, the iron hormone produced by the liver. Hepicidin normally
interferes with the flowing out of iron from the intestines and macrophages into the plasma
and inhibits iron absorption. As might be expected, hepicidin levels are reduced in all
currently known genetic forms of hemochromatosis.
Gross features (Fig. 6-10 A)
Hemosiderin deposition occurs in several organs & tissues e.g. the myocardium,
pituitary, adrenal, thyroid, parathyroid gland, joints, skin
The liver is typically chocolate brown in color.
Fibrous septa develop slowly, leading ultimately to micronodular cirrhosis in an
intensely pigmented liver.
15
Microscopic features
The golden-yellow hemosiderin granules accumulate in the cytoplasm of periportal
hepatocytes; these stain blue with the Prussian blue stain (Fig. 6-10 B).
With increasing iron load, there is progressive deposition in the rest of the lobule, along
with bile duct epithelium and Kupffer cells. (In secondary iron overload, the iron is mainly
in Kupffer cells, not hepatocytes, at least initially)
Iron is a direct hepatotoxin, and inflammation is characteristically absent.
In normal individuals the iron content of unfixed liver tissue is less than 1000 μg/gm dry
weight. Adult patients with hereditary hemochromatosis exhibit over 10,000 μg/gm dry
weight of iron; hepatic iron concentrations in excess of 22,000 μg/gm dry weight are
associated with the development of fibrosis and cirrhosis.
Males predominate (ratio of 5 to 7:1), partly because physiologic iron loss (menstruation,
pregnancy) retards iron accumulation in women. In the most common forms, caused by HFE
mutations, symptoms usually first appear in the age range of 40 to 60 years. The classic
clinical triad of cirrhosis (with hepatomegaly), skin pigmentation, and diabetes mellitus may
not develop until late in the course of the disease. Death may result from cirrhosis,
hepatocellular carcinoma, or cardiac involvement. Treatment of iron overload does not
remove the risk of hepatocellular carcinoma (200 times higher than in normal populations).
Wilson Disease (Hepatolenticular degeneration)
This autosomal recessive disorder of copper metabolism is characterized by the
accumulation of toxic levels of copper in many tissues and organs, principally the liver,
brain, and eyes. The genetic defect responsible for Wilson disease is a mutation in ATP7B,
the defective function of which leads to failure on the part of hepatocytes to excrete copper
into bile, which is the primary route for copper elimination from the body. The defect also
inhibits secretion of ceruloplasmin from hepatocytes into the plasma. Copper thus
accumulates progressively in the liver, apparently causing toxic liver injury. Usually by the
age of 5 years, copper that is not ceruloplasmin bound spills over into the circulation,
causing hemolysis and pathologic changes at other sites, such as brain, cornea, and kidneys.
Concomitantly, urinary excretion of copper increases markedly. The biochemical diagnosis
of Wilson disease is based on a decrease in serum ceruloplasmin, increase in hepatic copper
content, and increase in urinary excretion of copper.
Pathological features
Fatty change of the liver may be mild to moderate, the hepatocytes also show vacuolated
nuclei (glycogen or water) and focal necrosis.
An acute hepatitis can mimic acute viral hepatitis, except for the fatty change.
A chronic hepatitis resembles chronic hepatitis due to other causes but may show such
distinguishing features as fatty change, vacuolated nuclei, and Mallory bodies.
With progression of chronic hepatitis, cirrhosis develops.
The demonstration of increased copper content of the hepatocytes by using special stains is
not an exclusive feature of Wilson disease. However, the demonstration of hepatic copper
content in excess of 250 μg/gm dry weight is most helpful for making the diagnosis. In the
brain, toxic injury affects the basal ganglia, particularly the putamen, which shows atrophy &
cavitation (hepatolenticular degeneration). Nearly all patients with neurologic involvement
develop eye lesions called Kayser-Fleischer rings (green to brown deposits of copper in the
16
Descemet’s membrane of the cornea). (Fig. 6-11)Wilson disease rarely manifests before 6
years of age. The most common presentation is acute or chronic liver disease.
Neuropsychiatric manifestations, including frank psychosis, or a Parkinson disease-like
syndrome, are the initial features in most of the remaining cases. Demonstration of Kayser-
Fleischer rings or markedly elevated hepatic copper levels in a person with a low serum
ceruloplasmin value strongly favor the diagnosis.
α
1
-Antitrypsin (AAT) Deficiency
AAT deficiency is an autosomal recessive disorder characterized by abnormally low serum
levels of this protease inhibitor. The major function of AAT is the inhibition of proteases,
particularly neutrophil elastase released at sites of inflammation. AAT deficiency leads to
pulmonary emphysema because a relative lack of this protein permits the unrestrained
activity of destructive proteases. AAT is a plasma glycoprotein synthesized predominantly
by hepatocytes. The AAT gene is very polymorphic, and at least 75 forms have been
identified. However, homozygotes for the Z allele (PiZZ genotype) have circulating AAT
levels that are only 10% of normal levels. Because the mutant protein cannot be secreted by
the hepatocyte, it accumulates in the endoplasmic reticulum. Curiously, all individuals with
the PiZZ genotype accumulate AAT in the liver, but only 8% to 20% develop significant
liver damage.
Pathological features
Hepatocytes in AAT deficiency contain round to oval cytoplasmic globular inclusions of
retained AAT, which are strongly positive with PAS stain (Fig. 6-12).
Hepatic injury associated with PiZZ may range from marked cholestasis with hepatocyte
necrosis in newborns, to childhood cirrhosis, or to a chronic hepatitis or cirrhosis that
becomes apparent only late in life.
In older children, adolescents, and adults, presenting symptoms may be related to chronic
hepatitis, cirrhosis, or pulmonary disease. Hepatocellular carcinoma develops in 3% of PiZZ
adults.
Neonatal Cholestasis
Mild transient elevations in serum unconjugated bilirubin are common in normal newborns.
Prolonged conjugated hyperbilirubinemia in the newborn, termed neonatal cholestasis,
affects approximately 1 in 2500 live births.
The major causes are
1. Extrahepatic biliary atresia
2. Neonatal hepatitis; 50% of the cases are idiopathic
The finding of "neonatal cholestasis" should evoke a diligent search for recognizable toxic,
metabolic, and infectious liver diseases. 50% of cases of neonatal hepatitis are idiopathic.
Infants with any form of neonatal cholestasis present with jaundice, dark urine, light or
acholic stools, and hepatomegaly. Differentiation between the two most common causes of
neonatal cholestasis (extrahepatic atresia and idiopathic hepatitis) assumes great importance,
because definitive treatment of biliary atresia requires surgical intervention, whereas surgery
may adversely affect the clinical course of a child with idiopathic neonatal hepatitis.
Fortunately, discrimination between these diseases can be made in about 90% of cases using
clinical data and liver biopsy.
17
Reye Syndrome is a rare disease characterized by fatty change in the liver and
encephalopathy. It primarily affects children younger than 4 years of age, typically
developing few days after a viral illness. The majority recover, but 25% of the cases progress
to coma, accompanied by elevations in the serum levels of bilirubin, aminotransferases, and
particularly ammonia. Death occurs from progressive neurologic deterioration or liver
failure. Reye syndrome is now recognized as the prototype of a wide variety of conditions
known as "mitochondrial hepatopathies." Reye syndrome has been associated with aspirin
administration during viral illnesses, but there is no evidence that salicylates play a causal
role in this disorder. The key pathologic finding in the liver is microvesicular steatosis. In the
brain, cerebral edema is usually present.
DISEASES OF THE INTRAHEPATIC BILIARY TRACT (Fig. 6-13)
Primary Biliary Cirrhosis (PBC)
is a chronic, progressive cholestatic liver disease with
eventual development of micronodular cirrhosis and liver failure over years to decades. The
primary feature of this disease is an inflammatory destruction of small and medium-sized
intrahepatic bile ducts. In the early lesions there is a dense lymphocyte/plasma cell infiltrate
around small bile ducts in portal tracts, and granulomatous lesions may also appear. Primary
biliary cirrhosis is primarily a disease of middle-aged women. More than 90% of persons
with PBC have high titers of antimitochondrial antibodies. However, it is still unclear why
intrahepatic bile ducts are the targets for these antibodies. Recent evidence suggests that
exposure to certain xenobiotics may modify mitochondrial proteins leading to a decrease of
immunologic tolerance to some of these proteins. Pruritus is the initial presenting feature;
jaundice develops late. Serum alkaline phosphatase and cholesterol levels are almost always
elevated; hyperbilirubinemia is a late development and usually signifies incipient hepatic
decompensation.
Associated
extrahepatic
conditions include Sjögren syndrome,
scleroderma, thyroiditis, rheumatoid arthritis, Raynaud phenomenon, etc.
Primary Sclerosing Cholangitis (PSC)
is a chronic cholestatic disorder, characterized by
progressive fibrosis and destruction of extrahepatic and large intrahepatic bile ducts. Because
the changes in the ducts are patchy, retrograde cholangiography shows a characteristic
"beading" of the contrast medium in the affected segments of the biliary tree. The large bile
ducts show periductal fibrosis that obliterates the lumen, leaving a solid cord scar with few
inflammatory cells. Affected portal tracts show concentric periductal onion-skin fibrosis and
a modest lymphocytic infiltrate (Fig. 6-14). Primary sclerosing cholangitis is commonly seen
in association with inflammatory bowel disease, particularly chronic ulcerative colitis,
which coexists in approximately 70% of the PSC cases. The disorder tends to occur in the
age range of 20 to 50 years. Evidences suggest that PSC is an immunologically mediated
disease. Cholangiocarcinoma complicates PSC in 10% of individuals.
18
CIRCULATORY DISORDERS
Hepatic Artery Obstruction
:
liver infarcts are rare due to the double blood supply to the
liver. Interruption of the main hepatic artery does not always produce ischemic necrosis of
the organ, because of the accessory vessels and the portal venous supply that may sustain
the liver parenchyma. The one exception is hepatic artery thrombosis in the transplanted
liver, which generally leads to loss of the organ. Thrombosis or compression of an
intrahepatic branch of the hepatic artery by polyarteritis nodosa, embolism, neoplasia, or
sepsis may result in a localized parenchymal infarct.
Portal Vein Obstruction and Thrombosis
Occlusion of the portal vein or its major branches typically produces abdominal pain,
ascites and other manifestations of portal hypertension, principally esophageal varices that
are prone to rupture. The ascites, when present, is often massive and intractable.
Extrahepatic portal vein obstruction may arise from the following:
a.
Peritoneal sepsis (e.g., acute appendicitis leading to pylephlebitis)
b. Pancreatitis: this initiates splenic vein thrombosis, which propagates into the portal vein
c. Thrombogenic diseases and postsurgical thromboses
d. Vascular invasion by primary or secondary cancer in the liver that progressively occludes
portal inflow to the liver; extensions of hepatocellular carcinoma can even occlude the main
portal vein
e. Banti syndrome, in which subclinical thrombosis of the portal vein (as from neonatal
omphalitis or umbilical vein catheterization) produces a fibrotic, partially recanalized
vascular channel presenting as splenomegaly or esophageal varices years after the occlusive
event.
Intrahepatic thrombosis of a portal vein radicle, when acute, does not cause ischemic
infarction but instead results in a sharply demarcated area of red-blue discoloration (infarct
of Zahn). There is no necrosis, only hepatocellular atrophy and markedly congested &
distended sinusoids.
Impaired Blood Flow through the Liver
The most common intrahepatic cause of portal blood flow obstruction is cirrhosis. In
addition, physical occlusion of the sinusoids occurs in sickle cell disease, this leads to
panlobular necrosis. Disseminated intravascular coagulation may cause occlusion of
sinusoids. This is usually inconsequential except for the periportal sinusoidal occlusion and
parenchymal necrosis that may occur in the eclampsia of pregnancy. Subsequent suffusion of
blood under the capsule may precipitate a fatal intra-abdominal hemorrhage. (Fig. 6-15)
Passive Congestion and Centrilobular Necrosis
Right-sided cardiac failure leads to passive congestion of the liver, and if persistent, can
cause centrilobular necrosis, and perivenular fibrosis in the areas of necrosis. In most
instances, there is only a small elevation of serum aminotransferase levels & sometimes mild
to moderate jaundice.
Gross features
In right-sided heart failure, the liver is slightly enlarged, tense, and cyanotic, with
rounded edges.
Microscopic features
19
There is congestion of centrilobular sinusoids associated with atrophy of centrilobular
hepatocytes resulting in markedly attenuated liver cell cords.
An uncommon complication of sustained chronic severe congestive heart failure is cardiac
sclerosis (not cirrhosis). The pattern of liver fibrosis is distinctive, inasmuch as it is mostly
centrilobular.
Left-sided cardiac failure or shock may lead to hepatic hypoperfusion and hypoxia. In this
instance, centrilobular hepatocytes undergo ischemic necrosis.
The combination of left-sided hypoperfusion and right-sided retrograde congestion acts
synergistically to generate a distinctive lesion, centrilobular hemorrhagic necrosis The
liver takes on a variegated mottled appearance, reflecting hemorrhage and necrosis in the
centrilobular regions, alternating with pale midzonal areas, known traditionally as the
"nutmeg" liver. (Fig. 6-16).
Hepatic Vein Outflow Obstruction
1. Hepatic Vein Thrombosis (Budd-Chiari Syndrome) results from the thrombosis of two or
more major hepatic veins and is characterized by hepatomegaly, ascites, and abdominal
pain. Causes of hepatic vein thrombosis are (in order of frequency)
1. Myeloproliferative disorders including polycythemia vera
2. Pregnancy, the postpartum state, or the use of oral contraceptives
3. Paroxysmal nocturnal hemoglobinuria (PNH)
4. Intra-abdominal cancers, particularly hepatocellular carcinoma.
All of the above produce thrombotic tendencies or, in the case of liver cancers, sluggish
blood flow.
5. Mechanical obstruction to blood outflow, as by a massive intrahepatic abscess or
parasitic cyst, or by obstruction of the inferior vena cava at the level of the hepatic veins by
thrombus or tumor.
6. Idiopathic (10% of cases)
Gross features
With acutely developing thrombosis of the major hepatic veins or inferior vena cava, the
liver is swollen, red-purple, and has a tense capsule (Fig. 6-17).
Microscopic features
There is severe centrilobular congestion and necrosis.
Centrilobular fibrosis develops in instances in which the thrombosis is more slowly
developing.
The major veins may contain occlusive fresh thrombi or, in chronic cases, organized
adherent thrombi.
2. Sinusoidal Obstruction Syndrome (veno-occlusive disease) was originally described in
Jamaican drinkers of bush-tea containing pyrrolizidine alkaloid. It is caused by toxic injury
to sinusoidal endothelium. Damaged endothelial cells slough off and create emboli that
block blood flow. Endothelial damage is accompanied by passage of red blood cell into the
space of Disse, proliferation of stellate cells, and fibrosis of terminal branches of the hepatic
vein. This syndrome now occurs primarily in the first 20-30 days after bone marrow
transplantation (up to 20% of cases). The sinusoidal injury is believed to be caused by drugs
such as cyclophophamide, and by total body radiation, used in pre- or post-transplantation
20
regimens. The presentation of the disease varies from mild to severe. Severe sinusoidal
obstruction syndrome that does not resolve after 3 months of treatment can cause death.
TUMORS AND HEPATIC NODULES
The most common hepatic neoplasms are metastatic carcinomas, with colon, lung, and
breast heading the list as sites of the primary tumor.
Solitary or multiple benign hepatocellular nodules may develop in the liver. These include
1. Focal nodular hyperplasia
2. Macroregenerative nodules
3. Dysplastic nodules
Focal nodular hyperplasia is localized, well-demarcated but poorly encapsulated nodular
regeneration. It consists of hyperplastic hepatocyte with a central fibrous scar. (Fig. 6-18)
The nodules appear in noncirrhotic livers in response to local vascular injury and may reach
up to many centimeters in diameter. It is usually an incidental finding, most commonly in
women of reproductive age. In about 20% of cases, focal nodular hyperplasia coexists with
hepatic cavernous hemangiomas.
Macroregenerative nodules appear in cirrhotic livers (Fig. 6-19). They are larger than
surrounding cirrhotic nodules but do not display atypical features. They do not seem to be
precursors of malignant lesions.
Dysplastic nodules are lesions larger than 1 mm in diameter that appear in cirrhotic livers.
Hepatocytes in dysplastic nodules and in smaller lesions called dysplastic foci are highly
proliferative and show atypical features such as crowding and pleomorphism. The dysplastic
features can be of low or high grade. High-grade dysplastic lesions are considered to be
precursors of hepatocelluar cancers.
Benign Tumors
Cavernous hemangiomas (Fig. 6-20) are most common benign lesions of the liver are.
These well-circumscribed lesions consist of vascular channels and intervening stroma. They
appear as discrete red-blue, soft nodules, usually less than 2 cm in diameter, often directly
beneath the capsule. Their chief clinical significance is the importance of not mistaking them
for metastatic tumors; blind percutaneous needle biopsy may cause severe intra-abdominal
bleeding.
Hepatic (liver cell) Adenoma usually occurs in women of childbearing age who have used
oral contraceptive steroids, and it may regress on discontinuance of hormone use. The tumor
is yellow-tan, well-demarcated nodules, up to 30 cm in diameter and is often located beneath
the capsule (Fig. 6-21).
It is composed of sheets and cords of cells that may resemble normal hepatocytes with
prominent arteries and veins. Liver cell adenomas are significant for three reasons:
1. May be mistaken for HCC
2. May rupture, particularly during pregnancy causing life-threatening intra-abdominal
hemorrhage
3. With β-catenin mutations they carry a risk of cancerous transformation.
21
Hepatocellular Carcinomas (HCC)
The incidence (generally 5% of all cancers) varies widely in different areas of the world.
More than 85% of cases occur in countries with high rates of chronic HBV infection e.g.
Asian and African countries in which HBV is transmitted vertically, and thus the carrier state
starts in infancy. Moreover, many of these populations are exposed to aflatoxin, which,
combined with HBV infection, increases the risk of HCC development by more than 200-
fold over noninfected, nonexposed populations. The peak incidence of HCC in these areas is
between 20 and 40 years of age, and in almost 50% of cases, HCC may appear in the
absence of cirrhosis. In Western populations HCC is rare and seldom present before age 60,
and in 90% of cases tumors develop in cirrhotic livers. There is a pronounced male
preponderance of HCC throughout the world.
Pathogenesis
Three major etiologic associations have been established:
1. Infection with HBV or HCV
2. Alcoholic cirrhosis
3. Aflatoxin exposure
Other assiciations include
4. Hemochromatosis
5. Hereditary tyrosinemia (40% of patients develop HCC)
Cirrhosis seems to be an important, but not essential contributor to the occurrence of
HCC. In most cases, HCC develops from high-grade dysplastic nodules.
Carcinogenesis is greatly enhanced in the presence of cell injury and replication, as occurs
in chronic viral hepatitis. HCV infection is the greatest risk factor; HCC in such patients
occurs almost exclusively in the setting of cirrhosis. In certain regions of the world, such
as China and South Africa, where HBV is endemic, there is also high exposure to dietary
aflatoxins derived from the fungus Aspergillus flavus. Aflatoxin can bind covalently with
cellular DNA and cause a mutation in p53. Neither HBV nor HCV contains oncogenes.
The carcinogenic capacity of these viruses probably relates to their capacity to cause
continuing cell death, chronic inflammation, and regeneration; these are believed to be
main contributors to DNA damage.
Autonomous hepatocyte replication can occur by over-expression of specific cellular
genes (such as β-catenin), mutation of the tumor suppressor gene p53, methylation
changes, and expression of growth factors.
Gross features
There are three gross forms of HCC
1. Unifocal, usually a massive tumor (Fig. 6-22 A)
2. Multifocal i.e. made of variably sized nodules
3. Diffusely infiltrative i.e. permeating widely and sometimes involving the entire liver
Particularly in the latter two patterns, it may be difficult to distinguish regenerative
nodules of cirrhotic liver from nodules of neoplasm of similar size. The cancerous masses
are usually yellow-white, punctuated sometimes by bile staining and areas of hemorrhage
or necrosis.
All patterns of HCC have a strong propensity for invasion of vascular channels. Extensive
intrahepatic metastases ensue, and occasionally snakelike masses of tumor invade the
22
portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even
into the right side of the heart.
Microscopic features (Fig. 6-22 B)
HCCs range from well-differentiated to poorly differentiated lesions. In well differentiated
HCC the neoplastic hepatocytes are arranged in broad trabeculae, which are separated by
sinusoids.
Central necrosis in the broad trabeculae may produce a pseudoglandular pattern.
Poorly differentiated tumors are composed of large multinucleate anaplastic tumor giant
cells.
In the better differentiated variants, globules of bile may be found within the cytoplasm of
cells and in pseudocanaliculi between cells.
Mallory bodies may be found within the cytoplasm of the neoplastic cells.
HCC displays scant connective tissue stroma (that is why it is soft in consistency)
Fibrolamellar carcinoma is a distinctive clinicopathologic variant of HCC, in that
- It occurs in young male and female adults (20-40 years of age) with equal incidence
- It has no association with cirrhosis or other risk factors
- It usually appears grossly as a single large, hard "scirrhous" tumor
- Histologically it is composed of well-differentiated neoplastic hepatocytes growing in nests
or cords and separated by thick fibrous lamellae around groups of tumor cells. (Fig. 6-23)
In patients with cirrhosis a rapid increase in liver size, sudden worsening of ascites, or the
appearance of bloody ascites, fever, and pain call attention to the development of HCC.
Laboratory studies are helpful but not diagnostic. Half of the patients have elevated levels of
serum α-fetoprotein. However, this tumor "marker" lacks specificity, because moderate
elevations are also encountered in other conditions, such as cirrhosis, chronic hepatitis,
normal pregnancy, fetal death, fetal neural tube defects and gonadal germ cell tumors. Very
high levels (>1000 ng/mL), however, are rarely encountered except in HCC. This marker is
only rarely elevated to the levels considered diagnostic for HCC. The overall prognosis of
HCC is poor, but it is significantly better for individuals who have a single tumor less than 2
cm in diameter and good liver function. The median survival is 7 months.
Metastatic tumors (Fig. 6-24)
The following malignant tumors frequently involve the liver by direct extension
1. Gallbladder
2. Extrahepatic bile ducts
3. Pancreas
4. Stomach
The following carcinomas metastasize to the liver with regularly
1. large bowel
2. lung
3. breast
Sarcomas of soft tissues or internal organs and malignant melanomas also frequently
metastasize to this organ.
4. Pancreas
5. Kidney
6. Stomach
23
Gross features
• Most metastatic tumors in the liver form discrete masses that may locally elevate the
capsule.
• Central necrosis with umbilication occurs in the larger lesions
• metastases are very rare in cirrhotic livers; whatever the reason for this may be
(nonreceptive soil for the metastatic growth or simply the fact that most cirrhotic patients
do not live long enough to develop them), the conclusion can be drawn that the large
majority of malignant tumors occurring in cirrhotic livers are primary.
The microscopic picture reflects the features of the primary cancer.
DISORDERS OF GALLBLADDER AND EXTRAHEPATIC BILIARY TRACT
GALLBLADDER DISEASES
Cholelithiasis (Gallstones)
Gallstones trouble up to 20% of adult populations and are mainly of two types
1. Cholesterol stones composed of crystalline cholesterol monohydrate (80%)
2. Pigment stones composed predominantly of bilirubin calcium salts (20%)
Pathogenesis and Risk Factors
Bile is a major pathway for elimination of excess cholesterol from the body. Cholesterol
is rendered water soluble through mixing with bile salts and lecithins that are secreted
into bile. When cholesterol concentrations exceed the solubilizing capacity of bile
(supersaturation), cholesterol deposited as solid cholesterol crystals.
Cholesterol gallstone formation involves four concurrently occurring steps:
1. Supersaturation of the bile with cholesterol
2. Establishment of a nidus by microprecipitates of calcium salts
3. Hypomobility of the gallbladder (stasis), which promotes nidus formation
4. Mucus hypersecretion to trap the crystals and thus enhancing their aggregation
The presence of unconjugated bilirubin in the biliary tree increases the likelihood of
pigment stone formation. This occurs in hemolytic anemias and biliary tract infections.
The precipitates are insoluble calcium bilirubinate salts.
The majority of individuals with gallstones (80%) have no identifying risk factors
Contributory risk factors include
1. Age and gender: the incidence of gall stones increases with age in that only 5% of the
population younger than age 40 but 25% of those older than 80 years develop stones. The
prevalence in women is about twice as high as in men.
2. Ethnic and geographic: gallstones are more prevalent in Western industrialized societies
and uncommon in developing ones.
3. Heredity: family history imparts increased risk, as do a variety of inborn errors of
metabolism such as those associated with impaired bile salt synthesis and secretion.
4. Environment: estrogenic influences, including oral contraceptives and pregnancy,
increase hepatic cholesterol uptake and synthesis, leading to excess biliary secretion of
cholesterol.
5. Obesity, rapid weight loss, and treatment with the hypocholesterolemic agent clofibrate
are strongly associated with increased biliary cholesterol secretion.
24
6. Gallbladder hypomotility predisposes to gallstones. It is associated with pregnancy,
rapid weight loss, and spinal cord injury. In most cases, however, the hypomotility is
present without obvious cause.
Pathologic features
Pure cholesterol stones always formed within the gall bladder as pale to tan yellow, and
are ovoid and firm (Fig. 6-25). They may be single but most are often multiple. In the
latter instance, they assume a faceted surface from apposition to one another. Most
cholesterol stones are radiolucent, but 20%of them may have sufficient calcium carbonate
to render them radiopaque.
Pigment stones may arise anywhere in the biliary tree (gall bladder, intra- or extra-hepatic
bile ducts) and are either black or brown. In general, black pigment stones are found in
sterile bile, while brown stones are found in infected bile. Black stones are usually small,
present in large numbers (Fig. 6-26), and crumble easily. Brown stones tend to be single or
few in number. Because of the incorporation of calcium carbonates and phosphates, 50%
to 75% of black stones are radiopaque. Brown stones, which contain calcium soaps, are
radiolucent.
Gallstones are asymptomatic in 75% of the cases. Pain is the principal symptom and it
tends to be severe, either constant or "colicky" from an obstructed gallbladder or when
small gallstones move down-stream and lodge in the biliary tree. Inflammation of the
gallbladder, in association with stones, also generates pain.
Complications of gall stones include
1. Empyema
2. Perforation
3. Fistulae
4. Cholongitis
5. Obstructive cholestasis
6. Pancreatitis
It is the very small stones that are dangerous; the larger the calculi, the less likely they are
to enter the cystic or common ducts to produce obstruction. Occasionally a large stone may
erode directly into an adjacent loop of small bowel, generating intestinal obstruction
("gallstone ileus").
Cholecystitis
This may be acute, chronic, or acute superimposed on chronic, and almost always occurs
in association with gallstones. Its epidemiologic distribution closely parallels that of
gallstones.
Gross features
Acute cholecystitis (Fig. 6-27)
The gallbladder is usually enlarged, tense, and bright red or blotchy, violaceous to
green-black discoloration. The latter is due to subserosal hemorrhages.
The serosal covering is frequently covered by fibrin or suppurative exudate.
In 90% of cases stones are present, often obstructing the cystic duct.
The gallbladder lumen is filled with cloudy or turbid bile (contain fibrin, blood, and
frank pus). When the exudate is pure pus, the condition is referred to as empyema of the
gallbladder.
25
In mild cases the gallbladder wall is thickened, edematous, and hyperemic.
In more severe cases the gallbladder is transformed into a green-black necrotic organ,
termed gangrenous cholecystitis.
Microscopical features
The inflammatory reactions consist of the usual patterns of acute inflammation (i.e.,
edema, neutrophilic infiltration, vascular congestion. It may be suppurative with frank
abscess formation, or eventuates in gangrenous necrosis.
Acute Calculous Cholecystitis refers to acute inflammation of a gallbladder that contains
stones and is precipitated by obstruction of the gallbladder neck or cystic duct. It is the
most common major complication of gallstones and the most common reason for
emergency cholecystectomy.
Initially it is the result of chemical irritation and inflammation of the gallbladder wall in
the setting of obstruction to bile outflow.
Acute Non-Calculous Cholecystitis
Up to 10% of gallbladders removed for acute cholecystitis contain no gallstones. Most of
these cases occur in seriously ill patients e.g. after severe trauma such as a major surgery,
motor vehicle accidents, severe burns as well as sepsis. In such cases many events are
thought to contribute to this condition such dehydration, gallbladder stasis and sludging,
vascular compromise, and, ultimately, bacterial contamination.
Chronic Cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in
most instances it develops de novo. Like acute cholecystitis it is almost always associated
with gallstones but these do not seem to have a direct role in the initiation of
inflammation. Rather, supersaturation of bile predisposes to both chronic inflammation
and, in most instances, stone formation. Microorganisms, usually E. coli and enterococci,
can be cultured from the bile in only about one-third of cases.
Pathological features (Fig. 6-28)
The changes are extremely variable and sometimes minimal.
The mere presence of stones within the gallbladder, even in the absence of acute
inflammation, is often taken as sufficient justification for the diagnosis.
The gallbladder may be contracted, of normal size, or enlarged.
The submucosa and subserosa are often thickened from fibrosis.
In the absence of superimposed acute cholecystitis, mural lymphocytes are the only
feature of inflammation.
DISORDERS OF EXTRAHEPATIC BILE DUCTS
Choledocholithiasis and Cholangitis
are
frequently seen together. Choledocholithiasis is
the presence of stones within the biliary tree. Almost all these stones are derived from the
gallbladder. Symptoms are absent in 10% of the cases, but when occur they are due to
biliary obstruction or its sequele such as pancreatitis, cholangitis, hepatic abscess,
secondary biliary cirrhosis, or acute calculous cholecystitis.
Cholangitis refers to acute mostly bacterial inflammation of the wall of bile ducts. Most
cases are due to obstruction bile flow, mostly by choledocholithiasis. However, surgical
reconstruction of the biliary tree is also a recognized cause. Uncommon causes include
tumors, indwelling stents or catheters, acute pancreatitis, and benign strictures. Bacteria
26
most likely enter the biliary tract through the sphincter of Oddi, rather than by the
hematogenous route. Ascending cholangitis refers to the tendency of bacteria, once within
the biliary tree, to infect intrahepatic biliary ducts. The usual pathogens are E. coli,
Klebsiella, Clostridium, Bacteroides, etc.
Charcot's triad (pain, jaundice and fever) is the
most common mode of presentation.
The most severe form of cholangitis is suppurative cholangitis, in which purulent bile fills
and distends bile ducts, with an attendant risk of liver abscess formation.
Secondary Biliary Cirrhosis
Prolonged obstruction of the extrahepatic biliary tree results in secondary biliary cirrhosis.
Causes include
1. Extrahepatic cholelithiasis (the most common cause)
2. Malignancies of the biliary tree and head of the pancreas
3. Strictures resulting from previous surgical procedures
4. Biliary atresia
The initial morphologic features of cholestasis are entirely reversible with correction of the
obstruction. However, secondary inflammation resulting from biliary obstruction initiates
periportal fibrogenesis, which eventually leads to scarring and nodule formation,
generating secondary biliary cirrhosis. Subtotal obstruction may promote ascending
cholangitis, which further contributes to the damage. Enteric organisms such as coliforms
and enterococci are common offenders.
Biliary Atresia is a major cause of neonatal cholestasis (30%). Biliary atresia is defined as
a complete obstruction of bile flow caused by destruction or absence of all or part of the
extrahepatic bile ducts. It is the most frequent cause of death from liver disease in early
childhood. The salient features of biliary atresia include
1. Inflammatory fibrosing stricture of extrahepatic biliary tree (hepatic or common bile
ducts)
2. Inflammatory destruction of the major intrahepatic bile ducts
3. Features of biliary obstruction on liver biopsy
4. Periportal fibrosis and cirrhosis within 3 to 6 months of birth
Laboratory findings do not distinguish between biliary atresia and intrahepatic
cholestasis, but a liver biopsy provides evidence of bile duct obstruction in 90% of cases of
biliary atresia. Without surgical intervention, death usually occurs within 2 years of birth.
TUMORS
Carcinoma of the Gallbladder
is the most frequent malignant tumor of the biliary tract. It
occurs most frequently in the age group 60-70 years. The mean 5-year survival is 5%
because it is rarely discovered at a resectable stage. Gallstones are present in about 75% of
the cases. Presumably, gallbladders containing stones or infectious agents develop cancer
as a result of recurrent trauma and chronic inflammation. The presence of abnormal
choledocho-pancreatic duct junction is considered to be a risk factor.
Gross features
The cancer is either exophytic (fungating) or infiltrative growth.
The infiltrative pattern, which is the more common, usually appears as a poorly-defined
area of thickening and induration of part or whole of gall bladder wall.
27
The exophytic pattern grows into the lumen as cauliflower mass, but at the same time it
invades the underlying wall (Fig. 6-29).
Microscopic features
Well- to poorly-differentiated infiltrative adenocarcinomas that is sometimes papillary.
By the time gallbladder cancers are discovered, most have invaded the liver directly and
many have extended to the cystic duct and adjacent bile ducts and lymph nodes at the
portahepatis.
Preoperative diagnosis of gall bladder carcinoma is seen in only a 20% of the cases. The
fortunate person develops early obstruction and acute cholecystitis before extension of the
tumor into adjacent structures or undergoes cholecystectomy for coexistent symptomatic
gallstones. Preoperative diagnosis rests largely on detection of gallstones along with
abnormalities in the gallbladder wall documented by imaging studies.
Cholangiocarcinomas
are adenocarcinomas arising from cholangiocytes (epithelial cells
lining) in bile ducts within and outside of the liver. Extrahepatic cholangiocarcinomas (2/3
of the cases) may develop at the hilum (Klatskin tumors) or more distally in the biliary
tree, down to the peripancreatic portion of the distal common bile duct. They occur mostly
in individuals 50 to 70 years of age. The prognosis of cholangiocarcinomas is poor because
they are generally asymptomatic until late, and most patients have unresectable tumors.
Risk factors include
1. Primary sclerosing cholangitis
2. Fibrocystic diseases of the biliary tree
3. Exposure to Thorotrast (which is no longer used in radiography of the biliary tree).
Pathological features (Fig. 6-30).
Due to early development of obstructive jaundice, these tumors are detected as small
firm, gray nodules within the bile duct wall. Alternatively, they are diffusely infiltrative
lesions that create thickening of the wall.
These adenocarcinomas are generally well-differentiated with an abundant fibrous
stroma
Cholangiocarcinomas may spread to extrahepatic sites such as regional lymph nodes,
lungs, & bones.
Mean survival time is around 12 months.
THE EXOCRINE PANCREAS
CONGENITAL ANOMALIES
Pancreas divisum is the most common clinically significant congenital anomaly resulting
from failure of fusion of pancreatic ducts. This leads to the main pancreatic duct draining
only a small portion of the head, while the bulk of the pancreas drains through a minor duct.
This creates a state of inadequate drainage for the bulky pancreatic secretions thus
predisposes to chronic pancreatitis.
Annular pancreas results from abnormal pancreatic fusion due to failure of ventral bud to
rotate properly; head of pancreas encircles duodenum as a collar and may constrict lumen
completely. It can lead to duodenal obstruction.
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Ectopic Pancreas is uncommon; favored sites are the stomach and duodenum. The ectopic
tissue is small and submucosal in location. It can cause localized inflammation, or mucosal
bleeding.
Congenital cysts: the kidney, liver, and pancreas can all contain cysts ( polycystic disease).
PANCREATITIS
Acute Pancreatitis
is relatively common in developed countries. Causes implicated include
1. Gallstones and excessive alcohol intake; these are the main offenders.
2. Non-gallstone obstruction of the pancreatic ducts e.g. by periampullary tumors
3. Medications as with thiazide & frusemide diuretics
4. Trauma, both blunt and iatrogenic during surgery or endoscopy
5. Others such as metabolic disorders, ischemia and infections as with mumps
In up to 20% of patients there is no identifiable cause (idiopathic pancreatitis).
Gross features (Fig. 6-31)
In milder forms there is edema & congestion of the organ with foci of fat necrosis. Fat
necrosis results from enzymatic destruction of fat cells; the released fatty acids combine
with calcium to form insoluble salts that precipitate locally and appear as yellow-white
chalky deposits within & outside the pancreas e.g. in the omentum and mesentery.
The peritoneal cavity contains a brown-tinged fluid with fat globules.
In the most severe forms there is extensive parenchymal necrosis accompanied by diffuse
hemorrhage.
Microscopical features
These parallel the gross changes of edema, acute inflammation, and focal fat necrosis.
In more severe forms, necrosis involves all tissue constituents including islets of
Langerhans
Vascular damage causes hemorrhage into the parenchyma of the pancreas.
Pathogenesis
The microscopic changes favor autodigestion of the pancreatic substance by activated
pancreatic enzymes. Trypsin seems to have a central role because it can activate other
enzymes (e.g. phospholipases and elastases) that can participate in the process of
autodigestion. Trypsin can also leads to activation of the kinin system & factor XII and
thus the clotting and complement systems.
Pancreatic duct obstruction causes an increase in intraductal pressure, thus allowing
accumulation of an enzyme-rich interstitial fluid that causes tissue injury. Edema further
compromises local blood flow, causing vascular insufficiency and ischemic injury to
acinar cells.
The role of alcohol as a cause of pancreatitis is still unknown, proposed mechanisms
include contraction of the sphincter of Oddi and direct toxic effects on acinar cells.
Inherited mutations in genes important for normal pancreatic exocrine function are
investigated.
Laboratory findings include markedly elevated serum amylase during the first 24 hours,
followed (within 3-4 days) by rising serum lipase levels. Hypocalcemia can result from
precipitation of calcium in the extensive areas of fat necrosis. The enlarged inflamed
pancreas can be visualized by CT or MRI. Although most individuals with acute pancreatitis
eventually recover, some die from shock; ARDS and acute renal failure. In those who
survive complications include pancreatic abscesses or pancreatic pseudocysts.
29
Pancreatic Pseudocyst
is the most common cystic lesion of the pancreas and a common
complication of acute pancreatitis. Liquefied necrotic pancreatic tissues become surrounded
by fibrous tissue wall to form a cystic space, lacking an epithelial lining ("pseudo").
Drainage of pancreatic secretions into this space over months to years (from damaged
pancreatic ducts) can cause massive enlargement of the cyst (up to 30 cm in diameter). They
can become secondarily infected, and larger pseudocysts can compress or even perforate into
adjacent structures. It is commonly attached to the surface of the gland and may involve
peripancreatic tissues. (Fig. 6-32)
Chronic Pancreatitis
is characterized by longstanding inflammation and fibrosis with
destruction of the exocrine pancreas; in the late stages, the islets are also lost.
Causes of chronic pancreatitis include
1. Chronic alcoholism (the most common cause).
2. Long-standing pancreatic duct obstruction (e.g., by pseudocysts, calculi, neoplasms)
3. Tropical pancreatitis: seen in Africa and Asia, and attributed to malnutrition
4. Hereditary pancreatitis due to mutations of genes, some encoding trypsin inhibitor.
5. Cystic fibrosis
In some cases there is no obvious cause (idiopathic); as with acute pancreatitis, a growing
number of these cases are associated with inherited mutations in genes concerned with
normal pancreatic exocrine function.
Gross features: the gland is hard, sometimes with extremely dilated ducts and visible
calcifications
Microscopic features (Fig. 6-33)
Parenchymal fibrosis, reduced number and size of acini, and variable dilation of the ducts.
A chronic inflammatory infiltrate around remaining lobules and ducts.
Islets of Langerhans are relatively spared but eventually they disappear.
Pathogenesis
This is still not established with certainity. However, several hypotheses are proposed:
1. Ductal obstruction by concretions: alcohol increases the protein concentration of
pancreatic secretions; these can form ductal plugs.
2. Toxic: alcohol can exert a direct toxic effect on acinar cells leading to their destruction
3. Oxidative stress induced by alcohol generates free radicals in acinar cells, which lead to
fusion of lysosomes and zymogen granules with resulting acinar cell necrosis, inflammation,
and fibrosis.
4. Necrosis-fibrosis due to recurrent episodes of acute pancreatitis
Chronic pancreatitis can present with repeated bouts of jaundice, persistent or recurrent
abdominal and back pain. It may be entirely silent until pancreatic insufficiency and diabetes
develop.
Chronic pancreatitis may present as attacks of abdominal pain with some elevation of serum
amylase. Gallstone-induced obstruction may cause jaundice &/or elevation in serum alkaline
phosphatase. A helpful finding is visualization of calcifications within the pancreas by CT or
ultrasonography. Weight loss and hypoalbuminemia with edema from malabsorption can
also occur.
30
PANCREATIC NEOPLASMS
Cystic Neoplasms
Some of these are entirely benign (e.g., serous cystadenoma); others, such as mucinous
cystic neoplasms, can be benign but frequently have malignant potential.
Pancreatic Carcinoma
has a very poor prognosis in that the 5-year survival rate is less than
5%.
Pathogenesis: like all cancers, it arises as a consequence of inherited and acquired mutations
in cancer-associated genes. There is a progressive accumulation of genetic changes in
pancreatic epithelium as it proceeds from non-neoplastic, to noninvasive lesions in small
ducts and ductules, to invasive carcinoma. Antecedent lesions are called "pancreatic
intraepithelial neoplasias" (PanINs). They are often found adjacent to infiltrating carcinomas
and share with the latter a number of the same genetic mutations. The more common
molecular alterations in pancreatic carcinogenesis affect K-RAS (oncogene), and the tumor
suppressor genes p16, SMAD4, and p53.
Carcinoma is primarily a disease of the elderly (60 and 80 years). Smoking has the strongest
environmental influence. Chronic pancreatitis and diabetes mellitus are also associated with
an increased risk. Familial clustering of pancreatic cancer has been reported, and familial
pancreatitis (related to mutations in a trypsinogen gene) is associated with up to 80-fold
increased risk.
Gross features (Fig. 6-34)
The head is most commonly involved (60%), whereas the tail is the least common site
(5%)
The cancer is usually hard, gray-white, poorly defined mass.
Most carcinomas of the head obstruct the distal common bile duct leading to distention of
the biliary tree, and obstructive jaundice.
In marked contrast, carcinomas of the body and tail do not interrupt the biliary tract and
hence remain silent for some time. They may be quite large and widely disseminated by
the time of the diagnosis.
The regional lymph nodes & the liver are often involved by metastases as are the lungs &
bones.
Microscopical features
Most carcinomas are ductal adenocarcinomas .
Two features are characteristic of pancreatic cancer:
1. It is highly invasive; even in the early stages, thus infiltrates peripancreatic tissues
extensively
2. It elicits an intense fibroblastic (desmoplastic) response.
Perineural and lymphatic invasions are commonly seen.
Migratory thrombophlebitis (Trousseau syndrome) occurs in about 10% of patients.
Endoscopic ultrasonography and CT, are helpful in diagnosis and in performing guided
percutaneous needle biopsy.