hepatobilary system hala kfoury kassouf, md. normal liver

HEPATOBILARY HEPATOBILARY SYSTEMSYSTEM

Hala Kfoury Kassouf, MDHala Kfoury Kassouf, MD

NORMAL LIVERNORMAL LIVER

Cut surface normal liver. Note portal vein Cut surface normal liver. Note portal vein carrying blood to liver, with accompanying carrying blood to liver, with accompanying

hepatic artery and bile ducts. At lower right is hepatic artery and bile ducts. At lower right is a branch of hepatic vein draining blood from a branch of hepatic vein draining blood from

the liver to the inferior vena cavathe liver to the inferior vena cava

Liver is divided histologically into lobules. The Liver is divided histologically into lobules. The center of the lobule is the central vein. At the center of the lobule is the central vein. At the

periphery of the lobule are portal triads. periphery of the lobule are portal triads. Functionally, the liver can be divided into Functionally, the liver can be divided into

three zones, based upon oxygen supply.three zones, based upon oxygen supply.

Predominantly Unconjugated Predominantly Unconjugated HyperbilirubinemiaHyperbilirubinemia

Excess production of bilirubinExcess production of bilirubin Hemolytic anemias Hemolytic anemias Resorption of blood from internal Resorption of blood from internal

hemorrhage (e.g., alimentary tract hemorrhage (e.g., alimentary tract bleeding, hematomas)bleeding, hematomas)

Ineffective erythropoiesis syndromes Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia) (e.g., pernicious anemia, thalassemia)

Reduced hepatic uptakeReduced hepatic uptake


Drug interference with membrane Drug interference with membrane carrier systems carrier systems

Some cases of Gilbert syndrome Some cases of Gilbert syndrome Impaired bilirubin conjugation Impaired bilirubin conjugation Physiologic jaundice of the newborn Physiologic jaundice of the newborn

(decreased UGT1A1 activity, (decreased UGT1A1 activity, decreased excretion) decreased excretion)

Breast milk jaundice (Breast milk jaundice (β-β-glucuronidases in milk)glucuronidases in milk)


Genetic deficiency of UGT1A1 Genetic deficiency of UGT1A1 activity (Crigler-Najjar syndrome activity (Crigler-Najjar syndrome types I and II)types I and II)

Gilbert syndrome (mixed etiologies)Gilbert syndrome (mixed etiologies) Diffuse hepatocellular disease (e.g., Diffuse hepatocellular disease (e.g.,

viral or drug-induced hepatitis, viral or drug-induced hepatitis, cirrhosis)cirrhosis)

Predominantly Predominantly Conjugated Conjugated

HyperbilirubinemiaHyperbilirubinemia Deficiency of canalicular membrane Deficiency of canalicular membrane

transporters (Dubin-Johnson transporters (Dubin-Johnson syndrome, Rotor syndrome) syndrome, Rotor syndrome)

Impaired bile flowImpaired bile flow

Hereditary Hereditary HyperbilirubinemiasHyperbilirubinemias

DisorderInheritanc

e

Defects in Bilirubin Metabolis

mLiver

PathologyClinical Course

Unconjugated Hyperbilirubinemia

Crigler-Najjar syndrome type I

Autosomal recessive

Absent UGT1A1 activity

Normal Fatal in neonatal period

Crigler-Najjar syndrome type II

Autosomal dominant with variable penetrance

Decreased UGT1A1 activity

Normal Generally mild, occasional kernicterus

Gilbert syndrome

Autosomal dominant?

Decreased UGT1A1 activity

Normal Innocuous

Hereditary Hereditary HyperbilirubinemiasHyperbilirubinemias

Conjugated Hyperbilirubinemia

Dubin-Johnson syndrome

Autosomal recessive

Impaired biliary excretion of bilirubin glucuronides due to mutation in canalicular multidrug resistance protein 2 (MRP2)

Pigmented cytoplasmic globules; ?epinephrine metabolites

Innocuous

Rotor syndrome

Autosomal recessive

Decreased hepatic uptake and storage? Decreased biliary excretion?

Normal Innocuous

CirrhosisCirrhosis

Cirrhosis is among the top 10 causes Cirrhosis is among the top 10 causes of death in the Western world. The of death in the Western world. The chief worldwide contributors are chief worldwide contributors are alcohol abuse and viral hepatitis. alcohol abuse and viral hepatitis. Other causes include biliary disease, Other causes include biliary disease, and iron overload. Cirrhosis is the and iron overload. Cirrhosis is the end-stage of chronic liver diseaseend-stage of chronic liver disease

CirrhosisCirrhosis

Cirrhosis is defined by three characteristicsCirrhosis is defined by three characteristics

11)Fibrosis)Fibrosis in the form of delicate bands or in the form of delicate bands or broad scars/septa broad scars/septa

2)Nodules2)Nodules containing regenerating containing regenerating hepatocytes encircled by fibrosis, with hepatocytes encircled by fibrosis, with diameters varying from very small (<3 mm, diameters varying from very small (<3 mm, micronodules) to large (several micronodules) to large (several centimeters, macronodules) centimeters, macronodules)

3)Disruption of the architecture of the entire 3)Disruption of the architecture of the entire liverliver

features of cirrhosisfeatures of cirrhosis

Vascular architecture is reorganizedVascular architecture is reorganized by by

the parenchymal damage and scarring, the parenchymal damage and scarring, with the formation of abnormal with the formation of abnormal interconnections between vascular interconnections between vascular inflow and hepatic vein outflow inflow and hepatic vein outflow channels. channels.

Fibrosis is the key feature of progressive Fibrosis is the key feature of progressive damage to the liver.damage to the liver. Once cirrhosis has Once cirrhosis has developed, reversal is thought to be developed, reversal is thought to be rare. rare.

Classifiation of cirrhosisClassifiation of cirrhosis

The classification is based on the The classification is based on the underlying etiology.underlying etiology.

Many forms of cirrhosis (particularly Many forms of cirrhosis (particularly alcoholic cirrhosis) are initially alcoholic cirrhosis) are initially micronodular, but there is a micronodular, but there is a tendency for nodules to increase in tendency for nodules to increase in size with time.size with time.

Classifiation of cirrhosis Classifiation of cirrhosis based on causesbased on causes

Alcoholic liver disease 60% to 70%Alcoholic liver disease 60% to 70% Viral hepatitis 10%Viral hepatitis 10% Biliary diseases 5% to 10%Biliary diseases 5% to 10% Primary hemochromatosis 5%Primary hemochromatosis 5% Wilson disease RareWilson disease Rare α1-Antitrypsin deficiency Rareα1-Antitrypsin deficiency Rare Cryptogenic cirrhosis 10% to 15%Cryptogenic cirrhosis 10% to 15%

Classifiation of cirrhosisClassifiation of cirrhosis

Infrequent types of cirrhosis also include Infrequent types of cirrhosis also include the cirrhosis developing in infants and children the cirrhosis developing in infants and children

with galactosemia and tyrosinosiswith galactosemia and tyrosinosis drug-induced cirrhosis. drug-induced cirrhosis. Severe fibrosis can occur in the setting of Severe fibrosis can occur in the setting of

cardiac disease (sometimes called "cardiac cardiac disease (sometimes called "cardiac cirrhosis,"). cirrhosis,").

In some cases there is no cause and these are In some cases there is no cause and these are referred to as referred to as cryptogenic cirrhosis.cryptogenic cirrhosis.

Once cirrhosis is established, it is usually Once cirrhosis is established, it is usually impossible to establish an etiologic diagnosis impossible to establish an etiologic diagnosis on morphologic grounds aloneon morphologic grounds alone

Pathogenesis of cirrhosisPathogenesis of cirrhosis

The pathogenetic processes in cirrhosis The pathogenetic processes in cirrhosis are progressive fibrosis and are progressive fibrosis and reorganization of the vascular reorganization of the vascular microarchitecture of the livermicroarchitecture of the liver

In the normal liver, interstitial In the normal liver, interstitial collagens (types I and III) are collagens (types I and III) are concentrated in portal tracts and concentrated in portal tracts and around central veins. The type IV around central veins. The type IV collagen(reticulin) is in the space of collagen(reticulin) is in the space of Disse. Disse.


In cirrhosis, types I and III collagen are In cirrhosis, types I and III collagen are deposited in the lobule, creating deposited in the lobule, creating delicate or broad septal tracts. delicate or broad septal tracts.

There is loss of fenestrations in the There is loss of fenestrations in the sinusoidal endothelial cells sinusoidal endothelial cells (capillarization of sinusoids, that is the (capillarization of sinusoids, that is the sinusoidal space comes to resemble a sinusoidal space comes to resemble a capillary rather than a channel for capillary rather than a channel for exchange of solutes between exchange of solutes between hepatocytes and plasma). hepatocytes and plasma).


The major source of excess collagen The major source of excess collagen in cirrhosis is the perisinusoidal in cirrhosis is the perisinusoidal stellate cells ( Ito cells), which lie in stellate cells ( Ito cells), which lie in the space of Disse. Although the space of Disse. Although normally functioning as normally functioning as vitamin A fat-storing cells, during the fat-storing cells, during the development of cirrhosis they development of cirrhosis they become activated and transform into become activated and transform into myofibroblast-like cells. myofibroblast-like cells.


Collagen synthesis is stimulated byCollagen synthesis is stimulated by Chronic inflammation, with production of Chronic inflammation, with production of

inflammatory cytokines. inflammatory cytokines. Cytokine production by activated Cytokine production by activated

endogenous cells (Kupffer cells, endothelial endogenous cells (Kupffer cells, endothelial cells, hepatocytes, and bile duct epithelial cells, hepatocytes, and bile duct epithelial cells). cells).

Disruption of the normal extracellular Disruption of the normal extracellular matrix. matrix.

Direct stimulation of stellate cells by toxins Direct stimulation of stellate cells by toxins

The cirrhotic patient may The cirrhotic patient may develop jaundice and even develop jaundice and even hepatic failure’hepatic failure’

Clinical FeaturesClinical Features

All forms of cirrhosis may be All forms of cirrhosis may be clinically silent.clinically silent.

When symptomatic they lead to When symptomatic they lead to nonspecific clinical manifestations: nonspecific clinical manifestations: anorexia, weight loss, weakness, anorexia, weight loss, weakness, osteoporosis, and, in advanced osteoporosis, and, in advanced disease, frank debilitation. disease, frank debilitation.

Incipient or overt hepatic failure Incipient or overt hepatic failure may develop.may develop.


The ultimate mechanism of The ultimate mechanism of most cirrhotic deaths is most cirrhotic deaths is

(1)(1) progressive liver failure , progressive liver failure ,

(2)(2) a complication related to portal a complication related to portal hypertension, or hypertension, or

(3)(3) the development of the development of hepatocellular carcinomahepatocellular carcinoma

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The nodules seen here are larger than 3 The nodules seen here are larger than 3 mm and, hence, this is an example of mm and, hence, this is an example of

"macronodular" cirrhosis."macronodular" cirrhosis.

Micronodular cirrhosis: The Micronodular cirrhosis: The regenerative nodules are quite regenerative nodules are quite

small, averaging less than 3 mm in small, averaging less than 3 mm in size. The most common cause for size. The most common cause for

this is chronic alcoholism.this is chronic alcoholism.

Regenerative nodules of hepatocytes are Regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that surrounded by fibrous connective tissue that

bridges between portal tracts. Within this bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes collagenous tissue are scattered lymphocytes

as well as a proliferation of bile ductsas well as a proliferation of bile ducts..

HEPATITISHEPATITIS

Infectious DisordersInfectious Disorders

Inflammatory disorders of the liver Inflammatory disorders of the liver dominate the clinical practice of dominate the clinical practice of hepatology. Among inflammatory hepatology. Among inflammatory disorders, infection is by far the most disorders, infection is by far the most frequent. The foremost hepatic frequent. The foremost hepatic infections are viral in origin. infections are viral in origin.

Other infections in which the hepatic Other infections in which the hepatic lesion is prominent include miliary lesion is prominent include miliary tuberculosis, malaria, staphylococcal tuberculosis, malaria, staphylococcal bacteremia, the salmonelloses, candida, bacteremia, the salmonelloses, candida, and amebiasisand amebiasis

VIRAL HEPATITISVIRAL HEPATITIS

The term "viral hepatitis" is reserved for The term "viral hepatitis" is reserved for infection of the liver caused by a group infection of the liver caused by a group of viruses having a particular affinity of viruses having a particular affinity for the liver called Hepatotropic for the liver called Hepatotropic viruses. viruses.

Hepatitis A Virus Hepatitis A Virus Hepatitis B Virus Hepatitis B Virus Hepatitis C Virus Hepatitis C Virus Hepatitis D VirusHepatitis D Virus Hepatitis E VirusHepatitis E Virus

Hepatitis A Virus Hepatitis A Virus infectioninfection

Is a benign, self-limited disease with an Is a benign, self-limited disease with an incubation period of 2 to 6 weeks.incubation period of 2 to 6 weeks.

HAV does not cause chronic hepatitis or a HAV does not cause chronic hepatitis or a carrier state.carrier state.

Fulminant hepatitis is rare. Fulminant hepatitis is rare. HAV is a small, nonenveloped, single-HAV is a small, nonenveloped, single-

stranded RNA picornavirus that occupies stranded RNA picornavirus that occupies its own genus, its own genus, HepatovirusHepatovirus. .

Ultrastructurally, HAV is an icosahedral Ultrastructurally, HAV is an icosahedral capsid capsid

Hepatitis A VirusHepatitis A Virus

HAV is spread by ingestion of HAV is spread by ingestion of contaminated water and foods and is contaminated water and foods and is shed in the stool for 2 to 3 weeks shed in the stool for 2 to 3 weeks before and 1 week after the onset of before and 1 week after the onset of jaundice. jaundice.

Thus, close personal contact with an Thus, close personal contact with an infected individual or fecal-oral infected individual or fecal-oral contamination during is the mode of contamination during is the mode of spread.spread.

Hepatitis A VirusHepatitis A Virus This accounts for most cases of This accounts for most cases of

outbreaks in institutional settings outbreaks in institutional settings such as schools and nurseries and such as schools and nurseries and the waterborne epidemics in places the waterborne epidemics in places where people live in overcrowded, where people live in overcrowded, unsanitary conditions.unsanitary conditions.

Infected workers in the food Infected workers in the food industry may also be the source of industry may also be the source of outbreaksoutbreaks

Hepatitis A VirusHepatitis A Virus

HAV is not shed in any significant HAV is not shed in any significant quantities in saliva, urine, or semen. quantities in saliva, urine, or semen.

Because HAV viremia is transient, Because HAV viremia is transient, blood-borne transmission of HAV blood-borne transmission of HAV occurs only rarely; therefore, occurs only rarely; therefore, donated blood is not specifically donated blood is not specifically screened for this virus.screened for this virus.

Serologic Diagnosis of HAVSerologic Diagnosis of HAV

Acute infection is marked by Acute infection is marked by anti-HAV IgM in serumanti-HAV IgM in serum

IgG appears as IgM declines IgG appears as IgM declines (with in a few months) and can (with in a few months) and can persist for years, conferring persist for years, conferring immunity.immunity.

Hepatitis B VirusHepatitis B Virus

Hepatitis B virus (HBV) can produce Hepatitis B virus (HBV) can produce (1) an asymptomatic carrier state(1) an asymptomatic carrier state (2) acute hepatitis with recovery (2) acute hepatitis with recovery (3) chronic hepatitis, either indolent or (3) chronic hepatitis, either indolent or

progressiveprogressive (4) progression to cirrhosis, (4) progression to cirrhosis, (5) fulminant hepatitis with massive liver (5) fulminant hepatitis with massive liver

necrosis, and necrosis, and (6) the backdrop for hepatitis D virus infection. (6) the backdrop for hepatitis D virus infection. HBV also plays an important role in the HBV also plays an important role in the

development of hepatocellular carcinoma. development of hepatocellular carcinoma.

Hepatitis B VirusHepatitis B Virus Liver disease due to HBV is an enormous Liver disease due to HBV is an enormous

problem globally, with an estimated problem globally, with an estimated worldwide carrier rate of 350 million. It is worldwide carrier rate of 350 million. It is estimated that HBV has infected over 2 estimated that HBV has infected over 2 billion of the individuals alive today at some billion of the individuals alive today at some point in their lives. Seventy-five percent of point in their lives. Seventy-five percent of all chronic carriers live in Asia and the all chronic carriers live in Asia and the Western Pacific rim. Western Pacific rim.

Because circulating host IgG antibodies Because circulating host IgG antibodies effectively neutralize HBV, the HBV vaccine effectively neutralize HBV, the HBV vaccine has been highly effective in reducing the has been highly effective in reducing the prevalence of HBV in endemic areas.prevalence of HBV in endemic areas.


HBV is a member of the Hepadnaviridae, HBV is a member of the Hepadnaviridae, a family of DNA-containing viruse. a family of DNA-containing viruse.

The mature HBV virion is a 42-nm, The mature HBV virion is a 42-nm, spherical double-layered "Dane particle" spherical double-layered "Dane particle" that has an outer surface envelope of that has an outer surface envelope of protein, lipid, and carbohydrate and an protein, lipid, and carbohydrate and an inner 28-nm core particle (nucleocapsid) inner 28-nm core particle (nucleocapsid) containing DNA polymerase and double containing DNA polymerase and double stranded circular DNA.stranded circular DNA.


Three major antigens are associated Three major antigens are associated with HBVwith HBV

An outer coat antigen called as An outer coat antigen called as HBsAg/Australia antigen (hepatitis HBsAg/Australia antigen (hepatitis surface antigen).surface antigen).

2 antigens associated with the viral 2 antigens associated with the viral nucleocapsid core, HBcAg (core nucleocapsid core, HBcAg (core antigen) and HBeAg. antigen) and HBeAg.


HBV has a prolonged incubation HBV has a prolonged incubation period (4 to 26 weeks). period (4 to 26 weeks).

It is present in all physiologic and It is present in all physiologic and pathologic body fluids, with the pathologic body fluids, with the exception of stool. exception of stool.

HBV is a hardy virus and can HBV is a hardy virus and can withstand extremes of temperature withstand extremes of temperature and humidity. and humidity.


It spreads mainly by parenteral It spreads mainly by parenteral routes (transfusion, blood products, routes (transfusion, blood products, needle-stick accidents, shared needle-stick accidents, shared needles among drug addicts and to needles among drug addicts and to new born infants during parturition), new born infants during parturition), or via body fluids (saliva, semen, and or via body fluids (saliva, semen, and vaginal fluid), hence the risk of vaginal fluid), hence the risk of sexual transmission. Health care sexual transmission. Health care workers are also at risk. workers are also at risk.

Hepatitis B VirusHepatitis B Virus Blood and body fluids are the primary vehicles of Blood and body fluids are the primary vehicles of

transmission, virus may also be spread by transmission, virus may also be spread by contact with body secretions such as semen, contact with body secretions such as semen, saliva, sweat, tears, breast milk, and pathologic saliva, sweat, tears, breast milk, and pathologic effusions.effusions.

Transfusion, blood products, dialysis, needle-Transfusion, blood products, dialysis, needle-stick accidents among health care workers, stick accidents among health care workers, intravenous drug abuse, and homosexual activity intravenous drug abuse, and homosexual activity constitute the primary risk categories for HBV constitute the primary risk categories for HBV infection.infection.

In endemic regions such as Africa and Southeast In endemic regions such as Africa and Southeast Asia, spread from an infected mother to a Asia, spread from an infected mother to a neonate during birth (neonate during birth (vertical transmissionvertical transmission) is ) is common. These neonatal infections often lead to common. These neonatal infections often lead to the carrier state for life the carrier state for life

Hepatitis B Virus: Hepatitis B Virus: Serologic Serologic DiagnosisDiagnosis

After exposure to HBV, the long After exposure to HBV, the long asymptomatic 4- to 26-week incubation asymptomatic 4- to 26-week incubation period (mean: 6 to 8 weeks) is followed period (mean: 6 to 8 weeks) is followed by acute disease lasting many weeks to by acute disease lasting many weeks to months. Most patients experience a self-months. Most patients experience a self-limited illness. limited illness.

HBsAg appears before the onset of HBsAg appears before the onset of symptoms, peaks during overt disease, symptoms, peaks during overt disease, and then declines to undetectable levels and then declines to undetectable levels in 3 to 6 months. It is a marker of active in 3 to 6 months. It is a marker of active infection.infection.


HBeAg, HBV-DNA, and DNA HBeAg, HBV-DNA, and DNA polymerase appear in the serum polymerase appear in the serum soon after HBsAg before the onset of soon after HBsAg before the onset of acute disease, and all signify active acute disease, and all signify active viral replication. viral replication.

HBeAg usually declines within HBeAg usually declines within weeks and persustence indicates weeks and persustence indicates probable progression to chronic probable progression to chronic disease.disease.


IgM anti-HBc is the first antibody to appear IgM anti-HBc is the first antibody to appear and it becomes detectable in serum shortly and it becomes detectable in serum shortly before the onset of symptoms, concurrent before the onset of symptoms, concurrent with the onset of elevation of serum with the onset of elevation of serum aminotransferases. Over months, the IgM aminotransferases. Over months, the IgM antibody is replaced by IgG anti-HBc.antibody is replaced by IgG anti-HBc.

Anti-HBe follows IgM anti-HBc and is Anti-HBe follows IgM anti-HBc and is detectable shortly after the disappearance detectable shortly after the disappearance of HBeAg, implying that the acute infection of HBeAg, implying that the acute infection has peaked and the disease is on the wane. has peaked and the disease is on the wane.


IgG anti-HBs does not rise until the IgG anti-HBs does not rise until the acute disease is over and is usually not acute disease is over and is usually not detectable for a few weeks to several detectable for a few weeks to several months after the disappearance of months after the disappearance of HBsAg. It signifyies the end of acute HBsAg. It signifyies the end of acute disease and persists for years disease and persists for years conferring immunity and protection. conferring immunity and protection. This is the basis for current vaccination This is the basis for current vaccination strategies using noninfectious HBsAgstrategies using noninfectious HBsAg

Figure 18-11 Sequence of serologic markers for hepatitis B viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic infection.

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Hepatitis B Virus Hepatitis B Virus carrier carrier state state

The carrier state is defined by the The carrier state is defined by the presence of HBsAg in serum for 6 presence of HBsAg in serum for 6 months or longer after initial months or longer after initial detection. detection.

90% of infants infected at birth 90% of infants infected at birth become carriers.become carriers.

Hepatitis C virusHepatitis C virus

HCV is a major cause of liver disease HCV is a major cause of liver disease worldwide. worldwide.

Causes 90% of transfusion-associated hepatitis.Causes 90% of transfusion-associated hepatitis. Patients have greater predilection to develop Patients have greater predilection to develop

chronic liver disease then with HBV chronic liver disease then with HBV and and cirrhosis eventually occurs in approximately cirrhosis eventually occurs in approximately 20% of patients with chronic HCV infection20% of patients with chronic HCV infection

Hence, the prevalence of life-limiting chronic Hence, the prevalence of life-limiting chronic liver disease and the risk of hepatocellular liver disease and the risk of hepatocellular carcinoma are only expected to increase.carcinoma are only expected to increase.

Hepatitis C VirusHepatitis C Virus

The major routes of transmission are The major routes of transmission are inoculations and blood transfusions inoculations and blood transfusions

intravenous drug users, hemophilacs and intravenous drug users, hemophilacs and hemodialysis patients are the primary hemodialysis patients are the primary risk group. Health care workers are also risk group. Health care workers are also at risk. at risk.

Sexual transmission is rare.Sexual transmission is rare.


A characteristic feature of HCV A characteristic feature of HCV infection, is repeated bouts of infection, is repeated bouts of hepatic damage. hepatic damage. Persistent infection Persistent infection and chronic hepatitis are the and chronic hepatitis are the hallmarks of HCV infectionhallmarks of HCV infection, despite , despite the generally asymptomatic nature the generally asymptomatic nature of the acute illness. of the acute illness.

Cirrhosis may develop over 5 to 20 Cirrhosis may develop over 5 to 20 years after acute infection.years after acute infection.


HCV is a hepacivirus and HCV is a hepacivirus and occupies a genus in the occupies a genus in the Flaviviridae family. HCV is a Flaviviridae family. HCV is a small, enveloped, single-small, enveloped, single-stranded RNA virus. stranded RNA virus.

The incubation period for HCV The incubation period for HCV hepatitis ranges from 2 to 26 hepatitis ranges from 2 to 26 weeks. weeks.

Serologic Diagnosis of HCVSerologic Diagnosis of HCV

HCV RNA is detectable in blood for 1 to HCV RNA is detectable in blood for 1 to 3 weeks during active infection, 3 weeks during active infection, coincident with elevations in serum coincident with elevations in serum transaminases .transaminases .

In acute HCV infection, anti-HCV In acute HCV infection, anti-HCV antibodies are detected. The clinical antibodies are detected. The clinical course of acute HCV hepatitis is milder course of acute HCV hepatitis is milder than that of HBV; rare cases may be than that of HBV; rare cases may be severe.severe.

Serologic Diagnosis of HCVSerologic Diagnosis of HCV

In chronic HCV infection, circulating HCV In chronic HCV infection, circulating HCV RNA persists in many patients despite the RNA persists in many patients despite the presence of neutralizing antibodies. presence of neutralizing antibodies.

A clinical feature that is quite characteristic A clinical feature that is quite characteristic of chronic HCV infection is episodic of chronic HCV infection is episodic elevations in serum aminotransferases, with elevations in serum aminotransferases, with intervening normal or near-normal periodsintervening normal or near-normal periods. .

Note: elevated titers of anti-HCV IgG Note: elevated titers of anti-HCV IgG following active infection do not confer following active infection do not confer effective immunity.effective immunity.

HEPATITIS D VIRUSHEPATITIS D VIRUS

Also called "hepatitis delta virus," Also called "hepatitis delta virus," hepatitis D virus (HDV) is a unique hepatitis D virus (HDV) is a unique single stranded RNA virus that is single stranded RNA virus that is replication defective, causing infection replication defective, causing infection only when it is encapsulated by HBsAg. only when it is encapsulated by HBsAg.

Thus, Thus, HDV is absolutelyHDV is absolutely dependent on dependent on the genetic information provided by the genetic information provided by HBV for multiplication and causes HBV for multiplication and causes hepatitis only in the presence of HBVhepatitis only in the presence of HBV. .

Delta hepatitis thus arises in two Delta hepatitis thus arises in two settings settings

Acute Acute coinfectioncoinfection by HDV and HBV. by HDV and HBV. SuperinfectionSuperinfection of a chronic carrier of a chronic carrier

of HBV by HDV . The carrier may of HBV by HDV . The carrier may have been previously "healthy" or have been previously "healthy" or may have had underlying chronic may have had underlying chronic hepatitishepatitis

Hepatitis D VirusHepatitis D Virus

The virus is probably transmitted The virus is probably transmitted much in the same manner as HBV.much in the same manner as HBV.


When HDV is superimposed on chronic When HDV is superimposed on chronic HBV infection, there are three possible HBV infection, there are three possible outcomes: outcomes:

(1)(1) acute, severe hepatitis may erupt in a acute, severe hepatitis may erupt in a previously healthy HBV carrier; previously healthy HBV carrier;

(2)(2) mild HBV hepatitis may be converted mild HBV hepatitis may be converted into fulminant disease; and/or into fulminant disease; and/or

(3)(3) chronic, progressive disease may chronic, progressive disease may develop (in 80% of patients), often develop (in 80% of patients), often culminating in cirrhosisculminating in cirrhosis


HDV resembles the "Dane particle" HDV resembles the "Dane particle" of HBV with a single stranded RNA. of HBV with a single stranded RNA.

Serology: HDV-RNA is present in Serology: HDV-RNA is present in blood and in liver just before and in blood and in liver just before and in initial acute phase of infection.initial acute phase of infection.

Hepatitis E virusHepatitis E virus HEV hepatitis is an enterically HEV hepatitis is an enterically

transmitted, water-borne infection that transmitted, water-borne infection that occurs primarily in young to middle-aged occurs primarily in young to middle-aged adults.adults.

Epidemics have been reported from Epidemics have been reported from Asia , Africa, and Mexico. Asia , Africa, and Mexico.

It has a high mortality rate in pregnant It has a high mortality rate in pregnant women (20%).women (20%).

In most cases, the disease is self-limiting; In most cases, the disease is self-limiting; HEV is not associated with chronic liver HEV is not associated with chronic liver disease.disease.

Hepatitis E virusHepatitis E virus

The average incubation period The average incubation period following exposure is 6 weeks. following exposure is 6 weeks.

HEV is an unenveloped, single-HEV is an unenveloped, single-stranded RNA Caliciviridae virus .stranded RNA Caliciviridae virus .

A specific antigen (HEV Ag) can be A specific antigen (HEV Ag) can be identified in the cytoplasm of identified in the cytoplasm of hepatocytes during active infection, hepatocytes during active infection, and virions are shed in stool during and virions are shed in stool during the acute illness. the acute illness.

HepatHepatitis A itis A VirusVirus

Hepatitis B Hepatitis B VirusVirus

Hepatitis C Hepatitis C VirusVirus

Hepatitis Hepatitis D VirusD Virus

HepHepatitiatitis E s E

ViruViruss

HepatiHepatitis G tis G VirusVirus

AgentAgent IcosahIcosahedral edral capsidcapsid, , ssRNAssRNA

Enveloped Enveloped dsDNAdsDNA

Enveloped Enveloped ssRNAssRNA

Enveloped Enveloped ssRNAssRNA

UnenUnenvelopveloped ed ssRNssRNAA

ssRNA ssRNA virusvirus

TransTransmissiomissionn

Fecal-Fecal-oraloral

Parenteral; Parenteral; close contactclose contact

Parenteral; Parenteral; close contactclose contact

Parenteral; Parenteral; close close contactcontact

WateWaterborrbornene

ParentParenteraleral

IncubIncubation ation periodperiod

2-6 wk2-6 wk 4-26 wk4-26 wk 2-26 wk2-26 wk 4-7 wk4-7 wk 2-8 2-8 wkwk

UnknoUnknownwn

CarrieCarrier r statestate

NoneNone 0.1-1.0% of 0.1-1.0% of blood donors blood donors in U.S. and in U.S. and Western worldWestern world

0.2-1.0% of 0.2-1.0% of blood donors blood donors in U.S. and in U.S. and Western worldWestern world

1-10% in 1-10% in drug drug addicts and addicts and hemophiliahemophiliacscs

UnkUnknownownn

1-2% 1-2% of of blood blood donors donors in U.S.in U.S.

ChronChronic ic hepatihepatitistis

NoneNone 5-10% of 5-10% of acute acute infectionsinfections

>50%>50% <5% <5% coinfection, coinfection, 80% upon 80% upon superinfectsuperinfectionion

NoneNone NoneNone

HepatHepatocelluocellular lar carcincarcinomaoma

NoNo YesYes YesYes No No increase increase above HBVabove HBV

UnkUnknownown, n, but but unlikunlikelyely

NoneNone

Clinical features of Clinical features of hepatitishepatitis

A number of clinical syndromes A number of clinical syndromes may develop following exposure may develop following exposure to hepatitis viruses (each of the to hepatitis viruses (each of the hepatotropic viruses can cause hepatotropic viruses can cause acute asymptomatic or acute asymptomatic or symptomatic infection):symptomatic infection):

Clinical features of Clinical features of hepatitis hepatitis

Acute asymptomatic infectionAcute asymptomatic infection with with recovery: serologic evidence only recovery: serologic evidence only

Acute symptomatic hepatitisAcute symptomatic hepatitis with with recovery: anicteric or icteric recovery: anicteric or icteric

Chronic hepatitisChronic hepatitis: without or with : without or with progression to cirrhosis progression to cirrhosis

Fulminant hepatitisFulminant hepatitis: with massive : with massive to submassive hepatic necrosisto submassive hepatic necrosis

Carrier state Carrier state

Acute Asymptomatic Acute Asymptomatic Infection with Recovery Infection with Recovery

Patients in this group are identified Patients in this group are identified only incidentally on the basis of only incidentally on the basis of minimally elevated serum minimally elevated serum transaminases or, after the fact, by transaminases or, after the fact, by the presence of antiviral antibodies. the presence of antiviral antibodies. Worldwide, HAV and HBV infection Worldwide, HAV and HBV infection are frequently subclinical events in are frequently subclinical events in childhood.childhood.

Acute Symptomatic Acute Symptomatic Infection with Recovery Infection with Recovery

Any one of the hepatotropic viruses can cause Any one of the hepatotropic viruses can cause symptomatic acute viral hepatitis, although this symptomatic acute viral hepatitis, although this is uncommon for acute HCV infection. is uncommon for acute HCV infection. Whatever the agent, Whatever the agent, the disease is more or less the disease is more or less the same and can be divided into four phases: the same and can be divided into four phases:

(1)(1) an incubation period, an incubation period, (2)(2) a symptomatic preicteric phase, a symptomatic preicteric phase, (3)(3) a symptomatic icteric phase, and a symptomatic icteric phase, and (4)(4) convalescence.convalescence. Peak infectivity occurs during the last Peak infectivity occurs during the last

asymptomatic days of the incubation period asymptomatic days of the incubation period and the early days of acute symptoms and the early days of acute symptoms

Acute Symptomatic Acute Symptomatic Infection with Recovery: Infection with Recovery:

preicteric phasepreicteric phase The The preicteric phasepreicteric phase is marked by is marked by

nonspecific, constitutional symptoms. nonspecific, constitutional symptoms. Malaise is followed in a few days by Malaise is followed in a few days by general fatigability, nausea, and loss of general fatigability, nausea, and loss of appetite. Weight loss, low-grade fever, appetite. Weight loss, low-grade fever, headaches, muscle and joint aches, and headaches, muscle and joint aches, and pains and diarrhea are inconstant pains and diarrhea are inconstant symptoms.symptoms.

Physical examination reveals a mildly Physical examination reveals a mildly enlarged, tender liver. enlarged, tender liver.


icteric phaseicteric phase The The icteric phaseicteric phase, is caused mainly by , is caused mainly by

conjugated hyperbilirubinemia. conjugated hyperbilirubinemia. Curiously, as jaundice appears and these Curiously, as jaundice appears and these

patients enter the icteric phase, other patients enter the icteric phase, other symptoms begin to abate and the patient symptoms begin to abate and the patient feels better. The jaundice is caused feels better. The jaundice is caused predominantly by conjugated predominantly by conjugated hyperbilirubinemia and hence is accompanied hyperbilirubinemia and hence is accompanied by dark-colored urine related to the presence by dark-colored urine related to the presence of conjugated bilirubin. The stools may of conjugated bilirubin. The stools may become lighter owing to cholestasis.become lighter owing to cholestasis.


icteric phaseicteric phase Retention of bile acids can cause distressing Retention of bile acids can cause distressing

pruritus. The liver may be mildly enlarged pruritus. The liver may be mildly enlarged and moderately tender to percussion. and moderately tender to percussion.

Laboratory findings include elevated serum Laboratory findings include elevated serum liver enzymes, prolonged prothrombin time liver enzymes, prolonged prothrombin time and hyperglobulinemia, hyperbilirubinemia; and hyperglobulinemia, hyperbilirubinemia; the serum alkaline phosphatase is usually the serum alkaline phosphatase is usually only mildly elevated. only mildly elevated.

In a few weeks to perhaps several months, In a few weeks to perhaps several months, the jaundice and most of the other systemic the jaundice and most of the other systemic symptoms clear as convalescence begins. symptoms clear as convalescence begins.

Key Morphologic Features of Key Morphologic Features of Acute Acute ViralViral Hepatitis Hepatitis

Enlarged, reddened liver; greenish if cholestaticEnlarged, reddened liver; greenish if cholestatic Parenchymal changesParenchymal changes:: -Hepatocyte injury: swelling (ballooning -Hepatocyte injury: swelling (ballooning

degeneration)degeneration) -Hepatocyte necrosis: isolated cells or clusters of cells -Hepatocyte necrosis: isolated cells or clusters of cells

or the entire lobule show necrosis: or the entire lobule show necrosis: -hepatocytes can undergo apoptotsis (councilman -hepatocytes can undergo apoptotsis (councilman

bodies). bodies).

--In severe cases: bridging necrosis (portal-portal, In severe cases: bridging necrosis (portal-portal, central-central, portal-central). Macrophages central-central, portal-central). Macrophages (Kupffer cells) engulf necrotic hepatocytes(Kupffer cells) engulf necrotic hepatocytes

-Lobular disarray: loss of normal architecture-Lobular disarray: loss of normal architecture

Key Morphologic Features of Key Morphologic Features of Acute Acute ViralViral Hepatitis Hepatitis

Portal tractsPortal tracts -Inflammation: predominantly -Inflammation: predominantly

mononuclearmononuclear -Inflammatory spillover into adjacent -Inflammatory spillover into adjacent

parenchyma, with hepatocyte necrosis parenchyma, with hepatocyte necrosis called ascalled as iinterface hepatitis/piecemeal nterface hepatitis/piecemeal necrosisnecrosis can occur in both acute and chronic can occur in both acute and chronic hepatitis.hepatitis.

Other findingsOther findings: cholestasis, hypertrophy and : cholestasis, hypertrophy and hyperplasia of Kupffer cells and sinusoidal hyperplasia of Kupffer cells and sinusoidal cells.cells.

A mononuclear inflammatory cell A mononuclear inflammatory cell infiltrate extends from portal areas and infiltrate extends from portal areas and disrupts limiting plate of hepatocytes disrupts limiting plate of hepatocytes

which are undergoing necrosis, which are undergoing necrosis, (piecemeal) necrosis of chronic active (piecemeal) necrosis of chronic active

hepatitishepatitis. .

Hepatitis B: large pink cell undergoing Hepatitis B: large pink cell undergoing "ballooning degeneration" (right "ballooning degeneration" (right

arrow). At later stage, a dying arrow). At later stage, a dying hepatocyte is seen shrinking to form an hepatocyte is seen shrinking to form an

eosinophilic "councilman body" (left eosinophilic "councilman body" (left

arrow).arrow).

Chronic hepatitisChronic hepatitis Chronic hepatitis is defined as symptomatic, Chronic hepatitis is defined as symptomatic,

biochemical, or serologic evidence of biochemical, or serologic evidence of continuing or relapsing hepatic disease for continuing or relapsing hepatic disease for more than 6 months, with histologically more than 6 months, with histologically documented inflammation and necrosis.documented inflammation and necrosis.

Although the hepatitis viruses (HBV, HCV, and Although the hepatitis viruses (HBV, HCV, and HBV + HDV) are responsible for most cases of HBV + HDV) are responsible for most cases of chronic hepatitis, there are many other causes chronic hepatitis, there are many other causes of chronic hepatitis and they include chronic of chronic hepatitis and they include chronic alcoholism, Wilson disease, α1-antitrypsin alcoholism, Wilson disease, α1-antitrypsin deficiency, various drugs and autoimmunity.deficiency, various drugs and autoimmunity.

In all instances of chronic hepatitis, etiology is In all instances of chronic hepatitis, etiology is the single most important indicator of the single most important indicator of likelihood to progress to cirrhosis.likelihood to progress to cirrhosis.

Chronic viral hepatitisChronic viral hepatitis

Chronic viral hepatitis constitutes a Chronic viral hepatitis constitutes a "carrier" state, in that these individuals "carrier" state, in that these individuals harbor replicating virus and therefore can harbor replicating virus and therefore can transmit an organism.transmit an organism. With "carriers" of With "carriers" of hepatotropic viruses, there are hepatotropic viruses, there are

(1)(1)those who harbor one or more of the viruses those who harbor one or more of the viruses but are suffering little or no adverse clinical but are suffering little or no adverse clinical or histologic effects (healthy carriers) or histologic effects (healthy carriers)

(2)(2)those who have chronic disease by those who have chronic disease by laboratory or histologic findings but are laboratory or histologic findings but are essentially free of symptoms or disabilityessentially free of symptoms or disability

(3)(3)those who have clinically symptomatic those who have clinically symptomatic chronic disease. chronic disease.

Chronic viral hepatitisChronic viral hepatitis

All constitute reservoirs of infection. In the All constitute reservoirs of infection. In the case of HBV, infection early in life, case of HBV, infection early in life, particularly via vertical transmission particularly via vertical transmission during childbirth, produces a carrier state during childbirth, produces a carrier state 90% to 95% of the time. In contrast, only 90% to 95% of the time. In contrast, only 1% to 10% of adult HBV infections yield a 1% to 10% of adult HBV infections yield a carrier state. carrier state. Individuals with impaired Individuals with impaired immunity are particularly likely to become immunity are particularly likely to become HBV carriersHBV carriers. HCV can clearly induce a . HCV can clearly induce a carrier state given its high rate of carrier state given its high rate of chronicity.chronicity.

Chronic Hepatitis, morphologyChronic Hepatitis, morphology

Some changes are shared with acute hepatitis.Some changes are shared with acute hepatitis. Hepatocyte injury, necrosis, and regenerationHepatocyte injury, necrosis, and regeneration Sinusoidal cell reactive changesSinusoidal cell reactive changes Portal tract Inflammation:Portal tract Inflammation: -Confined to portal tracts, -Confined to portal tracts, oror -Spillover into adjacent parenchyma, with necrosis of -Spillover into adjacent parenchyma, with necrosis of

hepatocytes ("interface hepatitis"), hepatocytes ("interface hepatitis"), oror -Bridging inflammation and necrosis-Bridging inflammation and necrosis Fibrosis: Fibrosis: -continued loss of hepatocytes results in fibrous septa -continued loss of hepatocytes results in fibrous septa

formation which ultimately leads to cirrhosisformation which ultimately leads to cirrhosis HBV: "ground-glass" hepatocytes, "sanded" nucleiHBV: "ground-glass" hepatocytes, "sanded" nuclei HCV: bile duct damage, lymphoid aggregate formationHCV: bile duct damage, lymphoid aggregate formation Cirrhosis: The end-stage outcomeCirrhosis: The end-stage outcome

Viral hepatitis C which is at a high Viral hepatitis C which is at a high stage with extensive fibrosis and stage with extensive fibrosis and

progression to macronodular cirrhosis, progression to macronodular cirrhosis, as evidenced by the large regenerative as evidenced by the large regenerative

nodule at the center right.nodule at the center right.

Morphology of Acute and Morphology of Acute and Chronic HepatitisChronic Hepatitis

HBV-infected hepatocytes may HBV-infected hepatocytes may exhibit a cytoplasm packed with exhibit a cytoplasm packed with spheres and tubules of HBsAg, spheres and tubules of HBsAg, producing a finely granular producing a finely granular eosinophilic cytoplasm (eosinophilic cytoplasm ("ground "ground glass hepatocytes,"glass hepatocytes," . .

HCV-infected livers frequently show HCV-infected livers frequently show lymphoid aggregates within portal lymphoid aggregates within portal tracts and macrovesicular steatosis. tracts and macrovesicular steatosis.

Chronic Hepatitis.Chronic Hepatitis. The histologic features of The histologic features of chronic hepatitis range from exceedingly mild chronic hepatitis range from exceedingly mild to severe. In the mildest forms, inflammation to severe. In the mildest forms, inflammation is only in portal tracts and consists mainly of is only in portal tracts and consists mainly of lymphocytes and macrophages. lymphocytes and macrophages.

The hallmark of irreversible liver damage The hallmark of irreversible liver damage is the deposition of fibrous tissue.is the deposition of fibrous tissue. At first, At first, only portal tracts exhibit increased fibrosis, only portal tracts exhibit increased fibrosis, but with time, but with time, periportalperiportal septal septal fibrosisfibrosis occurs, followed by linking of fibrous septa occurs, followed by linking of fibrous septa between lobules (between lobules (bridging fibrosisbridging fibrosis). ).

The extent of chronic hepatitis can The extent of chronic hepatitis can be be gradedgraded by the degree of activity by the degree of activity (necrosis and inflammation) and (necrosis and inflammation) and stagedstaged by the degree of fibrosis. by the degree of fibrosis.

clinical courseclinical course

The clinical course of viral hepatitis is The clinical course of viral hepatitis is unpredictable. Patients may experience unpredictable. Patients may experience spontaneous remission or may have indolent spontaneous remission or may have indolent disease without progression for many years. disease without progression for many years. Conversely, some patients have rapidly Conversely, some patients have rapidly progressive disease and develop cirrhosis progressive disease and develop cirrhosis within a few years. The major causes of death within a few years. The major causes of death are cirrhosis, with liver failure and hepatic are cirrhosis, with liver failure and hepatic encephalopathy or massive hematemesis from encephalopathy or massive hematemesis from esophageal varices, and hepatocellular esophageal varices, and hepatocellular carcinoma in those with long-standing HBV carcinoma in those with long-standing HBV (particularly neonatal) or HCV infection (particularly neonatal) or HCV infection

fulminant hepatitisfulminant hepatitis When hepatic insufficiency progresses from onset of When hepatic insufficiency progresses from onset of

symptoms to hepatic encephalopathy within 2 to 3 symptoms to hepatic encephalopathy within 2 to 3 weeks, it is termed weeks, it is termed fulminant hepatic failurefulminant hepatic failure. A less rapid . A less rapid course, extending up to 3 months, is called course, extending up to 3 months, is called subfulminant subfulminant failurefailure. Causes of include. Causes of include

1)1) Acute viral hepatitisAcute viral hepatitis2)2) Acute drug induced hepatitis eg Acute drug induced hepatitis eg acetaminophen, ,

isoniazid etc. etc. 3)3) Acute hepatitis due to poisoning eg. exposure to the Acute hepatitis due to poisoning eg. exposure to the

mycotoxins of the mushroom mycotoxins of the mushroom Amanita phalloidesAmanita phalloides 4)4) Others eg. ischemic hepatic necrosis, obstruction of the Others eg. ischemic hepatic necrosis, obstruction of the

hepatic veins, massive malignant infiltration of the liver, hepatic veins, massive malignant infiltration of the liver, Wilson disease, hyperthermia (heat stroke), and Wilson disease, hyperthermia (heat stroke), and microvesicular steatosis syndromes, particularly acute microvesicular steatosis syndromes, particularly acute fatty liver of pregnancy. fatty liver of pregnancy.

Autoimmune hepatitisAutoimmune hepatitis is a chronic hepatitis with histologic features like is a chronic hepatitis with histologic features like

that of chronic viral hepatitis. This disease may that of chronic viral hepatitis. This disease may run an indolent or severe course; salient features run an indolent or severe course; salient features include the following:include the following:

Female predominance, particularly in young and Female predominance, particularly in young and perimenopausal women. perimenopausal women.

The absence of viral serologic markers The absence of viral serologic markers Elevated serum IgG and γ-globulin levels (>1.5 Elevated serum IgG and γ-globulin levels (>1.5

times normal) times normal) High serum titers of autoantibodies in 80% of High serum titers of autoantibodies in 80% of

cases, including antinuclear (ANA), antismooth cases, including antinuclear (ANA), antismooth muscle (SMA) etc.muscle (SMA) etc.

Negative anti-mitochondrial antibodiesNegative anti-mitochondrial antibodies

Autoimmune hepatitisAutoimmune hepatitis

In untreated severe disease, as many as In untreated severe disease, as many as 40% of patients die within 6 months of 40% of patients die within 6 months of diagnosis, and cirrhosis develops in at diagnosis, and cirrhosis develops in at least 40% of survivors.least 40% of survivors.

Treatment include immunosuppressive Treatment include immunosuppressive therapy, and liver transplantation. therapy, and liver transplantation.

Associated with other autoimmune Associated with other autoimmune diseases eg. Rheumatoid arthritis, diseases eg. Rheumatoid arthritis, Sjogren’s syndrome etc.Sjogren’s syndrome etc.

Intrahepatic Biliary Intrahepatic Biliary Tract Disease Tract Disease

three disorders of intrahepatic bile three disorders of intrahepatic bile ductsducts

secondary biliary cirrhosissecondary biliary cirrhosis primary biliary cirrhosisprimary biliary cirrhosis primary sclerosing cholangitis primary sclerosing cholangitis

Secondary biliary Secondary biliary cirrhosiscirrhosis

Prolonged obstruction of the extrahepatic Prolonged obstruction of the extrahepatic biliary tree results in profound alteration of biliary tree results in profound alteration of the liver itself. the liver itself.

The most common cause of obstruction in The most common cause of obstruction in adults is extrahepatic cholelithiasis adults is extrahepatic cholelithiasis (gallstones), followed by malignancies of the (gallstones), followed by malignancies of the biliary tree or head of the pancreas and biliary tree or head of the pancreas and strictures resulting from previous surgical strictures resulting from previous surgical procedures. Obstructive conditions in procedures. Obstructive conditions in children include biliary atresia, cystic children include biliary atresia, cystic fibrosis, choledochal cysts (a cystic anomaly fibrosis, choledochal cysts (a cystic anomaly of the extrahepatic biliary tree). of the extrahepatic biliary tree).

Secondary biliary cirrhosis: Secondary biliary cirrhosis: morphologymorphology

Secondary inflammation resulting from biliary Secondary inflammation resulting from biliary obstruction initiates periportal fibrosis, which obstruction initiates periportal fibrosis, which eventually leads to hepatic scarring and nodule eventually leads to hepatic scarring and nodule formation, generating secondary biliary formation, generating secondary biliary cirrhosis. cirrhosis.

Subtotal obstruction may promote secondary Subtotal obstruction may promote secondary bacterial infection of the biliary tree (bacterial infection of the biliary tree (ascending ascending cholangitischolangitis), which aggravates the ), which aggravates the inflammatory injury. Enteric organisms such as inflammatory injury. Enteric organisms such as coliforms and enterococci are common culprits. coliforms and enterococci are common culprits.

Etiology Extrahepatic bile duct obstruction: biliary atresia, gallstones, stricture, carcinoma of pancreatic head

Sex predilection Symptoms and signs

None.Pruritus, jaundice, malaise, dark urine, light stools, hepatosplenomegaly

Laboratory findings Conjugated hyperbilirubinemia, increased serum alkaline phosphatase, bile acids, cholesterol

Important pathologic findings before cirrhosis develops

Prominent bile stasis in bile ducts, bile ductular proliferation with surrounding neutrophils, portal tract edema

Secondary biliary Secondary biliary cirrhosiscirrhosis

Primary biliary cirrhosisPrimary biliary cirrhosis

Primary biliary cirrhosis is a chronic, Primary biliary cirrhosis is a chronic, progressive, and often fatal cholestatic liver progressive, and often fatal cholestatic liver disease, characterized by the destruction of disease, characterized by the destruction of intrahepatic bile ducts, portal inflammation intrahepatic bile ducts, portal inflammation and scarring, and the eventual development and scarring, and the eventual development of cirrhosis and liver failure. of cirrhosis and liver failure.

The primary feature of this disease is a The primary feature of this disease is a nonsuppurative, inflammatory destruction nonsuppurative, inflammatory destruction of medium-sized intrahepatic bile ducts.of medium-sized intrahepatic bile ducts.

Cirrhosis develops only after many years. Cirrhosis develops only after many years.


middle-aged women, middle-aged women, female:male predominance (6:1). female:male predominance (6:1). Pathogenesis:Pathogenesis: autoimmune autoimmune

etiology.etiology.


Clinical features include pruritus, Clinical features include pruritus, jaundice, hepatomegaly. Xanthomas and jaundice, hepatomegaly. Xanthomas and xanthelasmas arise owing to cholesterol xanthelasmas arise owing to cholesterol retention. . Over a period of time patients retention. . Over a period of time patients develop portal hypertension and hepatic develop portal hypertension and hepatic encephalopathy. Serum alkaline encephalopathy. Serum alkaline phosphatase and cholesterol are elevated; phosphatase and cholesterol are elevated; hyperbilirubinemia is a late development . hyperbilirubinemia is a late development . 90% of patients have circulating 90% of patients have circulating "antimitochrondrial antibodies.""antimitochrondrial antibodies."


Morphology.Morphology. During the precirrhotic stage, portal tracts During the precirrhotic stage, portal tracts

and bile ducts are infiltrated by lymphocytes and bile ducts are infiltrated by lymphocytes and may exhibit noncaseating and may exhibit noncaseating granulomatous inflammation. There is bile granulomatous inflammation. There is bile duct destruction. duct destruction.

With time, there is bile ductular With time, there is bile ductular proliferation, inflammation, and necrosis of proliferation, inflammation, and necrosis of the adjacent periportal hepatic parenchyma.the adjacent periportal hepatic parenchyma.

Over years to decades, relentless portal Over years to decades, relentless portal tract scarring and bridging fibrosis lead to tract scarring and bridging fibrosis lead to cirrhosis. cirrhosis.


In most cases, the end-stage In most cases, the end-stage picture is indistinguishable from picture is indistinguishable from secondary biliary cirrhosis or the secondary biliary cirrhosis or the cirrhosis that follows chronic cirrhosis that follows chronic hepatitis from other causeshepatitis from other causes

Primary biliary cirrhosisPrimary biliary cirrhosisEtiology


Laboratory findings


Possibly autoimmune

Female to male: 6:1 Same as secondary biliary cirrhosis

Same as secondary biliary cirrhosis, plus elevated serum autoantibodies (especially antimitochondrial antibody-AMA)

Dense lymphocytic infiltrate in portal tracts with granulomatous destruction of bile ducts

Primary sclerosing Primary sclerosing cholangitischolangitis

Primary sclerosing cholangitis is characterized Primary sclerosing cholangitis is characterized by inflammation and obliterative fibrosis of by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, with intrahepatic and extrahepatic bile ducts, with dilation of preserved segments.dilation of preserved segments.

Characteristic "beading" of a barium column in Characteristic "beading" of a barium column in radiographs of the intrahepatic and radiographs of the intrahepatic and extrahepatic biliary tree is attributable to the extrahepatic biliary tree is attributable to the irregular strictures and dilations of affected irregular strictures and dilations of affected bile ducts. bile ducts.

It is commonly seen in association with It is commonly seen in association with inflammatory bowel diseaseinflammatory bowel disease , particularly , particularly chronic ulcerative colitis,chronic ulcerative colitis,

males predominate 2:1 males predominate 2:1 Pathogenesis: Pathogenesis: unknown. unknown.

Primary sclerosing cholangitis: Primary sclerosing cholangitis: MorphologyMorphology

Primary sclerosing cholangitis is a Primary sclerosing cholangitis is a fibrosing cholangitis of bile ducts, with a fibrosing cholangitis of bile ducts, with a lymphocytic infiltrate, progressive lymphocytic infiltrate, progressive atrophy of the bile duct epithelium, and atrophy of the bile duct epithelium, and obliteration of the lumenobliteration of the lumen. .

The concentric periductal fibrosis around The concentric periductal fibrosis around affected ducts ("onion-skin fibrosis") is affected ducts ("onion-skin fibrosis") is followed by their disappearance, leaving followed by their disappearance, leaving behind a solid, cordlike fibrous scar. behind a solid, cordlike fibrous scar.

As the disease progresses, the liver becomes As the disease progresses, the liver becomes cirrhotic like that seen with primary and cirrhotic like that seen with primary and secondary biliary cirrhosis secondary biliary cirrhosis

Primary sclerosing Primary sclerosing cholangitischolangitis

Unknown, possibly autoimmune; 50-70% associated with inflammatory bowel disease

Female to male: 1:2 Same as secondary biliary cirrhosis; insidious onset

Same as secondary biliary cirrhosis, plus elevated serum IgM, hypergammaglobulinemia

Periductal portal tract fibrosis, segmental stenosis of extrahepatic and intrahepatic bile ducts

Etiology


Laboratory findings


Alcoholic liver diseaseAlcoholic liver disease

Tumors of LiverTumors of Liver

BENIGN NEOPLASMSBENIGN NEOPLASMS

HEMANGIOMAHEMANGIOMA

The most common benign lesions The most common benign lesions are are cavernous hemangiomascavernous hemangiomas, , blood vessel tumors identical to blood vessel tumors identical to those occurring elsewhere. They those occurring elsewhere. They appear as discrete red-blue, soft appear as discrete red-blue, soft nodules, usually less than 2 cm nodules, usually less than 2 cm in diameter, and often occur in diameter, and often occur directly beneath the capsule.directly beneath the capsule.

Liver cell adenomasLiver cell adenomas

Benign neoplasms developing Benign neoplasms developing from hepatocytes are called from hepatocytes are called liver liver cell asdenomacell asdenoma. These tend to . These tend to occur in young women who have occur in young women who have used oral contraceptives and used oral contraceptives and regress on discontinuance of regress on discontinuance of their use. their use.

Liver cell adenomasLiver cell adenomas

Liver cell adenomas have clinical significance Liver cell adenomas have clinical significance for three reasons: for three reasons:

When they present as an intrahepatic mass, When they present as an intrahepatic mass, they may be mistaken for the more ominous they may be mistaken for the more ominous hepatocellular carcinoma. hepatocellular carcinoma.

Subcapsular adenomas have a tendency to Subcapsular adenomas have a tendency to rupture, particularly during pregnancy (under rupture, particularly during pregnancy (under estrogen stimulation), causing severe estrogen stimulation), causing severe intraperitoneal hemorrhage. intraperitoneal hemorrhage.

Rarely, they may harbor hepatocellular Rarely, they may harbor hepatocellular carcinomacarcinoma

Liver cell adenomas: Liver cell adenomas: Morphology.Morphology.

are pale, yellow-tan well demarcated are pale, yellow-tan well demarcated nodules, found anywhere in the hepatic nodules, found anywhere in the hepatic substance but often beneath the substance but often beneath the capsule. capsule.

On microscopic examination, liver cell On microscopic examination, liver cell adenomas are composed of sheets and adenomas are composed of sheets and cords of cells that may resemble normal cords of cells that may resemble normal hepatocytes. Portal tracts are absent; hepatocytes. Portal tracts are absent; instead, prominent arterial vessels and instead, prominent arterial vessels and draining veins are distributed through draining veins are distributed through the substance of the tumor.the substance of the tumor.

At the upper right is a well-At the upper right is a well-circumscribed neoplasm that is arising circumscribed neoplasm that is arising

in liver. This is an hepatic adenomain liver. This is an hepatic adenoma

The cut surface of the liver reveals The cut surface of the liver reveals the hepatic adenoma. Note how the hepatic adenoma. Note how

well circumscribed it is.well circumscribed it is.

Normal liver with portal tract (left). Normal liver with portal tract (left). Hepatic adenoma seen on right is made Hepatic adenoma seen on right is made

of cells that resemble normal of cells that resemble normal hepatocytes, but tissue is disorganized hepatocytes, but tissue is disorganized

and does not show normal lobular and does not show normal lobular

architecturearchitecture

BILE DUCT ADENOMABILE DUCT ADENOMA

These are usually small encapsulated These are usually small encapsulated spherical, yellow white nodules spherical, yellow white nodules ranging upto 1 cm in diameter.ranging upto 1 cm in diameter.

Microscopically, multiple small acini Microscopically, multiple small acini lined by epithelium similar to that lined by epithelium similar to that present in small bile ducts is seen present in small bile ducts is seen and sre surrounded by fibrous and sre surrounded by fibrous stroma. Unlike liver adenomas, these stroma. Unlike liver adenomas, these are more frequent in males.are more frequent in males.

MALIGNANT TUMORSMALIGNANT TUMORS The liver and lungs are the visceral The liver and lungs are the visceral

organs that are most often involved by organs that are most often involved by metastatic tumors. metastatic tumors.

Primary carcinomas of the liver are Primary carcinomas of the liver are relatively uncommon. Most arise from relatively uncommon. Most arise from hepatocytes and are termed hepatocytes and are termed hepatocellular carcinomahepatocellular carcinoma (HCC). Much (HCC). Much less common are carcinomas of bile less common are carcinomas of bile duct origin, duct origin, cholangiocarcinomascholangiocarcinomas. .

The are two rare forms of primary liver The are two rare forms of primary liver cancer : hepatoblastomas and cancer : hepatoblastomas and angiosarcomas. angiosarcomas.

Hepatocellular Hepatocellular CarcinomasCarcinomas

male predominance male predominance More than 85% of cases of HCC More than 85% of cases of HCC

occur in countries with high rates of occur in countries with high rates of chronic HBV infection.chronic HBV infection. In these In these regions, the HBV carrier state regions, the HBV carrier state begins in infancy following vertical begins in infancy following vertical transmission of virus from infected transmission of virus from infected mothers, conferring a 200-fold mothers, conferring a 200-fold increased risk for HCC by adulthoodincreased risk for HCC by adulthood

Hepatocellular Hepatocellular CarcinomasCarcinomas

In the Western world where HBV is In the Western world where HBV is not prevalent, cirrhosis is present in not prevalent, cirrhosis is present in 85% to 90% of cases of HCC, usually 85% to 90% of cases of HCC, usually in the setting of other chronic liver in the setting of other chronic liver diseases; diseases;

Pathogenesis of HCCPathogenesis of HCC

The following have been implicated in The following have been implicated in human hepatocarcinogenesis: human hepatocarcinogenesis:

1)1) viral infection (HBV, HCV): Extensive viral infection (HBV, HCV): Extensive studies link chronic HBV and chronic studies link chronic HBV and chronic HCV infection with liver cancer. HCV infection with liver cancer.

2)2) Cirrhosis: the development of cirrhosis Cirrhosis: the development of cirrhosis appears to be an important, but not appears to be an important, but not requisite, contributor to the emergence requisite, contributor to the emergence of HCC. of HCC.

3)3) Chronic alcoholism.Chronic alcoholism.

Pathogenesis of HCCPathogenesis of HCC

4) Food contaminants (primarily 4) Food contaminants (primarily aflatoxins from aspergillus). High aflatoxins from aspergillus). High exposure to dietary aflatoxins derived exposure to dietary aflatoxins derived from the fungus from the fungus Aspergillus flavusAspergillus flavus. . These highly carcinogenic toxins are These highly carcinogenic toxins are found in "moldy" grains and peanuts. found in "moldy" grains and peanuts.

5) Other conditions include tyrosinemia 5) Other conditions include tyrosinemia and hereditary hemochromatosis. and hereditary hemochromatosis.

Morphology of HCCMorphology of HCC

Grossly it may be (1) a Grossly it may be (1) a unifocalunifocal mass mass

(2) (2) multifocalmultifocal, multipe nodules of , multipe nodules of variable size; or (3) a variable size; or (3) a diffusely diffusely infiltrativeinfiltrative cancer. cancer.

All three patterns may cause liver All three patterns may cause liver enlargement. enlargement. All patterns of All patterns of hepatocellular carcinomas have a hepatocellular carcinomas have a strong propensity for invasion of strong propensity for invasion of vascular channelsvascular channels. .

Morphology of HCCMorphology of HCC Extensive intrahepatic metastases may occurExtensive intrahepatic metastases may occur tumor may invade the portal vein (with tumor may invade the portal vein (with

occlusion of the portal circulation) or inferior occlusion of the portal circulation) or inferior vena cava, extending even into the right side vena cava, extending even into the right side of the heart. of the heart.

Lymph node metastases to the perihilar, Lymph node metastases to the perihilar, peripancreatic, and para-aortic nodes above peripancreatic, and para-aortic nodes above and below the diaphragm can be present.and below the diaphragm can be present.

Hepatocellular carcinomas range from well-Hepatocellular carcinomas range from well-differentiated to highly anaplastic differentiated to highly anaplastic undifferentiated lesions. undifferentiated lesions.

Morphology of HCCMorphology of HCC

In well-differentiated and moderately In well-differentiated and moderately well-differentiated tumors, cells that well-differentiated tumors, cells that are recognizable as hepatocytic in are recognizable as hepatocytic in origin. Bile pigment is usually present. origin. Bile pigment is usually present. The malignant cells may be positive for The malignant cells may be positive for alpha-fetoprotein.alpha-fetoprotein.

In poorly differentiated forms, tumor In poorly differentiated forms, tumor cells can take on a pleomorphic cells can take on a pleomorphic appearance with numerous anaplastic appearance with numerous anaplastic giant cells, can become small and giant cells, can become small and completely undifferentiated cells.completely undifferentiated cells.

fibrolamellar carcinomafibrolamellar carcinoma A distinctive variant of hepatocellular A distinctive variant of hepatocellular

carcinoma is the carcinoma is the fibrolamellar carcinomafibrolamellar carcinoma. . This tumor occurs in young male and female This tumor occurs in young male and female

adults (20 to 40 years of age), has no adults (20 to 40 years of age), has no association with HBV or cirrhosis, and often association with HBV or cirrhosis, and often has a better prognosis.has a better prognosis.

It usually presents as single large, hard It usually presents as single large, hard "scirrhous" tumor with fibrous bands coursing "scirrhous" tumor with fibrous bands coursing through it. On microscopic examination, it is through it. On microscopic examination, it is composed of well-differentiated polygonal composed of well-differentiated polygonal cells growing in nests or cords and separated cells growing in nests or cords and separated by parallel lamellae of dense collagen bundlesby parallel lamellae of dense collagen bundles

Hepatocellular carcinoma. Such liver cancers arise in Hepatocellular carcinoma. Such liver cancers arise in the setting of cirrhosis. Worldwide, viral hepatitis is the the setting of cirrhosis. Worldwide, viral hepatitis is the most common cause, but in the U.S., chronic alcoholism most common cause, but in the U.S., chronic alcoholism is the most common cause. The neoplasm is large and is the most common cause. The neoplasm is large and bulky and has a greenish cast because it contains bile. bulky and has a greenish cast because it contains bile.

To the right of the main mass are smaller satellite To the right of the main mass are smaller satellite

nodulesnodules. .

The satellite nodules of this The satellite nodules of this hepatocellular carcinoma.hepatocellular carcinoma.

Malignant cells of HCC (seen mostly on Malignant cells of HCC (seen mostly on right) are well differentiated and right) are well differentiated and interdigitate with normal, larger interdigitate with normal, larger

hepatocytes (seen mostly at left).hepatocytes (seen mostly at left).

Clinical FeaturesClinical Features ill-defined upper abdominal pain, ill-defined upper abdominal pain,

malaise, fatigue, weight loss, and malaise, fatigue, weight loss, and feeling of abdominal fullness. feeling of abdominal fullness.

In many cases, the enlarged liver In many cases, the enlarged liver can be felt on palpation. Jaundice can be felt on palpation. Jaundice and fever are uncommon.and fever are uncommon.

Laboratory studies: Elevated levels Laboratory studies: Elevated levels of serum α-fetoprotein are found in of serum α-fetoprotein are found in 50% to 75% of patients with HCC. 50% to 75% of patients with HCC.

Overall, death usually occurs from (1) Overall, death usually occurs from (1) cachexia, (2) gastrointestinal or cachexia, (2) gastrointestinal or esophageal variceal bleeding, (3) liver esophageal variceal bleeding, (3) liver failure with hepatic coma, or, rarely, (4) failure with hepatic coma, or, rarely, (4) rupture of the tumor with fatal rupture of the tumor with fatal hemorrhage. hemorrhage.

CholangiocarcinomaCholangiocarcinoma

Cholangiocarcinoma is a malignancy Cholangiocarcinoma is a malignancy of the biliary tree, arising from bile of the biliary tree, arising from bile ducts within and outside of the liver. ducts within and outside of the liver.

The risk conditions for The risk conditions for development of development of

cholangiocarcinoma includecholangiocarcinoma include primary sclerosing cholangitis, primary sclerosing cholangitis, congenital fibropolycystic diseases of the congenital fibropolycystic diseases of the

biliary system (particularly Caroli disease biliary system (particularly Caroli disease and choledochal cysts), and choledochal cysts),

previous exposure to Thorotrast previous exposure to Thorotrast (formerly used in radiography of the (formerly used in radiography of the biliary tract). biliary tract).

In the Orient, the incidence rates are In the Orient, the incidence rates are higher, and it is due to chronic infection higher, and it is due to chronic infection of the biliary tract by the liver fluke of the biliary tract by the liver fluke Opisthorchis sinensis.Opisthorchis sinensis.

MorphologyMorphology Intrahepatic cholangiocarcinomasIntrahepatic cholangiocarcinomas occur occur

in the non-cirrhotic liver and may track along in the non-cirrhotic liver and may track along the intrahepatic portal tract system to create the intrahepatic portal tract system to create a treelike tumorous mass within the liver or a a treelike tumorous mass within the liver or a massive tumor nodule. Lymphatic and massive tumor nodule. Lymphatic and vascular invasion are common.vascular invasion are common.

By microscopy, cholangiocarcinomas By microscopy, cholangiocarcinomas resemble adenocarcinomas arising in other resemble adenocarcinomas arising in other parts of the body. Most are well to moderately parts of the body. Most are well to moderately differentiated. differentiated. Cholangiocarcinomas are Cholangiocarcinomas are rarely bile stainedrarely bile stained, because differentiated , because differentiated bile duct epithelium does not synthesize bile. bile duct epithelium does not synthesize bile.

MorphologyMorphology

Mixed variants occur, in which Mixed variants occur, in which elements of both hepatocellular elements of both hepatocellular carcinoma and cholangiocarcinoma carcinoma and cholangiocarcinoma are present. are present.

Hematogenous metastases to the Hematogenous metastases to the lungs, bones (mainly vertebrae), lungs, bones (mainly vertebrae), adrenals, brain. Lymph node adrenals, brain. Lymph node metastases to the regional lymph metastases to the regional lymph nodes are also foundnodes are also found

The carcinoma at the left has a glandular appearance. The carcinoma at the left has a glandular appearance. Cholangiocarcinomas do not make bile, but the cells do Cholangiocarcinomas do not make bile, but the cells do

make mucin, and they can be almost impossible to make mucin, and they can be almost impossible to distinguish from metastatic adenocarcinoma on biopsy distinguish from metastatic adenocarcinoma on biopsy

or fine needle aspirateor fine needle aspirate


Intrahepatic cholangiocarcinoma is Intrahepatic cholangiocarcinoma is usually detected late in its course, either usually detected late in its course, either as the result of obstruction to bile flow as the result of obstruction to bile flow through the hilum of the liver or as a through the hilum of the liver or as a symptomatic liver mass. symptomatic liver mass.

Prognosis is poor. The median time from Prognosis is poor. The median time from diagnosis to death is 6 months. diagnosis to death is 6 months. Aggressive surgery remains the only Aggressive surgery remains the only treatment offering hope for long-term treatment offering hope for long-term survival.survival.

Alpha-fetoprorein is not elevated.Alpha-fetoprorein is not elevated.

Metastatic tumorsMetastatic tumors Metastatic involvement of the liver is far Metastatic involvement of the liver is far

more common than primary neoplasia. more common than primary neoplasia. Although the most common primaries Although the most common primaries

producing hepatic metastases are those of producing hepatic metastases are those of the breast, lung, and colon, any cancer in any the breast, lung, and colon, any cancer in any site of the body may spread to the liver, site of the body may spread to the liver, including leukemias and lymphomas. including leukemias and lymphomas.

Typically, multiple nodular metastases are Typically, multiple nodular metastases are found that often cause striking hepatomegaly found that often cause striking hepatomegaly and may replace over 80% of existent hepatic and may replace over 80% of existent hepatic parenchyma. The liver weight can exceed parenchyma. The liver weight can exceed several kilograms.several kilograms.

Numerous mass lesions of variable size. Numerous mass lesions of variable size. Some of the larger ones demonstrate Some of the larger ones demonstrate

central necrosis. The masses are central necrosis. The masses are

metastases to the liver.metastases to the liver.

ANGIOSARCOMAANGIOSARCOMA

This consists of pleomorphic This consists of pleomorphic endothelial cells with large endothelial cells with large hyperchromatic nuclei, giant cells in hyperchromatic nuclei, giant cells in frequent mitosis and irregular frequent mitosis and irregular anastomosing vascular channels. The anastomosing vascular channels. The cells may appear spindle shaped and cells may appear spindle shaped and cirrhosis is present in 20% to 40% of cirrhosis is present in 20% to 40% of the cases. These have also been linked the cases. These have also been linked to vinyl chloride and thorostrast to vinyl chloride and thorostrast exposure.exposure.

HEPATOBLASTOMAHEPATOBLASTOMA

HepatoblastomaHepatoblastoma is the most common is the most common liver tumor of young childhood almost liver tumor of young childhood almost always seen below the age of 2yrs. It always seen below the age of 2yrs. It usually fatal if not resected. This usually fatal if not resected. This tumor has two anatomic variants: tumor has two anatomic variants:

The The epithelial typeepithelial type, composed of small, polygonal , composed of small, polygonal fetal cells or embryonal cells vaguely fetal cells or embryonal cells vaguely recapitulating liver development. recapitulating liver development.

The The mixed epithelial and mesenchymal typemixed epithelial and mesenchymal type, which , which contains foci of mesenchymal differentiation that contains foci of mesenchymal differentiation that may consist of primitive mesenchyme, osteoid, may consist of primitive mesenchyme, osteoid, cartilage, or striated muscle. cartilage, or striated muscle.

GALL BLADDER AND GALL BLADDER AND BILIARY TRACTBILIARY TRACT

Disorders of the Gallbladder Disorders of the Gallbladder CHOLELITHIASIS CHOLELITHIASIS (GALLSTONES)(GALLSTONES)

Majority of gallstones (>80%) are "silent," Majority of gallstones (>80%) are "silent," and most individuals remain free of biliary and most individuals remain free of biliary pain or stone complications for decades. pain or stone complications for decades.

There are two main types of gallstones. There are two main types of gallstones. AAbout 80% are bout 80% are cholesterol stonescholesterol stones, , containing more than 50% of crystalline containing more than 50% of crystalline cholesterol monohydratecholesterol monohydrate. . The remainder The remainder are composed predominantly of bilirubin are composed predominantly of bilirubin calcium saltscalcium salts and are designatedand are designated pigment pigment stonesstones. .

Prevalence and Risk Factors.Prevalence and Risk Factors. The The major risk factors for cholesterol major risk factors for cholesterol stone are . stone are .

Cholesterol StonesCholesterol Stones

Demography: Northern Europe, North and South America, Native Demography: Northern Europe, North and South America, Native Americans, Mexican AmericansAmericans, Mexican Americans

Advancing ageAdvancing age

Female sex hormonesFemale sex hormones

Female genderFemale gender

Oral contraceptivesOral contraceptives

PregnancyPregnancy

ObesityObesity

Rapid weight reductionRapid weight reduction

Gallbladder stasisGallbladder stasis

Inborn disorders of bile acid metabolismInborn disorders of bile acid metabolism

Hyperlipidemia syndromesHyperlipidemia syndromes

Pigment StonesPigment Stones

Demography: Asian more than Western, rural more than urbanDemography: Asian more than Western, rural more than urban

Chronic hemolytic syndromesChronic hemolytic syndromes

Biliary infectionBiliary infection

Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiencyor bypass, cystic fibrosis with pancreatic insufficiency

Pathogenesis of Cholesterol Pathogenesis of Cholesterol StonesStones

Cholesterol is rendered soluble in bile by Cholesterol is rendered soluble in bile by aggregation with water-soluble bile salts and aggregation with water-soluble bile salts and water-insoluble lecithins, both of which act as water-insoluble lecithins, both of which act as detergents. detergents.

When cholesterol concentrations exceed the When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed cholesterol can no longer remain dispersed and nucleates into solid cholesterol and nucleates into solid cholesterol monohydrate crystals.monohydrate crystals.

Cholesterol gallstone formation involves four Cholesterol gallstone formation involves four simultaneous defectssimultaneous defects: :


1)1) Supersaturation of bile with Supersaturation of bile with cholesterol is the result of cholesterol is the result of hepatocellular hypersecretion of hepatocellular hypersecretion of cholesterol.cholesterol.

2)2) Gallbladder hypomotility ensues.Gallbladder hypomotility ensues. It It promotes nucleation typically promotes nucleation typically arround a calcium salt crystal nidus. arround a calcium salt crystal nidus.

3)3) Cholesterol nucleation in bile is Cholesterol nucleation in bile is accelerated. accelerated.


4) Mucus hypersecretion in the gallbladder traps 4) Mucus hypersecretion in the gallbladder traps the crystals, permitting their aggregation into the crystals, permitting their aggregation into stones. stones.

prolonged fasting, pregnancy, rapid weight loss, prolonged fasting, pregnancy, rapid weight loss, total parenteral nutrition, and spinal cord injury total parenteral nutrition, and spinal cord injury also promote stone formation. also promote stone formation.

Pathogenesis of Pigment Pathogenesis of Pigment StonesStones

Pathogenesis of pigment stones is based on Pathogenesis of pigment stones is based on the presence in the biliary tract of the presence in the biliary tract of unconjugated bilirubin (which is poorly unconjugated bilirubin (which is poorly soluble in water) and precipitation of calcium soluble in water) and precipitation of calcium bilirubin salts. bilirubin salts.

Thus, infection of the biliary tract, as with Thus, infection of the biliary tract, as with Escherichia coliEscherichia coli or or Ascaris lumbricoidesAscaris lumbricoides or by or by the liver fluke the liver fluke Opisthorchis sinensisOpisthorchis sinensis, increases , increases the likelihood of pigment stone formation. the likelihood of pigment stone formation.

Chronic hemolytic conditions also promote Chronic hemolytic conditions also promote formation of unconjugated bilirubin in the formation of unconjugated bilirubin in the biliary tree. biliary tree.

MorphologyMorphology Cholesterol stonesCholesterol stones arise exclusively in arise exclusively in

the gallbladder and are composed of the gallbladder and are composed of cholesterol ranging from 100% pure cholesterol ranging from 100% pure (which is rare) down to around 50%. (which is rare) down to around 50%.

pale yellow, round to ovoid to faceted, and pale yellow, round to ovoid to faceted, and have a finely granular, hard external have a finely granular, hard external surface.surface.

Stones composed largely of Stones composed largely of cholesterol are radiolucent; only 10% cholesterol are radiolucent; only 10% to 20% of cholesterol stones are radio-to 20% of cholesterol stones are radio-opaque.opaque.

MorphologyMorphology Pigment gallstonesPigment gallstones are black and brown. are black and brown. "Black" pigment stones are found in sterile "Black" pigment stones are found in sterile

gallbladder. gallbladder. "Brown" pigment stones are found in infected "Brown" pigment stones are found in infected

intrahepatic or extrahepatic bile ducts. intrahepatic or extrahepatic bile ducts. Both are soft and usually multiple. Both are soft and usually multiple. Brown stone are greasy. Brown stone are greasy. Because of calcium carbonates and phosphates, Because of calcium carbonates and phosphates,

approximately 50% to 75% of black stones approximately 50% to 75% of black stones are radio-opaque.are radio-opaque.

CholesterolosisCholesterolosis

An incidental finding, is An incidental finding, is cholesterolosischolesterolosis. Cholesterol . Cholesterol hypersecretion by the liver promotes hypersecretion by the liver promotes excessive accumulation of excessive accumulation of cholesterol esters within the lamina cholesterol esters within the lamina propria of the gallbladder. The propria of the gallbladder. The mucosal surface is studded with mucosal surface is studded with minute yellow flecks, producing the minute yellow flecks, producing the "strawberry gallbladder "strawberry gallbladder

Clinical FeaturesClinical Features 70% to 80% of patients remain asymptomatic throughout 70% to 80% of patients remain asymptomatic throughout

their lives. their lives. Symptoms: spasmodic or "colicky" fighrt upper quadrant Symptoms: spasmodic or "colicky" fighrt upper quadrant

pain, which tends to be excruciating . It is usually due to pain, which tends to be excruciating . It is usually due to obstruction of bile ducts by passing stones.obstruction of bile ducts by passing stones.

More severe complications include empyema, perforation, More severe complications include empyema, perforation, fistulae, inflammation of the biliary tree (cholangitis), and fistulae, inflammation of the biliary tree (cholangitis), and obstructive cholestasis or pancreatitis with ensuing obstructive cholestasis or pancreatitis with ensuing problems. The larger the calculi, the less likely they are to problems. The larger the calculi, the less likely they are to enter the cystic or common ducts to produce obstruction; enter the cystic or common ducts to produce obstruction; it is the very small stones, or "gravel," that are the more it is the very small stones, or "gravel," that are the more dangerous. Occasionally, a large stone may erode directly dangerous. Occasionally, a large stone may erode directly into an adjacent loop of small bowel, generating intestinal into an adjacent loop of small bowel, generating intestinal obstruction ("gallstone ileus"). Most notable is the obstruction ("gallstone ileus"). Most notable is the increased risk for carcinoma of the gallbladder.increased risk for carcinoma of the gallbladder.

CHOLECYSTITISCHOLECYSTITIS

Inflammation of the gallbladder may Inflammation of the gallbladder may be acute, chronic, or acute be acute, chronic, or acute superimposed on chronic. It almost superimposed on chronic. It almost always occurs in association with always occurs in association with gallstones. gallstones.

Acute CholecystitisAcute Cholecystitis Acute calculous cholecystitis is an acute Acute calculous cholecystitis is an acute

inflammation of the gallbladder, precipitated 90% of inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct.the time by obstruction of the neck or cystic duct.

It is the primary complication of gallstones and the It is the primary complication of gallstones and the most common reason for emergency most common reason for emergency cholecystectomy. cholecystectomy.

Acute acalculous cholecystitis occurs in the absence Acute acalculous cholecystitis occurs in the absence of gallstones, generally in severely ill patient. Most of gallstones, generally in severely ill patient. Most cases of occur in the following circumstances: (1) cases of occur in the following circumstances: (1) the postoperative state after major, nonbiliary the postoperative state after major, nonbiliary surgery; (2) severe trauma (motor vehicle accidents, surgery; (2) severe trauma (motor vehicle accidents, war injuries); (3) severe burns; (4) multisystem war injuries); (3) severe burns; (4) multisystem organ failure; (5) sepsis; (6) prolonged intravenous organ failure; (5) sepsis; (6) prolonged intravenous hyperalimentation; and (7) the postpartum state. hyperalimentation; and (7) the postpartum state.

Acute Acute CholecystitisCholecystitis :Pathogenesis. :Pathogenesis.

Acute calculous cholecystitis results Acute calculous cholecystitis results from chemical irritation and from chemical irritation and inflammation of the obstructed inflammation of the obstructed gallbladder. gallbladder. These events occur in These events occur in the absence of bacterial infectionthe absence of bacterial infection; ; only later in the course may only later in the course may bacterial contamination develop.bacterial contamination develop.

Acute Acute CholecystitisCholecystitis :Morphology. :Morphology. In In acute cholecystitisacute cholecystitis, the gallbladder , the gallbladder

is usually enlarged and tense, and is usually enlarged and tense, and bright red to green-black . The serosal bright red to green-black . The serosal covering is frequently layered by fibrin covering is frequently layered by fibrin and, in severe cases, by exudate. and, in severe cases, by exudate.

There are no morphologic differences There are no morphologic differences between acute acalculous and calculous between acute acalculous and calculous cholecystitis, except for the absence of cholecystitis, except for the absence of macroscopic stones in the former. In macroscopic stones in the former. In the latter instance, an obstructing stone the latter instance, an obstructing stone is usually present in the neck of the is usually present in the neck of the gallbladder or the cystic duct. gallbladder or the cystic duct.

Acute Acute CholecystitisCholecystitis :Morphology. :Morphology. The gallbladder lumen is filled with a cloudy The gallbladder lumen is filled with a cloudy

or turbid bile that may contain fibrin and or turbid bile that may contain fibrin and frank pus, as well as hemorrhage. When the frank pus, as well as hemorrhage. When the contained exudate is virtually pure pus, the contained exudate is virtually pure pus, the condition is referred to as condition is referred to as empyema of the empyema of the gallbladdergallbladder. .

In mild cases, the gallbladder wall is In mild cases, the gallbladder wall is thickened, edematous, and hyperemic.thickened, edematous, and hyperemic.

In more severe cases, it is transformed into a In more severe cases, it is transformed into a green-black necrotic organ, termed green-black necrotic organ, termed gangrenous cholecystitisgangrenous cholecystitis, with small-to-, with small-to-large perforations. large perforations.

Acute CholecystitisAcute Cholecystitis :Clinical :Clinical FeaturesFeatures

Progressive right upper quadrant or Progressive right upper quadrant or epigastric pain, frequently associated with epigastric pain, frequently associated with mild fever, anorexia, tachycardia, sweating, mild fever, anorexia, tachycardia, sweating, and nausea and vomiting. The upper and nausea and vomiting. The upper abdomen is tender. Most patients are free abdomen is tender. Most patients are free of jaundiceof jaundice

Acute calculous cholecystitis may appear Acute calculous cholecystitis may appear with remarkable suddenness and constitute with remarkable suddenness and constitute an acute surgical emergency or may an acute surgical emergency or may present with mild symptoms that resolve present with mild symptoms that resolve without medical intervention.without medical intervention.

Acute CholecystitisAcute Cholecystitis :Clinical :Clinical FeaturesFeatures

Clinical symptoms of acute acalculous Clinical symptoms of acute acalculous cholecystitis tend to be more insidious, cholecystitis tend to be more insidious, since symptoms are obscured by the since symptoms are obscured by the underlying conditions precipitating the underlying conditions precipitating the attacks. A higher proportion of patients attacks. A higher proportion of patients have no symptoms referable to the have no symptoms referable to the gallbladder. The incidence of gangrene gallbladder. The incidence of gangrene and perforation is much higher than in and perforation is much higher than in calculous cholecystitis. calculous cholecystitis.

Chronic cholecystitisChronic cholecystitis Chronic cholecystitis may be a sequel to Chronic cholecystitis may be a sequel to

repeated bouts of mild to severe acute repeated bouts of mild to severe acute cholecystitis, but in many instances, it cholecystitis, but in many instances, it develops in the apparent absence of develops in the apparent absence of antecedent attacks. antecedent attacks.

It is associated with cholelithiasis in over It is associated with cholelithiasis in over 90% of cases.90% of cases.

Chronic cholecystitisChronic cholecystitis

The symptoms of calculous chronic The symptoms of calculous chronic cholecystitis are similar to those of cholecystitis are similar to those of the acute form and range from biliary the acute form and range from biliary colic to indolent right upper quadrant colic to indolent right upper quadrant pain and epigastric distress. pain and epigastric distress.

Patients often have intolerance to Patients often have intolerance to fatty food, belching and postprandial fatty food, belching and postprandial epigastric distress, sometimes epigastric distress, sometimes include nausea and vomiting. include nausea and vomiting.

MorphologyMorphology

The morphologic changes in chronic The morphologic changes in chronic cholecystitis are extremely variable cholecystitis are extremely variable and sometimes minimal. Gall bladder and sometimes minimal. Gall bladder may be contracted (fibrosis), normal may be contracted (fibrosis), normal in size or enlarged (from in size or enlarged (from obstruction). The wall is variably obstruction). The wall is variably thickened. Stones are frequent.thickened. Stones are frequent.

MorphologyMorphology On histology, the degree of inflammation is variable. On histology, the degree of inflammation is variable.

Outpouchings of the mucosal epithelium through the Outpouchings of the mucosal epithelium through the wall (wall (Rokitansky-Aschoff sinusesRokitansky-Aschoff sinuses) may be quite ) may be quite prominent. prominent.

Rarely, extensive dystrophic calcification within the Rarely, extensive dystrophic calcification within the gallbladder wall may yield a gallbladder wall may yield a porcelain gallbladderporcelain gallbladder, , notable for a markedly increased incidence of notable for a markedly increased incidence of associated cancer. associated cancer.

Xanthogranulomatous cholecystitisXanthogranulomatous cholecystitis is also a rare is also a rare condition in which the gallbladder is shrunken, condition in which the gallbladder is shrunken, nodular, fibrosed and chronically inflamed with nodular, fibrosed and chronically inflamed with abundant lipid filled macrophages. abundant lipid filled macrophages.

Finally, an atrophic, chronically obstructed gallbladder Finally, an atrophic, chronically obstructed gallbladder may contain only clear secretions, a condition known as may contain only clear secretions, a condition known as hydrops of the gallbladderhydrops of the gallbladder..

Complications: acute and chronic Complications: acute and chronic cholecystitischolecystitis

Bacterial superinfection with cholangitis or Bacterial superinfection with cholangitis or sepsis sepsis

GB perforation & local abscess formation GB perforation & local abscess formation GB rupture with diffuse peritonitis GB rupture with diffuse peritonitis Biliary enteric (cholecystenteric) fistula with Biliary enteric (cholecystenteric) fistula with

drainage of bile into adjacent organs, and drainage of bile into adjacent organs, and potentially gallstone-induced intestinal potentially gallstone-induced intestinal obstruction (ileus) obstruction (ileus)

Aggravation of pre-existing medical illness, Aggravation of pre-existing medical illness, with cardiac, pulmonary, renal, or liver with cardiac, pulmonary, renal, or liver decompensation decompensation

Carcinoma of Carcinoma of GallbladderGallbladder

Carcinoma of the GB is slightly more Carcinoma of the GB is slightly more common in women and occurs in 7common in women and occurs in 7thth decade of life. decade of life.

Gallstones are present in 60 to 90% of Gallstones are present in 60 to 90% of cases. Also associated pyogenic and cases. Also associated pyogenic and parasitic diseases of biliary tree are parasitic diseases of biliary tree are common. common.

GB containing stones or infectious GB containing stones or infectious agents develop cancer due to irritative agents develop cancer due to irritative trauma and chronic inflammation. trauma and chronic inflammation.

Carcinoma of Gallbladder: Carcinoma of Gallbladder: MorphologyMorphology

Carcinomas of the gallbladder exhibit two Carcinomas of the gallbladder exhibit two patterns of growth: patterns of growth: infiltratinginfiltrating and and exophyticexophytic. .

Infiltrating pattern is more common and Infiltrating pattern is more common and appears as a poorly defined area of diffuse appears as a poorly defined area of diffuse thickening and induration of the thickening and induration of the gallbladder wall.gallbladder wall.

The exophytic pattern grows into the lumen The exophytic pattern grows into the lumen as an irregular, cauliflower mass but at the as an irregular, cauliflower mass but at the same time invades the underlying wall. same time invades the underlying wall.

Carcinoma of Gallbladder: Carcinoma of Gallbladder: MorphologyMorphology

Most carcinomas of the gallbladder are Most carcinomas of the gallbladder are adenocarcinomas. Some are well to adenocarcinomas. Some are well to moderately differentiated; others are moderately differentiated; others are infiltrative and poorly differentiated to infiltrative and poorly differentiated to undifferentiated. undifferentiated.

Rarely squamous cell carcinomas or Rarely squamous cell carcinomas or adenosquamous carcinoma, carcinoid or adenosquamous carcinoma, carcinoid or mesenchymal. mesenchymal.

Spread: local invasion of liver, extension to Spread: local invasion of liver, extension to cystic duct, portohepatic lymph nodes, cystic duct, portohepatic lymph nodes, peritoneum, lungs etc.peritoneum, lungs etc.

Disease of exocrine Disease of exocrine pancreaspancreas

PancreatitisPancreatitis Pancreatitis encompasses a group of disorders Pancreatitis encompasses a group of disorders

characterized by inflammation of the characterized by inflammation of the pancreas. The clinical manifestations can pancreas. The clinical manifestations can range in severity from a mild, self-limited range in severity from a mild, self-limited disease to a lifethreatening acute disease to a lifethreatening acute inflammatory process, and the duration of the inflammatory process, and the duration of the disease can range from a transient attack to disease can range from a transient attack to an irreversible loss of function. an irreversible loss of function.

In In acute pancreatitisacute pancreatitis, gland can return to , gland can return to normal if underlying cause of the pancreatitis normal if underlying cause of the pancreatitis is removed.is removed.

By contrast, By contrast, chronic pancreatitischronic pancreatitis is defined by is defined by irreversible destruction of exocrine pancreatic irreversible destruction of exocrine pancreatic parenchyma.parenchyma.

Acute pancreatitisAcute pancreatitis Acute pancreatitis is a group of Acute pancreatitis is a group of

reversible lesions characterized by reversible lesions characterized by inflammation of the pancreas ranging in inflammation of the pancreas ranging in severity from edema and fat necrosis to severity from edema and fat necrosis to parenchymal necrosis with severe parenchymal necrosis with severe hemorrhage.hemorrhage.

80% of cases in Western countries are 80% of cases in Western countries are associated with one of two conditions: associated with one of two conditions: biliary tract disease or alcoholism. biliary tract disease or alcoholism. Gallstones are present in 35% to 60% of Gallstones are present in 35% to 60% of cases of acute pancreatitis. cases of acute pancreatitis.

Acute pancreatitisAcute pancreatitisLess common causes of acute pancreatitis include the Less common causes of acute pancreatitis include the

following: following: Obstruction of the pancreatic duct system eg. Obstruction of the pancreatic duct system eg.

periampullary tumors, congenital cystic dilatation of the periampullary tumors, congenital cystic dilatation of the common bile duct, biliary "sludge," and parasites common bile duct, biliary "sludge," and parasites (particularly (particularly Ascariasis lumbricoidesAscariasis lumbricoides and and Clonorchis Clonorchis sinensissinensis organisms) organisms)

Medications. More than 85 drugs have been reported to Medications. More than 85 drugs have been reported to cause acute pancreatitis. These include thiazide diuretics, cause acute pancreatitis. These include thiazide diuretics, azathioprine , estrogens, etc , estrogens, etc

Metabolic disorders, including hypertriglyceridemia, Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states hyperparathyroidism, and other hypercalcemic states

Acute ischemia induced by vascular thrombosis, embolism, Acute ischemia induced by vascular thrombosis, embolism, vasculitis and shock vasculitis and shock

Trauma, both blunt trauma and iatrogenic injury during Trauma, both blunt trauma and iatrogenic injury during surgery or endoscopic retrograde surgery or endoscopic retrograde cholangiopancreatography cholangiopancreatography

Metabolic

Alcoholism

Hyperlipoproteinemia

Hypercalcemia

Drugs (e.g., thiazide diuretics)

Genetic

Mechanical

Trauma

Gallstones

Iatrogenic injury

Perioperative injury

Endoscopic procedures with dye injection

ETIOLOGIC FACTORS IN ETIOLOGIC FACTORS IN ACUTE PANCREATITISACUTE PANCREATITIS

Vascular

Shock

Atheroembolism

Polyarteritis nodosa

Infectious

Mumps

Coxsackievirus

Mycoplasma pneumoniae

ETIOLOGIC FACTORS IN ETIOLOGIC FACTORS IN ACUTE PANCREATITISACUTE PANCREATITIS

Acute pancreatitis: Acute pancreatitis: MorphologyMorphology

The morphology of acute pancreatitis ranges from The morphology of acute pancreatitis ranges from inflammation and edema to severe extensive inflammation and edema to severe extensive necrosis and hemorrhage. necrosis and hemorrhage.

The basic alterations are The basic alterations are (1) microvascular (1) microvascular leakage causing edema, (2) necrosis of fat by leakage causing edema, (2) necrosis of fat by lipolytic enzymes, (3) an acute inflammatory lipolytic enzymes, (3) an acute inflammatory reaction, (4) proteolytic destruction of reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of pancreatic parenchyma, and (5) destruction of blood vessels with subsequent interstitial blood vessels with subsequent interstitial hemorrhagehemorrhage. .

Fat necrosis, as we have seen, results from Fat necrosis, as we have seen, results from enzymatic destruction of fat cells. The released enzymatic destruction of fat cells. The released fatty acids combine with calcium to form insoluble fatty acids combine with calcium to form insoluble salts that precipitate in situ.salts that precipitate in situ.

Acute pancreatitisAcute pancreatitis

Pathogenesis.Pathogenesis. autodigestion of the autodigestion of the pancreatic substance by pancreatic substance by inappropriately activated pancreatic inappropriately activated pancreatic enzymesenzymes. Thus, . Thus, activation of activation of trypsinogen is an important trypsinogen is an important triggering event in acute triggering event in acute pancreatitispancreatitis. .

Acute pancreatitisAcute pancreatitis: Clinical : Clinical Features.Features.

Abdominal painAbdominal pain is the cardinal manifestation of acute is the cardinal manifestation of acute pancreatitis. Its severity varies from mild to severe. pancreatitis. Its severity varies from mild to severe.

Full-blown acute pancreatitis is a medical emergency of Full-blown acute pancreatitis is a medical emergency of the first magnitudethe first magnitude. These patients usually have the . These patients usually have the sudden onset of an "acute abdomen" that must be sudden onset of an "acute abdomen" that must be differentiated from diseases such as ruptured acute differentiated from diseases such as ruptured acute appendicitis, perforated peptic ulcer, acute cholecystitis appendicitis, perforated peptic ulcer, acute cholecystitis with rupture, and occlusion of mesenteric vessels with with rupture, and occlusion of mesenteric vessels with infarction of the bowel. Characteristically, the pain is infarction of the bowel. Characteristically, the pain is constant and intense and is often referred to the upper constant and intense and is often referred to the upper back. There is back. There is leukocytosisleukocytosis, , hemolysishemolysis, , disseminated disseminated intravascular coagulationintravascular coagulation, , fluid sequestration, acute fluid sequestration, acute respiratory distress syndromerespiratory distress syndrome, , and diffuse fat necrosisand diffuse fat necrosis. . Peripheral vascular collapse and shock with acute renal Peripheral vascular collapse and shock with acute renal tubular necrosis may occurtubular necrosis may occur


Laboratory findings: Laboratory findings: marked marked elevation of serum amylase levels elevation of serum amylase levels during the first 24 hours, followed during the first 24 hours, followed within 72 to 96 hours by a rising within 72 to 96 hours by a rising serum lipase level.serum lipase level.


The key to the management is "resting" The key to the management is "resting" the pancreas by total restriction of food the pancreas by total restriction of food and fluids and by supportive therapy. and fluids and by supportive therapy.

Most patients recover fully. About 5% die Most patients recover fully. About 5% die from shock during the first week of illness. from shock during the first week of illness. Acute respiratory distress syndrome and Acute respiratory distress syndrome and acute renal failure are fatal complications. acute renal failure are fatal complications.

In surviving patients, sequelae include a In surviving patients, sequelae include a sterile sterile pancreatic abscesspancreatic abscess and a and a pancreatic pseudocyst.pancreatic pseudocyst.

Chronic pancreatitisChronic pancreatitis Chronic pancreatitis is characterized by Chronic pancreatitis is characterized by

inflammation of the pancreas with inflammation of the pancreas with destruction of exocrine parenchyma, destruction of exocrine parenchyma, fibrosis, and, in the late stages, the fibrosis, and, in the late stages, the destruction of endocrine parenchyma. destruction of endocrine parenchyma.

The chief distinction between acute and The chief distinction between acute and chronic pancreatitis is the irreversible chronic pancreatitis is the irreversible impairment in pancreatic function that is impairment in pancreatic function that is characteristic of chronic pancreatitis. characteristic of chronic pancreatitis.

Chronic pancreatitisChronic pancreatitis


There is significant overlap in the There is significant overlap in the causes of acute and chronic causes of acute and chronic pancreatitis. By far pancreatitis. By far the most the most common cause of chronic common cause of chronic pancreatitis is long-term alcohol pancreatitis is long-term alcohol abuse and biliary tract diseaseabuse and biliary tract disease, and , and these patients are usually middle-these patients are usually middle-aged males. aged males.


Less common causes of chronic Less common causes of chronic pancreatitis include the following: pancreatitis include the following:

Hypercalcemia, hyperlipidemia.Hypercalcemia, hyperlipidemia. Long-standing Long-standing obstructionobstruction of the of the

pancreatic duct by pseudocysts, calculi, pancreatic duct by pseudocysts, calculi, trauma, neoplasms, or pancreas divisum. trauma, neoplasms, or pancreas divisum.

Tropical pancreatitisTropical pancreatitis, which is a poorly , which is a poorly characterized disease seen in Africa and characterized disease seen in Africa and Asia. It has been attributed to Asia. It has been attributed to malnutrition. malnutrition.

Hereditary pancreatitisHereditary pancreatitis Idiopathic chronic pancreatitisIdiopathic chronic pancreatitis. .

Chronic pancreatitis: Chronic pancreatitis: MorphologyMorphology

Chronic pancreatitis is characterized by Chronic pancreatitis is characterized by parenchymal fibrosis, reduced number parenchymal fibrosis, reduced number and size of acini with relative sparing of and size of acini with relative sparing of the islets of Langerhans, and variable the islets of Langerhans, and variable dilation of the pancreatic ductsdilation of the pancreatic ducts

These changes are usually accompanied by a These changes are usually accompanied by a chronic inflammatory infiltrate around lobules chronic inflammatory infiltrate around lobules and ducts.and ducts.

Grossly: gland is hard, sometimes with Grossly: gland is hard, sometimes with extremely dilated ducts and visible extremely dilated ducts and visible calcification calcification

Chronic pancreatitisChronic pancreatitis: : Clinical FeaturesClinical Features

Silent or repeated attacks of abdominal pain, or Silent or repeated attacks of abdominal pain, or persistent abdominal and back pain. Attacks may persistent abdominal and back pain. Attacks may be precipitated by alcohol abuse, overeating be precipitated by alcohol abuse, overeating (which increases demand on the pancreas), or the (which increases demand on the pancreas), or the use of opiates and other drugs. use of opiates and other drugs.

During an attack of abdominal pain, there may be During an attack of abdominal pain, there may be mild fever and mild-to-moderate elevations of mild fever and mild-to-moderate elevations of serum amylase. Calcifications can be seen within serum amylase. Calcifications can be seen within the pancreas by CT scan and ultrasonography. the pancreas by CT scan and ultrasonography.

Complications: Severe Complications: Severe pancreatic exocrine pancreatic exocrine insufficiency,insufficiency, chronic malabsorption, chronic malabsorption, diabetes diabetes mellitusmellitus (due to destruction of islets of (due to destruction of islets of Langerhans), Langerhans), severe chronic painsevere chronic pain and p and pancreatic ancreatic pseudocysts.pseudocysts.

PSEUDOCYSTS OF PSEUDOCYSTS OF PANCREASPANCREAS

Pseudocysts are localized collections of Pseudocysts are localized collections of necrotic-hemorrhagic material rich in necrotic-hemorrhagic material rich in pancreatic enzymes. Such cysts lack an pancreatic enzymes. Such cysts lack an epithelial lining (hence the prefix "pseudo"), epithelial lining (hence the prefix "pseudo"), and they account for majority of cysts in the and they account for majority of cysts in the pancreas. pancreas.

Pseudocysts usually arise after an episode of Pseudocysts usually arise after an episode of acute pancreatitis, or of chronic alcoholic acute pancreatitis, or of chronic alcoholic pancreatitis. pancreatitis.

Traumatic injury to the abdomen can also Traumatic injury to the abdomen can also give rise to pseudocystsgive rise to pseudocysts


Morphology.Morphology. Pseudocysts are usually Pseudocysts are usually solitary. Pseudocysts can range in size from 2 solitary. Pseudocysts can range in size from 2 to 30 cm in diameter. to 30 cm in diameter.

While many pseudocysts spontaneously While many pseudocysts spontaneously resolve, they may become secondarily resolve, they may become secondarily infected, and larger pseudocysts may infected, and larger pseudocysts may compress or even perforate into adjacent compress or even perforate into adjacent structures.structures.

They can produce abdominal pain and They can produce abdominal pain and predispose to intraperitoneal hemorrhage or predispose to intraperitoneal hemorrhage or peritonitis. peritonitis.

CYSTIC NEOPLASMSCYSTIC NEOPLASMS

Only 5% to 15% of all pancreatic cysts Only 5% to 15% of all pancreatic cysts are neoplastic (most cysts are are neoplastic (most cysts are pseudocysts).pseudocysts).

There are of 2 types: There are of 2 types:

1)serous cystadenoma, are entirely 1)serous cystadenoma, are entirely benign, benign,

2)mucinous cystic neoplasms, can 2)mucinous cystic neoplasms, can be benign, borderline malignant, or be benign, borderline malignant, or malignant. malignant.

CYSTIC NEOPLASMSCYSTIC NEOPLASMS: Serous : Serous cystadenomascystadenomas

Serous cystadenomasSerous cystadenomas are benign cystic are benign cystic neoplasms composed of cuboidal cells neoplasms composed of cuboidal cells surrounding small cysts containing clear, thin, surrounding small cysts containing clear, thin, straw-colored fluid..straw-colored fluid..

More common in women in the 7More common in women in the 7thth decade decade with nonspecific symptoms eg.abdominal with nonspecific symptoms eg.abdominal pain. pain.

May present as palpable abdominal mass. May present as palpable abdominal mass. Serous cystadenomas are almost always Serous cystadenomas are almost always

benign, and surgical resection is curative in benign, and surgical resection is curative in majority of patients. majority of patients.

Serous cystadenomaSerous cystadenoma

CYSTIC CYSTIC NEOPLASMSNEOPLASMS:Mucinous :Mucinous

cystic neoplasmscystic neoplasms Mucinous cystic neoplasmsMucinous cystic neoplasms almost almost

always arise in women usually in the always arise in women usually in the body or tail of the pancreas body or tail of the pancreas

Present as painless, slow-growing Present as painless, slow-growing masses. The cystic spaces are filled masses. The cystic spaces are filled with thick mucin, and the cysts are with thick mucin, and the cysts are lined by a columnar mucinous lined by a columnar mucinous epithelium with an associated dense epithelium with an associated dense stroma similar to ovarian stroma. stroma similar to ovarian stroma.

CYSTIC NEOPLASMS: CYSTIC NEOPLASMS: IPMNs)IPMNs)

Intraductal papillary mucinous Intraductal papillary mucinous neoplasms (IPMNs)neoplasms (IPMNs) is a rare cystic is a rare cystic neoplasm which is a solid and cystic neoplasm which is a solid and cystic and papillary areas.and papillary areas.

PANCREATIC CARCINOMAPANCREATIC CARCINOMA

Pancreatic cancer has one of the Pancreatic cancer has one of the highest mortality rates of any highest mortality rates of any cancer. It is carcinoma of the cancer. It is carcinoma of the exocrine pancreas. It arises from exocrine pancreas. It arises from ductal epithelial cells.ductal epithelial cells.

It occurs in the 6It occurs in the 6thth to 8 to 8thth decade, decade, blacks more than whites, males blacks more than whites, males more than females, diabetics more more than females, diabetics more than non-diabetics.than non-diabetics.

PANCREATIC CARCINOMAPANCREATIC CARCINOMA MorphologyMorphology

Approximately 60% of cancers of the Approximately 60% of cancers of the pancreas arise in the head of the gland, 15% pancreas arise in the head of the gland, 15% in the body, and 5% in the tail; in 20%, the in the body, and 5% in the tail; in 20%, the neoplasm diffusely involves the entire gland. neoplasm diffusely involves the entire gland.

Carcinomas of the pancreas are usually hard, Carcinomas of the pancreas are usually hard, stellate, gray-white, poorly defined masses.stellate, gray-white, poorly defined masses.

Majority of carcinomas are ductal Majority of carcinomas are ductal adenocarcinomas. Two features are adenocarcinomas. Two features are characteristic: It is highly invasive, and it characteristic: It is highly invasive, and it elicits an intense non-neoplastic host reaction elicits an intense non-neoplastic host reaction called a "desmoplastic response". called a "desmoplastic response".

PANCREATIC CARCINOMAPANCREATIC CARCINOMA MorphologyMorphology

Peripancreatic, gastric, mesenteric, Peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes omental, and portahepatic lymph nodes are frequently involved. Distant are frequently involved. Distant metastases occur, principally to the lungs metastases occur, principally to the lungs and bones.and bones.

Less common variants of pancreatic Less common variants of pancreatic cancer include cancer include acinar cell carcinomas, acinar cell carcinomas, adenosquamous carcinomasadenosquamous carcinomas, and , and undifferentiated carcinomas with undifferentiated carcinomas with osteoclast-like giant cellsosteoclast-like giant cells. .

PANCREATIC CARCINOMA: PANCREATIC CARCINOMA: CLINICAL FEATURESCLINICAL FEATURES

Jaundice, weight loss, pain ,massive Jaundice, weight loss, pain ,massive metastasis to liver and migratory metastasis to liver and migratory thrombophelebitisthrombophelebitis

PANCREATIC CARCINOMAPANCREATIC CARCINOMA

PANCREATOBLASTOMAPANCREATOBLASTOMA

Pancreatoblastomas are rare Pancreatoblastomas are rare neoplasms that occur primarily in neoplasms that occur primarily in children aged 1 to 15 years.children aged 1 to 15 years.

They have a distinct microscopic They have a distinct microscopic appearance with squamous islands appearance with squamous islands admixed with undifferentiated cells. admixed with undifferentiated cells.

These are malignant neoplasms.These are malignant neoplasms.

PATHOLOGY of DIABETES PATHOLOGY of DIABETES MELLITISMELLITIS

THE ENDOCRINE THE ENDOCRINE PANCREASPANCREAS

Normal Normal endocrine pancreas consists of about 1 endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets of million microscopic clusters of cells, the islets of Langerhans which contain the following cell Langerhans which contain the following cell types: types:

TheThe β β cell produces insulincell produces insulin. . TheThe α α cell secretes glucagoncell secretes glucagon δ δ cells contain somatostatin,cells contain somatostatin, which suppresses which suppresses

both insulin and glucagon release both insulin and glucagon release PP cells contain a unique pancreatic PP cells contain a unique pancreatic

polypeptidepolypeptide. . The two rare cell types are The two rare cell types are D1 cellsD1 cells and and

enterochromaffin cellsenterochromaffin cells. D1 cells elaborate . D1 cells elaborate vasoactive intestinal polypeptide (VIP)vasoactive intestinal polypeptide (VIP). . Enterochromaffin cells synthesize serotonin.Enterochromaffin cells synthesize serotonin.

Diabetes mellitusDiabetes mellitus Diabetes mellitus (DM) is not a single disease entity, Diabetes mellitus (DM) is not a single disease entity,

but rather a but rather a group of metabolic disorders sharing the group of metabolic disorders sharing the common underlying feature of hyperglycemia.common underlying feature of hyperglycemia.

Hyperglycemia in diabetes results from defects in Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, insulin secretion, insulin action, or, most commonly, both. both.

The chronic hyperglycemia may be associated with The chronic hyperglycemia may be associated with secondary damage in multiple organ systems, secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. especially the kidneys, eyes, nerves, and blood vessels.

Diabetes is one of the leading causes of end-stage Diabetes is one of the leading causes of end-stage renal disease, adult-onset blindness, and nontraumatic renal disease, adult-onset blindness, and nontraumatic lower extremity amputation. lower extremity amputation.

It is one of the most common noncommunicable It is one of the most common noncommunicable diseases.diseases.

DIAGNOSIS of DM DIAGNOSIS of DM Blood glucose values are normally Blood glucose values are normally

maintained in a very narrow range, usually maintained in a very narrow range, usually 70 to 120 mg/dL. The diagnosis of diabetes 70 to 120 mg/dL. The diagnosis of diabetes is established by noting elevation of blood is established by noting elevation of blood glucose by any one of three criteria: glucose by any one of three criteria:

A random glucose > 200 mg/dL, with A random glucose > 200 mg/dL, with classical signs and symptoms classical signs and symptoms

A fasting glucose > 126 mg/dL on more A fasting glucose > 126 mg/dL on more than one occasion than one occasion

An abnormal oral glucose tolerance test An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200 (OGTT), in which the glucose is > 200 mg/dL 2 hours after a standard mg/dL 2 hours after a standard carbohydrate loadcarbohydrate load

CLASSIFICATION of DMCLASSIFICATION of DM

The vast majority of cases of diabetes fall into The vast majority of cases of diabetes fall into one of two broad classes:one of two broad classes:

Type 1 diabetesType 1 diabetes is characterized by an is characterized by an absolute deficiency of insulin caused by absolute deficiency of insulin caused by pancreatic β-cell destruction. It accounts for pancreatic β-cell destruction. It accounts for approximately 10% of all cases. approximately 10% of all cases.

Type 2 diabetesType 2 diabetes is caused by a combination of is caused by a combination of peripheral resistance to insulin action and an peripheral resistance to insulin action and an inadequate secretory response by the inadequate secretory response by the pancreatic β-cells ("relative insulin pancreatic β-cells ("relative insulin deficiency"). Approximately 80% to 90% of deficiency"). Approximately 80% to 90% of patients have type 2 diabetes.patients have type 2 diabetes.

CLASSIFICATION of DMCLASSIFICATION of DM A variety of monogenic and secondary causes A variety of monogenic and secondary causes

are responsible for the remaining cases.are responsible for the remaining cases. Examples of secondary DM include Examples of secondary DM include

pancreatitis, pancreatectomy, tumors pancreatitis, pancreatectomy, tumors (pheochromocytoma, pituitary tumors), drugs (pheochromocytoma, pituitary tumors), drugs (corticosteroids), iron overload (corticosteroids), iron overload (hemochromatosis), some genetic (hemochromatosis), some genetic disorders( e.g. lipodystrophy).disorders( e.g. lipodystrophy).

Examples of monogenic forms include Examples of monogenic forms include maturity onset DM of young, mitochondrial maturity onset DM of young, mitochondrial DM, DM associated with insulin gene or DM, DM associated with insulin gene or insulin receptor mutations.insulin receptor mutations.

.1

Type 1 diabetes (β-cell destruction, leads to absolute insulin deficiency)Immune-mediatedIdiopathic

2.

Type 2 diabetes (insulin resistance with relative insulin deficiency)


3.

Genetic defects of β-cell functionMaturity-onset diabetes of the young (MODY), caused by mutations in:Hepatocyte nuclear factor 4α[HNF-4α] (MODY1)Glucokinase (MODY2)Hepatocyte nuclear factor 1α[HNF-1α] (MODY3)Insulin promoter factor [IPF-1] (MODY4)Hepatocyte nuclear factor 1β[HNF-1β] (MODY5)Neurogenic differentiation factor 1 [Neuro D1] (MODY6)Mitochondrial DNA mutations

4.

Genetic defects in insulin processing or insulin actionDefects in proinsulin conversionInsulin gene mutationsInsulin receptor mutations


5.

Exocrine pancreatic defectsChronic pancreatitisPancreatectomyNeoplasiaCystic fibrosisHemachromatosisFibrocalculous pancreatopathy

6.

EndocrinopathiesAcromegalyCushing syndromeHyperthyroidismPheochromocytomaGlucagonoma


7.

InfectionsCytomegalovirusCoxsackie virus B

8.

DrugsGlucocorticoidsThyroid hormoneα-interferonProtease inhibitorsβ-adrenergic agonistsThiazidesNicotinic acidPhenytoin


9.

Genetic syndromes associated with diabetesDown syndromeKleinfelter syndromeTurner syndrome

10.

Gestational diabetes mellitus


PATHOGENESIS OF TYPE 1 DIABETES MELLITUSPATHOGENESIS OF TYPE 1 DIABETES MELLITUS

This form of diabetes results from a severe This form of diabetes results from a severe lack of insulin caused by an immunologically lack of insulin caused by an immunologically mediated destruction of β cells. mediated destruction of β cells.

Most patients depend on insulin for survival; Most patients depend on insulin for survival; without insulin, they develop serious without insulin, they develop serious metabolic complications such as acute metabolic complications such as acute ketoacidosis and coma.ketoacidosis and coma.

It was also called "insulin-dependent diabetes It was also called "insulin-dependent diabetes mellitus" (IDDM)mellitus" (IDDM)

Type 1 diabetes most commonly develops in Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and childhood, becomes manifest at puberty, and progresses with age. progresses with age.

PATHOGENESIS OF TYPE 1 DIABETES PATHOGENESIS OF TYPE 1 DIABETES MELLITUSMELLITUS

Type 1 diabetes is an autoimmune disease Type 1 diabetes is an autoimmune disease in which islet destruction is caused in which islet destruction is caused primarily by T lymphocytes reacting against primarily by T lymphocytes reacting against as yet poorly definedas yet poorly defined β- β-cell antigens.cell antigens. As in As in all autoimmune diseases, genetic all autoimmune diseases, genetic susceptibility and environmental factors susceptibility and environmental factors play important roles in the pathogenesis. play important roles in the pathogenesis.

The classic manifestations of the disease The classic manifestations of the disease (hyperglycemia and ketosis) occur after (hyperglycemia and ketosis) occur after more than 90% of the β cells have been more than 90% of the β cells have been destroyeddestroyed


More commom than type 1. Pathogenesis is More commom than type 1. Pathogenesis is multifactorial.multifactorial.

Environmental factors, e.g. sedentary life style Environmental factors, e.g. sedentary life style and dietary habits, obesity play a major role. and dietary habits, obesity play a major role.

Genetic factors are even more important than Genetic factors are even more important than in type 1 diabetesin type 1 diabetes..

Unlike type 1 diabetes, the disease is not Unlike type 1 diabetes, the disease is not linked to genes involved in immune tolerance linked to genes involved in immune tolerance and regulation, and there is no evidence to and regulation, and there is no evidence to suggest an autoimmune basis for type 2 suggest an autoimmune basis for type 2 diabetes. diabetes.


The two metabolic defects that characterize The two metabolic defects that characterize type 2 diabetes are type 2 diabetes are

(1) a decreased ability of peripheral tissues (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and to respond to insulin (insulin resistance) and

(2)(2) β- β-cell dysfunction that is manifested as cell dysfunction that is manifested as inadequate insulin secretion in the face of inadequate insulin secretion in the face of insulin resistance and hyperglycemiainsulin resistance and hyperglycemia. .

In most cases, insulin resistance is the In most cases, insulin resistance is the primary event, and is followed by increasing primary event, and is followed by increasing degrees of β-cell dysfunction degrees of β-cell dysfunction

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

Insulin resistanceInsulin resistance Insulin resistance is defined as Insulin resistance is defined as

resistance to the effects of insulin on resistance to the effects of insulin on glucose uptake, metabolism, or storage. glucose uptake, metabolism, or storage. Insulin resistance is a characteristic Insulin resistance is a characteristic feature of most patients with type 2 feature of most patients with type 2 diabetes. diabetes.

Insulin resistance leads to decreased Insulin resistance leads to decreased uptake of glucose in muscle and adipose uptake of glucose in muscle and adipose tissues and an inability of the hormone to tissues and an inability of the hormone to suppress hepatic gluconeogenesis. suppress hepatic gluconeogenesis.


Insulin resistanceInsulin resistance

One of the things associated with insulin One of the things associated with insulin resistence is obesity and thereby tresistence is obesity and thereby the link he link between obesity and diabetes is mediated between obesity and diabetes is mediated via effects on insulin resistancevia effects on insulin resistance


β-cell dysfunctionβ-cell dysfunction β-cell dysfunction in type 2 diabetes β-cell dysfunction in type 2 diabetes

reflects the inability of these cells to reflects the inability of these cells to adapt themselves to the long-term adapt themselves to the long-term demands of peripheral insulin demands of peripheral insulin resistance and increased insulin resistance and increased insulin secretion. In states of insulin resistance secretion. In states of insulin resistance there is hyperinsulinemic state to there is hyperinsulinemic state to compensate for peripheral resistance compensate for peripheral resistance and can often maintain normal plasma and can often maintain normal plasma glucose for years. glucose for years.


β-cell dysfunctionβ-cell dysfunction

Eventually, β-cell compensation becomes Eventually, β-cell compensation becomes inadequate, and there is progression to inadequate, and there is progression to overt DM. The underlying basis for failure overt DM. The underlying basis for failure of β-cell adaptation is not known. It is of β-cell adaptation is not known. It is postulated that adverse effects of high postulated that adverse effects of high circulating free fatty acids ("lipotoxicity") or circulating free fatty acids ("lipotoxicity") or chronic hyperglycemia ("glucotoxicity"), chronic hyperglycemia ("glucotoxicity"), may play a role. may play a role.

β-β-cell dysfunction in type 2 diabetes cell dysfunction in type 2 diabetes manifests itself as both qualitative and manifests itself as both qualitative and quantitative defects.quantitative defects.

Maturity-Onset Diabetes of the Maturity-Onset Diabetes of the Young (MODY)Young (MODY)

2% to 5% of diabetic patients do not 2% to 5% of diabetic patients do not fall clearly into either the type 1 or fall clearly into either the type 1 or type 2 diabetes phenotype and are type 2 diabetes phenotype and are said to have "maturity-onset said to have "maturity-onset diabetes of the young." diabetes of the young."

In these patients, there is a In these patients, there is a primary primary defect indefect in β- β-cell function that occurs cell function that occurs withoutwithout β- β-cell loss, affecting eithercell loss, affecting either β- β-cells and/or insulin productioncells and/or insulin production. .

Maturity-Onset Diabetes of the Maturity-Onset Diabetes of the Young (MODY)Young (MODY)

MODY is the outcome of a MODY is the outcome of a heterogeneous group of genetic defects heterogeneous group of genetic defects characterized by characterized by

(1)(1) autosomal-dominant inheritance autosomal-dominant inheritance

(2)(2) early onset, usually before age 25, as early onset, usually before age 25, as opposed to after age 40 for most opposed to after age 40 for most patients with type 2 diabetes patients with type 2 diabetes

(3)(3) absence of obesityabsence of obesity

(4)(4) lack of islet cell autoantibodies and lack of islet cell autoantibodies and insulin resistance syndrome. insulin resistance syndrome.

PATHOGENESIS OF THE COMPLICATIONS OF PATHOGENESIS OF THE COMPLICATIONS OF DIABETESDIABETES

The morbidity associated with long-The morbidity associated with long-standing diabetes of either type standing diabetes of either type results from a number of serious results from a number of serious complications, involving both large- complications, involving both large- and medium-sized muscular arteries and medium-sized muscular arteries ((macrovascular disease),macrovascular disease), as well as as well as capillary dysfunction in target capillary dysfunction in target organs (organs (microvascular diseasemicrovascular disease). ).


Macrovascular disease causes Macrovascular disease causes accelerated atherosclerosisaccelerated atherosclerosis in diabetics, in diabetics, resulting in increased risk of myocardial resulting in increased risk of myocardial infarction, stroke, and lower-extremity infarction, stroke, and lower-extremity gangrene. gangrene.

Microvascular disease affects the retina, Microvascular disease affects the retina, kidneys, and peripheral nerves leading kidneys, and peripheral nerves leading to to diabetic retinopathydiabetic retinopathy, , nephropathynephropathy, , and and neuropathyneuropathy, respectively. Diabetes , respectively. Diabetes is one of the leading cause of blindness is one of the leading cause of blindness and end-stage renal disease.and end-stage renal disease.

PATHOGENESIS OF THE COMPLICATIONS OF PATHOGENESIS OF THE COMPLICATIONS OF DIABETES DIABETES

1) 1) Formation of Advanced Glycation End ProductsFormation of Advanced Glycation End Products.. AGEs are formed as a result of AGEs are formed as a result of

nonenzymatic reactions between nonenzymatic reactions between intracellular glucose-derived intracellular glucose-derived dicarbonyl precursors with the amino dicarbonyl precursors with the amino group of both intracellular and group of both intracellular and extracellular proteins.extracellular proteins.

AGEs have a number of chemical and AGEs have a number of chemical and biologic properties that are detrimental biologic properties that are detrimental to extracellular matrix components and to extracellular matrix components and the target cells of diabetic the target cells of diabetic complications (e.g., endothelial cells): complications (e.g., endothelial cells):


1) 1) Formation of Advanced Glycation End ProductsFormation of Advanced Glycation End Products..1) In case of e1) In case of extracellular matrix componentsxtracellular matrix components, such , such

as collagen or laminin, the formation of AGEs as collagen or laminin, the formation of AGEs causes cross-linking between polypeptides, causes cross-linking between polypeptides, resulting in abnormal matrix-matrix and matrix-resulting in abnormal matrix-matrix and matrix-cell interactions. cell interactions.

These AGE cross-linked proteins are resistant to These AGE cross-linked proteins are resistant to proteolytic digestion.proteolytic digestion. Thus, cross-linking Thus, cross-linking decreases protein removal while enhancing decreases protein removal while enhancing protein deposition. protein deposition.

These AGE-modified matrix components also These AGE-modified matrix components also trap trap nonglycated plasma or interstitial proteins e.g nonglycated plasma or interstitial proteins e.g in in large vessels, trapping low-density lipoprotein large vessels, trapping low-density lipoprotein (LDL), accelerates atherogenesis.(LDL), accelerates atherogenesis.


1) 1) Formation of Advanced Glycation End ProductsFormation of Advanced Glycation End Products

2) 2) Circulating plasma proteinsCirculating plasma proteins are modified by are modified by addition of AGE residues; these proteins, in addition of AGE residues; these proteins, in turn, bind to turn, bind to AGE receptorsAGE receptors on several cell on several cell types (endothelial cells, mesangial cells, types (endothelial cells, mesangial cells, macrophages) resulting inmacrophages) resulting in

a) release of a) release of cytokines and growth factorscytokines and growth factors from macrophages and mesangial cells from macrophages and mesangial cells

b) increased b) increased endothelial permeabilityendothelial permeability c) increased c) increased procoagulant activityprocoagulant activity on on

endothelial cells and macrophages endothelial cells and macrophages d) enhanced d) enhanced proliferation of and synthesis of proliferation of and synthesis of

extracellular matrixextracellular matrix by fibroblasts and by fibroblasts and smooth muscle cells. smooth muscle cells.

Table 24-7.

Effects

of

Advanced

Glycation

End

Products (AGEs)

Table 24-7.

Effects

of

Advanced

Glycation

End

Products (AGEs)

Table 24-7.

Effects

of

Advanced

Glycation

End

Products (AGEs)

Extracellular Matrix Components

Abnormal matrix-matrix and matrix-cell interactions

Corss-linking of polypeptides of same protein (e.g., collagen)

Trapping of nonglycated proteins (e.g., LDL, albumin)

Resistance to proteolytic digestion

Effects of advanced Effects of advanced glycation end productsglycation end products

Table 24-7.

Effects

of

Advanced

Glycation

End

Products (AGEs)

Effects

of

Advanced

Glycation

End

Products (AGEs)

Intracellular and Plasma Proteins

AGE receptor ligation leads to generation of reactive oxygen species and NF-κB activation

Target cells (endothelium, mesangial cells, macrophages) respond by:

Cytokines and growth factor secretion

Induction of procoagulant activity

Increased vascular permeability

Enhanced ECM production

Effects of advanced Effects of advanced glycation end productsglycation end products


2) 2) Activation of Protein Kinase CActivation of Protein Kinase C

Intracellular hyperglycemia cause Intracellular hyperglycemia cause abnormal activation of protein abnormal activation of protein kinase C which triggers multiple kinase C which triggers multiple pathways that lead to diabetic pathways that lead to diabetic retinopathy, atherosclerosis etc.retinopathy, atherosclerosis etc.


3) 3) Intracellular Hyperglycemia with Disturbances Intracellular Hyperglycemia with Disturbances in Polyol Pathwaysin Polyol Pathways

In some tissues that do not require In some tissues that do not require insulin for glucose transport (e.g., insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), nerves, lenses, kidneys, blood vessels), hyperglycemia leads to an increase in hyperglycemia leads to an increase in intracellular glucose that is then intracellular glucose that is then metabolized by the enzyme metabolized by the enzyme aldose aldose reductasereductase to sorbitol, a polyol, and to sorbitol, a polyol, and eventually to fructose. This ultimately eventually to fructose. This ultimately leads to increased cellular susceptibility leads to increased cellular susceptibility to oxidative stress. to oxidative stress.

MORPHOLOGY OF DIABETES AND ITS LATE MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONSCOMPLICATIONS

The morphologic changes are The morphologic changes are related to the late systemic related to the late systemic complications of diabetes. complications of diabetes.

There is extreme variability among There is extreme variability among patients in the time of onset of these patients in the time of onset of these complications, their severity, and the complications, their severity, and the particular organ or organs involved. particular organ or organs involved.

In individuals with tight control of In individuals with tight control of diabetes, the onset might be diabetes, the onset might be delayed.delayed.


In most patients, however, morphologic In most patients, however, morphologic changes are likely to be found in changes are likely to be found in arteries (arteries (macrovascular diseasemacrovascular disease), ), basement membranes of small vessels basement membranes of small vessels ((microangiopathymicroangiopathy), kidneys (), kidneys (diabetic diabetic nephropathynephropathy), retina (), retina (retinopathyretinopathy), ), nerves (nerves (neuropathyneuropathy), and other tissues. ), and other tissues.

These changes are seen in both type 1 These changes are seen in both type 1 and type 2 diabetes. and type 2 diabetes.

MORPHOLOGY OF DIABETES AND ITS LATE MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS PancreasCOMPLICATIONS Pancreas

Reduction in the number and size of Reduction in the number and size of islets,islets, mostly seen in type 1 DM. An increase mostly seen in type 1 DM. An increase in number and size of islets is characteristic in number and size of islets is characteristic of nondiabetic newborns of diabetic mothers of nondiabetic newborns of diabetic mothers (fetal islets show hyperplasia in response to (fetal islets show hyperplasia in response to maternal hyperglycemia. maternal hyperglycemia.

Leukocytic infiltration of the isletsLeukocytic infiltration of the islets (insulitis, mostly seen in type 1 DM) (insulitis, mostly seen in type 1 DM)

EM: show β-EM: show β-cell degranulationcell degranulation , (depletion , (depletion of stored insulin in the damaged β cells). of stored insulin in the damaged β cells).

Amyloid replacement of islets (type 2 Amyloid replacement of islets (type 2 DM).DM).

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS

Diabetic Diabetic Macrovascular DiseaseMacrovascular Disease

The hallmark of diabetic The hallmark of diabetic macrovascular disease is macrovascular disease is accelerated atherosclerosisaccelerated atherosclerosis involving aorta, large- & medium-involving aorta, large- & medium-sized arteries. sized arteries. Myocardial Myocardial infarction, due to atheroma of infarction, due to atheroma of coronary arteries, is most common coronary arteries, is most common cause of death in diabetics.cause of death in diabetics.

Gangrene of the lower extremities,Gangrene of the lower extremities, due to advanced vascular disease, is due to advanced vascular disease, is 100 times more common in diabetics 100 times more common in diabetics than in nondiabetics.than in nondiabetics.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONSMORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS

Hyaline arteriolosclerosisHyaline arteriolosclerosis

Hyaline arteriolosclerosisHyaline arteriolosclerosis, the , the vascular lesion associated with vascular lesion associated with hypertension is both more hypertension is both more prevalent and more severe in prevalent and more severe in diabetics than in nondiabetics, but diabetics than in nondiabetics, but it is not specific for diabetes and it is not specific for diabetes and may be seen in elderly may be seen in elderly nondiabetics without hypertensionnondiabetics without hypertension


Diabetic MicroangiopathyDiabetic Microangiopathy

A consistent finding is A consistent finding is diffuse thickening of diffuse thickening of basement membranesbasement membranes. The thickening is seen . The thickening is seen in the capillaries of skin, skeletal muscle, retina, in the capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla. It is also be renal glomeruli, and renal medulla. It is also be seen in nonvascular structures as renal tubules, seen in nonvascular structures as renal tubules, Bowman capsule and peripheral nerves. The Bowman capsule and peripheral nerves. The material is type IV collagen. material is type IV collagen.

Note: despite increase in the thickness of Note: despite increase in the thickness of basement membranes, basement membranes, diabetic capillaries are diabetic capillaries are more leaky to plasma proteins. more leaky to plasma proteins.

The microangiopathy underlies the The microangiopathy underlies the development of diabetic nephropathy, development of diabetic nephropathy, retinopathy etc.retinopathy etc.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONMORPHOLOGY OF DIABETES AND ITS LATE COMPLICATION

Diabetic Nephropathy Diabetic Nephropathy The kidneys are prime targets of The kidneys are prime targets of

diabetes. Renal failure is second diabetes. Renal failure is second only to myocardial infarction as a only to myocardial infarction as a cause of death from this disease. It cause of death from this disease. It is a major cause of morbidity and is a major cause of morbidity and mortality.mortality.

Three lesions are encountered: Three lesions are encountered: glomerular, vascular and glomerular, vascular and pyelonephritis.pyelonephritis.

MORPHOLOGY OF DIABETES AND ITS LATE MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONCOMPLICATION

Diabetic Nephropathy: Diabetic Nephropathy: glomerular glomerular lesionslesions

1) There is glomerular capillary 1) There is glomerular capillary basement membrane thickening, basement membrane thickening, diffuse mesangial sclerosis, nodular diffuse mesangial sclerosis, nodular glomerulosclerosis and/or exudative glomerulosclerosis and/or exudative lesions resulting in progressive lesions resulting in progressive proteinuria and chronic renal failureproteinuria and chronic renal failure

-Diffuse mesangial sclerosis: -Diffuse mesangial sclerosis: in in patients with >10 years of DM. patients with >10 years of DM.

-Nodular glomerulosclerosis:-Nodular glomerulosclerosis: Also Also called as called as Kimmelstiel-Wilson lesion.Kimmelstiel-Wilson lesion.


Diabetic Nephropathy: Diabetic Nephropathy: renal vascular renal vascular lesionslesions

2) Renal atherosclerosis and 2) Renal atherosclerosis and arteriolosclerosis constitute part of arteriolosclerosis constitute part of the macrovascular disease in the macrovascular disease in diabetics. The kidney is one of the diabetics. The kidney is one of the most frequently and severely most frequently and severely affected organs; Hyaline affected organs; Hyaline arteriolosclerosis affects not only arteriolosclerosis affects not only the afferent but also the efferent the afferent but also the efferent arteriole. arteriole.


Diabetic Nephropathy: Diabetic Nephropathy: pyelonephritis,pyelonephritis, 3) Pyelonephritis is an acute or 3) Pyelonephritis is an acute or

chronic inflammation of the kidneys chronic inflammation of the kidneys that usually begins in the that usually begins in the interstitial tissue and then spreads interstitial tissue and then spreads to affect the tubules. One special to affect the tubules. One special pattern of acute pyelonephritis, pattern of acute pyelonephritis, necrotizing papillitisnecrotizing papillitis (or papillary (or papillary necrosis), is much more prevalent necrosis), is much more prevalent in diabetics than in nondiabeticsin diabetics than in nondiabetics


Diabetic Ocular Complications.Diabetic Ocular Complications. The ocular involvement may take the The ocular involvement may take the form of retinopathy, cataract form of retinopathy, cataract formation, or glaucoma.formation, or glaucoma.

Diabetic Neuropathy.Diabetic Neuropathy. The central The central and peripheral nervous systems are and peripheral nervous systems are not spared by diabetes. not spared by diabetes.

CLINICAL FEATURES OF DIABETECLINICAL FEATURES OF DIABETES S TYPE 1TYPE 1

Type 1 diabetesType 1 diabetes was traditionally thought was traditionally thought to occur primarily in those under age 18 to occur primarily in those under age 18 but is now known to occur at any age. but is now known to occur at any age.

The onset is marked by polyuria, The onset is marked by polyuria, polydipsia, polyphagia. Despite the polydipsia, polyphagia. Despite the increased appetite, catabolic effects increased appetite, catabolic effects prevail, resulting in weight loss and prevail, resulting in weight loss and muscle weakness. muscle weakness. The combination of The combination of polyphagia and weight loss is polyphagia and weight loss is paradoxical and should always raise the paradoxical and should always raise the suspicion of diabetessuspicion of diabetes. .

CLINICAL FEATURES OF CLINICAL FEATURES OF DIABETES TYPE 1DIABETES TYPE 1

Diabetic ketoacidosisDiabetic ketoacidosis (DKA) is a serious (DKA) is a serious complication of type 1 diabetes but complication of type 1 diabetes but uncommomn in type 2 diabetes. These uncommomn in type 2 diabetes. These patients have marked insulin deficiency, and patients have marked insulin deficiency, and the release of the catecholamine hormone the release of the catecholamine hormone epinephrineepinephrine stimulates the release of stimulates the release of glucagon. The insulin deficiency coupled glucagon. The insulin deficiency coupled with glucagon excess, severely exacerbating with glucagon excess, severely exacerbating hyperglycemia. The hyperglycemia causes hyperglycemia. The hyperglycemia causes an osmotic diuresis and dehydration an osmotic diuresis and dehydration characteristic of ketoacidosis. characteristic of ketoacidosis.

CLINICAL FEATURES OF CLINICAL FEATURES OF DIABETES TYPE 1DIABETES TYPE 1

The second major effect of an alteration in the The second major effect of an alteration in the insulin:glucagon ratio is activation of the insulin:glucagon ratio is activation of the ketogenic machinery. Insulin deficiency ketogenic machinery. Insulin deficiency stimulates lipoprotein lipase, with resultant stimulates lipoprotein lipase, with resultant excessive breakdown of adipose stores, and excessive breakdown of adipose stores, and excessive release of free fatty acids from excessive release of free fatty acids from adipose tissue and hepatic oxidation generates adipose tissue and hepatic oxidation generates ketone bodies ketone bodies (acetoacetic acid and β- (acetoacetic acid and β-hydroxybutyric acid). The rate at which ketone hydroxybutyric acid). The rate at which ketone bodies are formed may exceed the rate at bodies are formed may exceed the rate at which acetoacetic acid and β-hydroxybutyric which acetoacetic acid and β-hydroxybutyric acid can be utilized by peripheral tissues, acid can be utilized by peripheral tissues, leading to leading to ketonemiaketonemia and and ketonuriaketonuria. This can . This can lead to systemic lead to systemic metabolic ketoacidosismetabolic ketoacidosis. .

CLINICAL FEATURES OF DIABETES CLINICAL FEATURES OF DIABETES TYPE 2TYPE 2

Type 2 DMType 2 DM may also present with polyuria may also present with polyuria and polydipsia, but unlike in type 1 and polydipsia, but unlike in type 1 diabetes, patients are often older (over 40 diabetes, patients are often older (over 40 years) and frequently obese. However, with years) and frequently obese. However, with the increase in obesity and sedentary the increase in obesity and sedentary lifestyle in our society, type 2 diabetes is lifestyle in our society, type 2 diabetes is now seen in children and adolescents with now seen in children and adolescents with increasing frequency. increasing frequency. Most frequently, Most frequently, however, the diagnosis is made after however, the diagnosis is made after routine blood or urine testing in routine blood or urine testing in asymptomatic personsasymptomatic persons..

CLINICAL FEATURES OF DIABETES CLINICAL FEATURES OF DIABETES TYPE 2TYPE 2

In the decompensated state, these patients In the decompensated state, these patients may develop may develop hyperosmolar nonketotic hyperosmolar nonketotic comacoma, a syndrome associated with severe , a syndrome associated with severe dehydration resulting from sustained dehydration resulting from sustained osmotic diuresis in patients who do not osmotic diuresis in patients who do not drink enough water to compensate for drink enough water to compensate for urinary losses from chronic hyperglycemia. urinary losses from chronic hyperglycemia.

Typically, patient is an elderly diabetic who Typically, patient is an elderly diabetic who is disabled by a stroke or an infection and is is disabled by a stroke or an infection and is unable to maintain adequate water intake. unable to maintain adequate water intake.

CLINICAL FEATURES OF DIABETES CLINICAL FEATURES OF DIABETES TYPE 1& 2TYPE 1& 2

In both forms, it is the long-term effects of In both forms, it is the long-term effects of diabetes, more than the acute metabolic diabetes, more than the acute metabolic complications, that are responsible for the complications, that are responsible for the overwhelming proportion of morbidity and overwhelming proportion of morbidity and mortality. mortality.

In most instances, these complications appear In most instances, these complications appear approximately 15 to 20 years after the onset of approximately 15 to 20 years after the onset of hyperglycemia. hyperglycemia.

Cardiovascular events such as myocardial Cardiovascular events such as myocardial infarction, renal vascular insufficiency, and infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common cerebrovascular accidents are the most common causes of mortality in long-standing diabetics.causes of mortality in long-standing diabetics.

HypertensionHypertension is approximately twice as frequent is approximately twice as frequent in diabetics as in those without the disease. in diabetics as in those without the disease.

DyslipidemiasDyslipidemias

CLINICAL FEATURES OF DIABETES CLINICAL FEATURES OF DIABETES TYPE 1& 2TYPE 1& 2

Diabetic nephropathyDiabetic nephropathy:leading cause of end-stage :leading cause of end-stage renal disease nephropathyrenal disease nephropathy

Visual impairment, sometimes total blindness, is Visual impairment, sometimes total blindness, is a consequences of long-standing diabetes.a consequences of long-standing diabetes.

Diabetic neuropathyDiabetic neuropathy can elicit a variety of clinical can elicit a variety of clinical syndromes, afflicting the central nervous system, syndromes, afflicting the central nervous system, peripheral sensorimotor nerves, and the peripheral sensorimotor nerves, and the autonomic nervous system. autonomic nervous system.

Diabetics are susceptibile to infections of the skin Diabetics are susceptibile to infections of the skin and to tuberculosisand to tuberculosis, , pneumoniapneumonia, , and and pyelonephritis.pyelonephritis. In an individual with diabetic In an individual with diabetic neuropathy, a trivial infection in a toe may be the neuropathy, a trivial infection in a toe may be the first event in a long succession of complications first event in a long succession of complications (gangrene, bacteremia, pneumonia) that may (gangrene, bacteremia, pneumonia) that may ultimately lead to death. ultimately lead to death.

PREVENTIONPREVENTION primary prevention of type 2 primary prevention of type 2

diabetes by lifestyle and dietary diabetes by lifestyle and dietary alterations alterations

secondary prevention of diabetic secondary prevention of diabetic complications by strict glycemic complications by strict glycemic control has become increasingly control has become increasingly recognized. recognized.

It is also hoped that islet cell It is also hoped that islet cell transplantation will result in a cure transplantation will result in a cure for those afflicted with type 1 for those afflicted with type 1 diabetesdiabetes

Type 1 DM Type 2 DM

Clinical Onset: <20 years Onset: >30 years

Normal weight Obese

Markedly decreased blood insulin

Increased blood insulin (early);normal to moderate decreased insulin (late)

Anti-islet cell antibodies No anti-islet cell antibodies

Ketoacidosis common Ketoacidosis rare; nonketotic hyperosmolar coma

Type 1 Versus Type 2 Type 1 Versus Type 2 Diabetes Mellitus (DM) Diabetes Mellitus (DM)

TYPE 1 DM TYPE 2 DM

Genetics

30-70% concordance in twins 50-90% concordance in twins

Linkage to MHC Class II HLA genes

No HLA linkageLinkage to candidate diabetogenic genes (PPARγ, calpain 10)

Type 1 Versus Type 2 Type 1 Versus Type 2 Diabetes Mellitus (DM)Diabetes Mellitus (DM)

TYPE 1 DM TYPE 2 DM

Pathogenesis

Autoimmune destruction of β-cells mediated by T cells and humoral mediators (TNF, IL-1, NO)

Insulin resistance in skeletal muscle, adipose tissue and liverβ-cell dysfunction and relative insulin deficiency

Absolute insulin deficiency


TYPE 1

TYPE 1 DM TYPE 2 DM

Islet cells

Insulitis early No insulitis

Marked atrophy and fibrosis

Focal atrophy and amyloid deposition

β-cell depletion Mild β-cell depletion


hepatobilary system hala kfoury kassouf, md. normal liver

Documents

branch of hepatic vein

portal vein

hepatic vein outflow

biliary disease

inferior vena cava liver

central vein

accompanying hepatic

viral hepatitis