HEPATOBILARY SYSTEM Hala Kfoury Kassouf, MD.

HEPATOBILARY SYSTEM Hala Kfoury Kassouf, MD

NORMAL LIVER

Cut surface normal liver
Cut surface normal liver. Note portal vein carrying blood to liver, with accompanying hepatic artery and bile ducts. At lower right is a branch of hepatic vein draining blood from the liver to the inferior vena cava

Liver is divided histologically into lobules
Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply.

Bilirubin metabolism and elimination
Bilirubin metabolism and elimination. 1, Normal bilirubin production from heme (0.2 to 0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins. 2, Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3, Hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile. 5, Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.

Predominantly Unconjugated Hyperbilirubinemia
Excess production of bilirubin Hemolytic anemias Resorption of blood from internal hemorrhage (e.g., alimentary tract bleeding, hematomas) Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia) Reduced hepatic uptake

Drug interference with membrane carrier systems Some cases of Gilbert syndrome Impaired bilirubin conjugation Physiologic jaundice of the newborn (decreased UGT1A1 activity, decreased excretion) Breast milk jaundice (β-glucuronidases in milk)

Genetic deficiency of UGT1A1 activity (Crigler-Najjar syndrome types I and II) Gilbert syndrome (mixed etiologies) Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)

Predominantly Conjugated Hyperbilirubinemia
Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome) Impaired bile flow

Hereditary Hyperbilirubinemias
Disorder Inheritance Defects in Bilirubin Metabolism Liver Pathology Clinical 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 Generally mild, occasional kernicterus Gilbert syndrome Autosomal dominant? Innocuous

Hereditary Hyperbilirubinemias
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 Decreased hepatic uptake and storage? Decreased biliary excretion? Normal

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

Cirrhosis Cirrhosis is defined by three characteristics
1)Fibrosis in the form of delicate bands or broad scars/septa 2)Nodules containing regenerating hepatocytes encircled by fibrosis, with diameters varying from very small (<3 mm, micronodules) to large (several centimeters, macronodules) 3)Disruption of the architecture of the entire liver

features of cirrhosis Vascular architecture is reorganized by the parenchymal damage and scarring, with the formation of abnormal interconnections between vascular inflow and hepatic vein outflow channels. Fibrosis is the key feature of progressive damage to the liver. Once cirrhosis has developed, reversal is thought to be rare.

Classifiation of cirrhosis
The classification is based on the underlying etiology. Many forms of cirrhosis (particularly alcoholic cirrhosis) are initially micronodular, but there is a tendency for nodules to increase in size with time.

Classifiation of cirrhosis based on causes
Alcoholic liver disease % to 70% Viral hepatitis % Biliary diseases % to 10% Primary hemochromatosis % Wilson disease Rare α1-Antitrypsin deficiency Rare Cryptogenic cirrhosis % to 15%

Classifiation of cirrhosis
Infrequent types of cirrhosis also include the cirrhosis developing in infants and children with galactosemia and tyrosinosis drug-induced cirrhosis. Severe fibrosis can occur in the setting of cardiac disease (sometimes called "cardiac cirrhosis,"). In some cases there is no cause and these are referred to as cryptogenic cirrhosis. Once cirrhosis is established, it is usually impossible to establish an etiologic diagnosis on morphologic grounds alone

Pathogenesis of cirrhosis
The pathogenetic processes in cirrhosis are progressive fibrosis and reorganization of the vascular microarchitecture of the liver In the normal liver, interstitial collagens (types I and III) are concentrated in portal tracts and around central veins. The type IV collagen(reticulin) is in the space of Disse.

In cirrhosis, types I and III collagen are deposited in the lobule, creating delicate or broad septal tracts. There is loss of fenestrations in the sinusoidal endothelial cells (capillarization of sinusoids, that is the sinusoidal space comes to resemble a capillary rather than a channel for exchange of solutes between hepatocytes and plasma).

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

Collagen synthesis is stimulated by Chronic inflammation, with production of inflammatory cytokines. Cytokine production by activated endogenous cells (Kupffer cells, endothelial cells, hepatocytes, and bile duct epithelial cells). Disruption of the normal extracellular matrix. Direct stimulation of stellate cells by toxins

The cirrhotic patient may develop jaundice and even hepatic failure’

Clinical Features All forms of cirrhosis may be clinically silent.
When symptomatic they lead to nonspecific clinical manifestations: anorexia, weight loss, weakness, osteoporosis, and, in advanced disease, frank debilitation. Incipient or overt hepatic failure may develop.

Clinical Features progressive liver failure ,
The ultimate mechanism of most cirrhotic deaths is progressive liver failure , a complication related to portal hypertension, or the development of hepatocellular carcinoma

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 9 March 2006 01:41 PM)
© 2005 Elsevier

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

Micronodular cirrhosis: The regenerative nodules are quite small, averaging less than 3 mm in size. The most common cause for this is chronic alcoholism.

Regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes as well as a proliferation of bile ducts.

HEPATITIS

Infectious Disorders Inflammatory disorders of the liver dominate the clinical practice of hepatology. Among inflammatory disorders, infection is by far the most frequent. The foremost hepatic infections are viral in origin. Other infections in which the hepatic lesion is prominent include miliary tuberculosis, malaria, staphylococcal bacteremia, the salmonelloses, candida, and amebiasis

VIRAL HEPATITIS The term "viral hepatitis" is reserved for infection of the liver caused by a group of viruses having a particular affinity for the liver called Hepatotropic viruses. Hepatitis A Virus Hepatitis B Virus Hepatitis C Virus Hepatitis D Virus Hepatitis E Virus

Hepatitis A Virus infection
Is a benign, self-limited disease with an incubation period of 2 to 6 weeks. HAV does not cause chronic hepatitis or a carrier state. Fulminant hepatitis is rare. HAV is a small, nonenveloped, single-stranded RNA picornavirus that occupies its own genus, Hepatovirus. Ultrastructurally, HAV is an icosahedral capsid

Hepatitis A Virus HAV is spread by ingestion of contaminated water and foods and is shed in the stool for 2 to 3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact with an infected individual or fecal-oral contamination during is the mode of spread.

Hepatitis A Virus This accounts for most cases of outbreaks in institutional settings such as schools and nurseries and the waterborne epidemics in places where people live in overcrowded, unsanitary conditions. Infected workers in the food industry may also be the source of outbreaks

Hepatitis A Virus HAV is not shed in any significant quantities in saliva, urine, or semen. Because HAV viremia is transient, blood-borne transmission of HAV occurs only rarely; therefore, donated blood is not specifically screened for this virus.

Serologic Diagnosis of HAV
Acute infection is marked by anti-HAV IgM in serum IgG appears as IgM declines (with in a few months) and can persist for years, conferring immunity.

Hepatitis B Virus Hepatitis B virus (HBV) can produce
(1) an asymptomatic carrier state (2) acute hepatitis with recovery (3) chronic hepatitis, either indolent or progressive (4) progression to cirrhosis, (5) fulminant hepatitis with massive liver necrosis, and (6) the backdrop for hepatitis D virus infection. HBV also plays an important role in the development of hepatocellular carcinoma.

Hepatitis B Virus Liver disease due to HBV is an enormous problem globally, with an estimated worldwide carrier rate of 350 million. It is estimated that HBV has infected over 2 billion of the individuals alive today at some point in their lives. Seventy-five percent of all chronic carriers live in Asia and the Western Pacific rim. Because circulating host IgG antibodies effectively neutralize HBV, the HBV vaccine has been highly effective in reducing the prevalence of HBV in endemic areas.

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

Hepatitis B Virus Three major antigens are associated with HBV
An outer coat antigen called as HBsAg/Australia antigen (hepatitis surface antigen). 2 antigens associated with the viral nucleocapsid core, HBcAg (core antigen) and HBeAg.

Hepatitis B Virus HBV has a prolonged incubation period (4 to 26 weeks). It is present in all physiologic and pathologic body fluids, with the exception of stool. HBV is a hardy virus and can withstand extremes of temperature and humidity.

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

Hepatitis B Virus Blood and body fluids are the primary vehicles of transmission, virus may also be spread by contact with body secretions such as semen, saliva, sweat, tears, breast milk, and pathologic effusions. Transfusion, blood products, dialysis, needle-stick accidents among health care workers, intravenous drug abuse, and homosexual activity constitute the primary risk categories for HBV infection. In endemic regions such as Africa and Southeast Asia, spread from an infected mother to a neonate during birth (vertical transmission) is common. These neonatal infections often lead to the carrier state for life

Hepatitis B Virus: Serologic Diagnosis
After exposure to HBV, the long asymptomatic 4- to 26-week incubation period (mean: 6 to 8 weeks) is followed by acute disease lasting many weeks to months. Most patients experience a self-limited illness. HBsAg appears before the onset of symptoms, peaks during overt disease, and then declines to undetectable levels in 3 to 6 months. It is a marker of active infection.

HBeAg, HBV-DNA, and DNA polymerase appear in the serum soon after HBsAg before the onset of acute disease, and all signify active viral replication. HBeAg usually declines within weeks and persustence indicates probable progression to chronic disease.

IgM anti-HBc is the first antibody to appear and it becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevation of serum aminotransferases. Over months, the IgM antibody is replaced by IgG anti-HBc. Anti-HBe follows IgM anti-HBc and is detectable shortly after the disappearance of HBeAg, implying that the acute infection has peaked and the disease is on the wane.

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

Figure Sequence of serologic markers for hepatitis B viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic infection. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 12 March :00 AM) © 2005 Elsevier

Hepatitis B Virus carrier state
The carrier state is defined by the presence of HBsAg in serum for 6 months or longer after initial detection. 90% of infants infected at birth become carriers.

Hepatitis C virus HCV is a major cause of liver disease worldwide.
Causes 90% of transfusion-associated hepatitis. Patients have greater predilection to develop chronic liver disease then with HBV and cirrhosis eventually occurs in approximately 20% of patients with chronic HCV infection Hence, the prevalence of life-limiting chronic liver disease and the risk of hepatocellular carcinoma are only expected to increase.

Hepatitis C Virus The major routes of transmission are inoculations and blood transfusions intravenous drug users, hemophilacs and hemodialysis patients are the primary risk group. Health care workers are also at risk. Sexual transmission is rare.

Hepatitis C Virus A characteristic feature of HCV infection, is repeated bouts of hepatic damage. Persistent infection and chronic hepatitis are the hallmarks of HCV infection, despite the generally asymptomatic nature of the acute illness. Cirrhosis may develop over 5 to 20 years after acute infection.

Hepatitis C Virus HCV is a hepacivirus and occupies a genus in the Flaviviridae family. HCV is a small, enveloped, single-stranded RNA virus. The incubation period for HCV hepatitis ranges from 2 to 26 weeks.

Serologic Diagnosis of HCV
HCV RNA is detectable in blood for 1 to 3 weeks during active infection, coincident with elevations in serum transaminases . In acute HCV infection, anti-HCV antibodies are detected. The clinical course of acute HCV hepatitis is milder than that of HBV; rare cases may be severe.

Serologic Diagnosis of HCV
In chronic HCV infection, circulating HCV RNA persists in many patients despite the presence of neutralizing antibodies. A clinical feature that is quite characteristic of chronic HCV infection is episodic elevations in serum aminotransferases, with intervening normal or near-normal periods. Note: elevated titers of anti-HCV IgG following active infection do not confer effective immunity.

HEPATITIS D VIRUS Also called "hepatitis delta virus," hepatitis D virus (HDV) is a unique single stranded RNA virus that is replication defective, causing infection only when it is encapsulated by HBsAg. Thus, HDV is absolutely dependent on the genetic information provided by HBV for multiplication and causes hepatitis only in the presence of HBV.

Delta hepatitis thus arises in two settings
Acute coinfection by HDV and HBV. Superinfection of a chronic carrier of HBV by HDV . The carrier may have been previously "healthy" or may have had underlying chronic hepatitis

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

Hepatitis D Virus When HDV is superimposed on chronic HBV infection, there are three possible outcomes: acute, severe hepatitis may erupt in a previously healthy HBV carrier; mild HBV hepatitis may be converted into fulminant disease; and/or chronic, progressive disease may develop (in 80% of patients), often culminating in cirrhosis

Hepatitis D Virus HDV resembles the "Dane particle" of HBV with a single stranded RNA. Serology: HDV-RNA is present in blood and in liver just before and in initial acute phase of infection.

Hepatitis E virus HEV hepatitis is an enterically transmitted, water-borne infection that occurs primarily in young to middle-aged adults. Epidemics have been reported from Asia , Africa, and Mexico. It has a high mortality rate in pregnant women (20%). In most cases, the disease is self-limiting; HEV is not associated with chronic liver disease.

Hepatitis E virus The average incubation period following exposure is 6 weeks. HEV is an unenveloped, single-stranded RNA Caliciviridae virus . A specific antigen (HEV Ag) can be identified in the cytoplasm of hepatocytes during active infection, and virions are shed in stool during the acute illness.

Hepatitis A Virus Hepatitis B Virus Hepatitis C Virus Hepatitis D Virus Hepatitis E Virus Hepatitis G Virus Agent Icosahedral capsid, ssRNA Enveloped dsDNA Enveloped ssRNA Unenveloped ssRNA ssRNA virus Transmission Fecal-oral Parenteral; close contact Waterborne Parenteral Incubation period 2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown Carrier state None % of blood donors in U.S. and Western world % of blood donors in U.S. and Western world 1-10% in drug addicts and hemophiliacs 1-2% of blood donors in U.S. Chronic hepatitis 5-10% of acute infections >50% <5% coinfection, 80% upon superinfection Hepatocellular carcinoma No Yes No increase above HBV Unknown, but unlikely

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

Clinical features of hepatitis
Acute asymptomatic infection with recovery: serologic evidence only Acute symptomatic hepatitis with recovery: anicteric or icteric Chronic hepatitis: without or with progression to cirrhosis Fulminant hepatitis: with massive to submassive hepatic necrosis Carrier state

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

Acute Symptomatic Infection with Recovery
Any one of the hepatotropic viruses can cause symptomatic acute viral hepatitis, although this is uncommon for acute HCV infection. Whatever the agent, the disease is more or less the same and can be divided into four phases: an incubation period, a symptomatic preicteric phase, a symptomatic icteric phase, and convalescence. Peak infectivity occurs during the last asymptomatic days of the incubation period and the early days of acute symptoms

Acute Symptomatic Infection with Recovery: preicteric phase
The preicteric phase is marked by nonspecific, constitutional symptoms. Malaise is followed in a few days by general fatigability, nausea, and loss of appetite. Weight loss, low-grade fever, headaches, muscle and joint aches, and pains and diarrhea are inconstant symptoms. Physical examination reveals a mildly enlarged, tender liver.

Acute Symptomatic Infection with Recovery: icteric phase
The icteric phase, is caused mainly by conjugated hyperbilirubinemia. Curiously, as jaundice appears and these patients enter the icteric phase, other symptoms begin to abate and the patient feels better. The jaundice is caused predominantly by conjugated hyperbilirubinemia and hence is accompanied by dark-colored urine related to the presence of conjugated bilirubin. The stools may become lighter owing to cholestasis.

Acute Symptomatic Infection with Recovery: icteric phase
Retention of bile acids can cause distressing pruritus. The liver may be mildly enlarged and moderately tender to percussion. Laboratory findings include elevated serum liver enzymes, prolonged prothrombin time and hyperglobulinemia, hyperbilirubinemia; the serum alkaline phosphatase is usually only mildly elevated. In a few weeks to perhaps several months, the jaundice and most of the other systemic symptoms clear as convalescence begins.

Key Morphologic Features of Acute Viral Hepatitis
Enlarged, reddened liver; greenish if cholestatic Parenchymal changes: -Hepatocyte injury: swelling (ballooning degeneration) -Hepatocyte necrosis: isolated cells or clusters of cells or the entire lobule show necrosis: -hepatocytes can undergo apoptotsis (councilman bodies). -In severe cases: bridging necrosis (portal-portal, central-central, portal-central). Macrophages (Kupffer cells) engulf necrotic hepatocytes -Lobular disarray: loss of normal architecture

Key Morphologic Features of Acute Viral Hepatitis
Portal tracts -Inflammation: predominantly mononuclear -Inflammatory spillover into adjacent parenchyma, with hepatocyte necrosis called as interface hepatitis/piecemeal necrosis can occur in both acute and chronic hepatitis. Other findings: cholestasis, hypertrophy and hyperplasia of Kupffer cells and sinusoidal cells.

A mononuclear inflammatory cell infiltrate extends from portal areas and disrupts limiting plate of hepatocytes which are undergoing necrosis, (piecemeal) necrosis of chronic active hepatitis.

Hepatitis B: large pink cell undergoing "ballooning degeneration" (right arrow). At later stage, a dying hepatocyte is seen shrinking to form an eosinophilic "councilman body" (left arrow).

Chronic hepatitis Chronic hepatitis is defined as symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis. Although the hepatitis viruses (HBV, HCV, and HBV + HDV) are responsible for most cases of chronic hepatitis, there are many other causes of chronic hepatitis and they include chronic alcoholism, Wilson disease, α1-antitrypsin deficiency, various drugs and autoimmunity. In all instances of chronic hepatitis, etiology is the single most important indicator of likelihood to progress to cirrhosis.

Chronic viral hepatitis
Chronic viral hepatitis constitutes a "carrier" state, in that these individuals harbor replicating virus and therefore can transmit an organism. With "carriers" of hepatotropic viruses, there are those who harbor one or more of the viruses but are suffering little or no adverse clinical or histologic effects (healthy carriers) those who have chronic disease by laboratory or histologic findings but are essentially free of symptoms or disability those who have clinically symptomatic chronic disease.

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

Chronic Hepatitis, morphology
Some changes are shared with acute hepatitis. Hepatocyte injury, necrosis, and regeneration Sinusoidal cell reactive changes Portal tract Inflammation: -Confined to portal tracts, or -Spillover into adjacent parenchyma, with necrosis of hepatocytes ("interface hepatitis"), or -Bridging inflammation and necrosis Fibrosis: -continued loss of hepatocytes results in fibrous septa formation which ultimately leads to cirrhosis HBV: "ground-glass" hepatocytes, "sanded" nuclei HCV: bile duct damage, lymphoid aggregate formation Cirrhosis: The end-stage outcome

Viral hepatitis C which is at a high stage with extensive fibrosis and progression to macronodular cirrhosis, as evidenced by the large regenerative nodule at the center right.

Morphology of Acute and Chronic Hepatitis
HBV-infected hepatocytes may exhibit a cytoplasm packed with spheres and tubules of HBsAg, producing a finely granular eosinophilic cytoplasm ("ground glass hepatocytes," . HCV-infected livers frequently show lymphoid aggregates within portal tracts and macrovesicular steatosis.

Chronic Hepatitis. The histologic features of chronic hepatitis range from exceedingly mild to severe. In the mildest forms, inflammation is only in portal tracts and consists mainly of lymphocytes and macrophages. The hallmark of irreversible liver damage is the deposition of fibrous tissue. At first, only portal tracts exhibit increased fibrosis, but with time, periportal septal fibrosis occurs, followed by linking of fibrous septa between lobules (bridging fibrosis).

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

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

fulminant hepatitis When hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2 to 3 weeks, it is termed fulminant hepatic failure. A less rapid course, extending up to 3 months, is called subfulminant failure. Causes of include Acute viral hepatitis Acute drug induced hepatitis eg acetaminophen, isoniazid etc. Acute hepatitis due to poisoning eg. exposure to the mycotoxins of the mushroom Amanita phalloides Others eg. ischemic hepatic necrosis, obstruction of the hepatic veins, massive malignant infiltration of the liver, Wilson disease, hyperthermia (heat stroke), and microvesicular steatosis syndromes, particularly acute fatty liver of pregnancy.

Autoimmune hepatitis is a chronic hepatitis with histologic features like that of chronic viral hepatitis. This disease may run an indolent or severe course; salient features include the following: Female predominance, particularly in young and perimenopausal women. The absence of viral serologic markers Elevated serum IgG and γ-globulin levels (>1.5 times normal) High serum titers of autoantibodies in 80% of cases, including antinuclear (ANA), antismooth muscle (SMA) etc. Negative anti-mitochondrial antibodies

Autoimmune hepatitis In untreated severe disease, as many as 40% of patients die within 6 months of diagnosis, and cirrhosis develops in at least 40% of survivors. Treatment include immunosuppressive therapy, and liver transplantation. Associated with other autoimmune diseases eg. Rheumatoid arthritis, Sjogren’s syndrome etc.

Intrahepatic Biliary Tract Disease
three disorders of intrahepatic bile ducts secondary biliary cirrhosis primary biliary cirrhosis primary sclerosing cholangitis

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

Secondary biliary cirrhosis: morphology
Secondary inflammation resulting from biliary obstruction initiates periportal fibrosis, which eventually leads to hepatic scarring and nodule formation, generating secondary biliary cirrhosis. Subtotal obstruction may promote secondary bacterial infection of the biliary tree (ascending cholangitis), which aggravates the inflammatory injury. Enteric organisms such as coliforms and enterococci are common culprits.

Secondary biliary cirrhosis
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

Primary biliary cirrhosis
Primary biliary cirrhosis is a chronic, progressive, and often fatal cholestatic liver disease, characterized by the destruction of intrahepatic bile ducts, portal inflammation and scarring, and the eventual development of cirrhosis and liver failure. The primary feature of this disease is a nonsuppurative, inflammatory destruction of medium-sized intrahepatic bile ducts. Cirrhosis develops only after many years.

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

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

Morphology. During the precirrhotic stage, portal tracts and bile ducts are infiltrated by lymphocytes and may exhibit noncaseating granulomatous inflammation. There is bile duct destruction. With time, there is bile ductular proliferation, inflammation, and necrosis of the adjacent periportal hepatic parenchyma. Over years to decades, relentless portal tract scarring and bridging fibrosis lead to cirrhosis.

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

Etiology Sex predilection Symptoms and signs Laboratory findings Important pathologic findings before cirrhosis develops 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 cholangitis
Primary sclerosing cholangitis is characterized by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, with dilation of preserved segments. Characteristic "beading" of a barium column in radiographs of the intrahepatic and extrahepatic biliary tree is attributable to the irregular strictures and dilations of affected bile ducts. It is commonly seen in association with inflammatory bowel disease , particularly chronic ulcerative colitis, males predominate 2:1 Pathogenesis: unknown.

Primary sclerosing cholangitis: Morphology
Primary sclerosing cholangitis is a fibrosing cholangitis of bile ducts, with a lymphocytic infiltrate, progressive atrophy of the bile duct epithelium, and obliteration of the lumen. The concentric periductal fibrosis around affected ducts ("onion-skin fibrosis") is followed by their disappearance, leaving behind a solid, cordlike fibrous scar. As the disease progresses, the liver becomes cirrhotic like that seen with primary and secondary biliary cirrhosis

Primary sclerosing cholangitis
Etiology Sex predilection Symptoms and signs Laboratory findings Important pathologic findings before cirrhosis develops 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

Alcoholic liver disease

Alcoholic liver disease: macrovesicular steatosis, involving most regions of the hepatic lobule. The intracytoplasmic fat is seen as clear vacuoles. Some early fibrosis (stained blue) is present (Masson trichrome).

Alcoholic hepatitis. A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte. A Mallory body is present in a second hepatocyte (arrow). B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous tissue (H&E).

Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous tissue (H&E).

Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (lower left of figure). B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top (Masson trichrome).

Tumors of Liver

BENIGN NEOPLASMS

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

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

Liver cell adenomas Liver cell adenomas have clinical significance for three reasons: When they present as an intrahepatic mass, they may be mistaken for the more ominous hepatocellular carcinoma. Subcapsular adenomas have a tendency to rupture, particularly during pregnancy (under estrogen stimulation), causing severe intraperitoneal hemorrhage. Rarely, they may harbor hepatocellular carcinoma

Liver cell adenomas: Morphology.
are pale, yellow-tan well demarcated nodules, found anywhere in the hepatic substance but often beneath the capsule. On microscopic examination, liver cell adenomas are composed of sheets and cords of cells that may resemble normal hepatocytes. Portal tracts are absent; instead, prominent arterial vessels and draining veins are distributed through the substance of the tumor.

At the upper right is a well-circumscribed neoplasm that is arising in liver. This is an hepatic adenoma

The cut surface of the liver reveals the hepatic adenoma
The cut surface of the liver reveals the hepatic adenoma. Note how well circumscribed it is.

Normal liver with portal tract (left)
Normal liver with portal tract (left). Hepatic adenoma seen on right is made of cells that resemble normal hepatocytes, but tissue is disorganized and does not show normal lobular architecture

BILE DUCT ADENOMA These are usually small encapsulated spherical, yellow white nodules ranging upto 1 cm in diameter. Microscopically, multiple small acini lined by epithelium similar to that present in small bile ducts is seen and sre surrounded by fibrous stroma. Unlike liver adenomas, these are more frequent in males.

MALIGNANT TUMORS The liver and lungs are the visceral organs that are most often involved by metastatic tumors. Primary carcinomas of the liver are relatively uncommon. Most arise from hepatocytes and are termed hepatocellular carcinoma (HCC). Much less common are carcinomas of bile duct origin, cholangiocarcinomas. The are two rare forms of primary liver cancer : hepatoblastomas and angiosarcomas.

Hepatocellular Carcinomas
male predominance More than 85% of cases of HCC occur in countries with high rates of chronic HBV infection. In these regions, the HBV carrier state begins in infancy following vertical transmission of virus from infected mothers, conferring a 200-fold increased risk for HCC by adulthood

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

Pathogenesis of HCC The following have been implicated in human hepatocarcinogenesis: viral infection (HBV, HCV): Extensive studies link chronic HBV and chronic HCV infection with liver cancer. Cirrhosis: the development of cirrhosis appears to be an important, but not requisite, contributor to the emergence of HCC. Chronic alcoholism.

Pathogenesis of HCC 4) Food contaminants (primarily aflatoxins from aspergillus). High exposure to dietary aflatoxins derived from the fungus Aspergillus flavus. These highly carcinogenic toxins are found in "moldy" grains and peanuts. 5) Other conditions include tyrosinemia and hereditary hemochromatosis.

Morphology of HCC Grossly it may be (1) a unifocal mass
(2) multifocal, multipe nodules of variable size; or (3) a diffusely infiltrative cancer. All three patterns may cause liver enlargement. All patterns of hepatocellular carcinomas have a strong propensity for invasion of vascular channels.

Morphology of HCC Extensive intrahepatic metastases may occur
tumor may invade the portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even into the right side of the heart. Lymph node metastases to the perihilar, peripancreatic, and para-aortic nodes above and below the diaphragm can be present. Hepatocellular carcinomas range from well-differentiated to highly anaplastic undifferentiated lesions.

Morphology of HCC In well-differentiated and moderately well-differentiated tumors, cells that are recognizable as hepatocytic in origin. Bile pigment is usually present. The malignant cells may be positive for alpha-fetoprotein. In poorly differentiated forms, tumor cells can take on a pleomorphic appearance with numerous anaplastic giant cells, can become small and completely undifferentiated cells.

fibrolamellar carcinoma
A distinctive variant of hepatocellular carcinoma is the fibrolamellar carcinoma. This tumor occurs in young male and female adults (20 to 40 years of age), has no association with HBV or cirrhosis, and often has a better prognosis. It usually presents as single large, hard "scirrhous" tumor with fibrous bands coursing through it. On microscopic examination, it is composed of well-differentiated polygonal cells growing in nests or cords and separated by parallel lamellae of dense collagen bundles

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

The satellite nodules of this hepatocellular carcinoma.

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

Clinical Features ill-defined upper abdominal pain, malaise, fatigue, weight loss, and feeling of abdominal fullness. In many cases, the enlarged liver can be felt on palpation. Jaundice and fever are uncommon. Laboratory studies: Elevated levels of serum α-fetoprotein are found in 50% to 75% of patients with HCC.

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

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

The risk conditions for development of cholangiocarcinoma include
primary sclerosing cholangitis, congenital fibropolycystic diseases of the biliary system (particularly Caroli disease and choledochal cysts), previous exposure to Thorotrast (formerly used in radiography of the biliary tract). In the Orient, the incidence rates are higher, and it is due to chronic infection of the biliary tract by the liver fluke Opisthorchis sinensis.

Morphology Intrahepatic cholangiocarcinomas occur in the non-cirrhotic liver and may track along the intrahepatic portal tract system to create a treelike tumorous mass within the liver or a massive tumor nodule. Lymphatic and vascular invasion are common. By microscopy, cholangiocarcinomas resemble adenocarcinomas arising in other parts of the body. Most are well to moderately differentiated. Cholangiocarcinomas are rarely bile stained, because differentiated bile duct epithelium does not synthesize bile.

Morphology Mixed variants occur, in which elements of both hepatocellular carcinoma and cholangiocarcinoma are present. Hematogenous metastases to the lungs, bones (mainly vertebrae), adrenals, brain. Lymph node metastases to the regional lymph nodes 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 make mucin, and they can be almost impossible to distinguish from metastatic adenocarcinoma on biopsy or fine needle aspirate

Clinical Features Intrahepatic cholangiocarcinoma is usually detected late in its course, either as the result of obstruction to bile flow through the hilum of the liver or as a symptomatic liver mass. Prognosis is poor. The median time from diagnosis to death is 6 months. Aggressive surgery remains the only treatment offering hope for long-term survival. Alpha-fetoprorein is not elevated.

Metastatic tumors Metastatic involvement of the liver is far more common than primary neoplasia. Although the most common primaries producing hepatic metastases are those of the breast, lung, and colon, any cancer in any site of the body may spread to the liver, including leukemias and lymphomas. Typically, multiple nodular metastases are found that often cause striking hepatomegaly and may replace over 80% of existent hepatic parenchyma. The liver weight can exceed several kilograms.

Numerous mass lesions of variable size
Numerous mass lesions of variable size. Some of the larger ones demonstrate central necrosis. The masses are metastases to the liver.

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

HEPATOBLASTOMA Hepatoblastoma is the most common liver tumor of young childhood almost always seen below the age of 2yrs. It usually fatal if not resected. This tumor has two anatomic variants: The epithelial type, composed of small, polygonal fetal cells or embryonal cells vaguely recapitulating liver development. The mixed epithelial and mesenchymal type, which contains foci of mesenchymal differentiation that may consist of primitive mesenchyme, osteoid, cartilage, or striated muscle.

GALL BLADDER AND BILIARY TRACT

Disorders of the Gallbladder CHOLELITHIASIS (GALLSTONES)
Majority of gallstones (>80%) are "silent," and most individuals remain free of biliary pain or stone complications for decades. There are two main types of gallstones. About 80% are cholesterol stones, containing more than 50% of crystalline cholesterol monohydrate. The remainder are composed predominantly of bilirubin calcium salts and are designated pigment stones.

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

Cholesterol Stones Demography: Northern Europe, North and South America, Native Americans, Mexican Americans Advancing age Female sex hormones Female gender Oral contraceptives Pregnancy Obesity Rapid weight reduction Gallbladder stasis Inborn disorders of bile acid metabolism Hyperlipidemia syndromes Pigment Stones Demography: Asian more than Western, rural more than urban Chronic hemolytic syndromes Biliary infection Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

Pathogenesis of Cholesterol Stones
Cholesterol is rendered soluble in bile by aggregation with water-soluble bile salts and water-insoluble lecithins, both of which act as detergents. When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and nucleates into solid cholesterol monohydrate crystals. Cholesterol gallstone formation involves four simultaneous defects:

Supersaturation of bile with cholesterol is the result of hepatocellular hypersecretion of cholesterol. Gallbladder hypomotility ensues. It promotes nucleation typically arround a calcium salt crystal nidus. Cholesterol nucleation in bile is accelerated.

4) Mucus hypersecretion in the gallbladder traps the crystals, permitting their aggregation into stones. prolonged fasting, pregnancy, rapid weight loss, total parenteral nutrition, and spinal cord injury also promote stone formation.

Pathogenesis of Pigment Stones
Pathogenesis of pigment stones is based on the presence in the biliary tract of unconjugated bilirubin (which is poorly soluble in water) and precipitation of calcium bilirubin salts. Thus, infection of the biliary tract, as with Escherichia coli or Ascaris lumbricoides or by the liver fluke Opisthorchis sinensis, increases the likelihood of pigment stone formation. Chronic hemolytic conditions also promote formation of unconjugated bilirubin in the biliary tree.

Morphology Cholesterol stones arise exclusively in the gallbladder and are composed of cholesterol ranging from 100% pure (which is rare) down to around 50%. pale yellow, round to ovoid to faceted, and have a finely granular, hard external surface. Stones composed largely of cholesterol are radiolucent; only 10% to 20% of cholesterol stones are radio-opaque.

Morphology Pigment gallstones are black and brown.
"Black" pigment stones are found in sterile gallbladder. "Brown" pigment stones are found in infected intrahepatic or extrahepatic bile ducts. Both are soft and usually multiple. Brown stone are greasy. Because of calcium carbonates and phosphates, approximately 50% to 75% of black stones are radio-opaque.

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

Clinical Features 70% to 80% of patients remain asymptomatic throughout their lives. Symptoms: spasmodic or "colicky" fighrt upper quadrant pain, which tends to be excruciating . It is usually due to obstruction of bile ducts by passing stones. More severe complications include empyema, perforation, fistulae, inflammation of the biliary tree (cholangitis), and obstructive cholestasis or pancreatitis with ensuing problems. The larger the calculi, the less likely they are to enter the cystic or common ducts to produce obstruction; it is the very small stones, or "gravel," that are the more dangerous. Occasionally, a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction ("gallstone ileus"). Most notable is the increased risk for carcinoma of the gallbladder.

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

Acute Cholecystitis Acute calculous cholecystitis is an acute inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct. It is the primary complication of gallstones and the most common reason for emergency cholecystectomy. Acute acalculous cholecystitis occurs in the absence of gallstones, generally in severely ill patient. Most cases of occur in the following circumstances: (1) the postoperative state after major, nonbiliary surgery; (2) severe trauma (motor vehicle accidents, war injuries); (3) severe burns; (4) multisystem organ failure; (5) sepsis; (6) prolonged intravenous hyperalimentation; and (7) the postpartum state.

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

Acute Cholecystitis :Morphology.
In acute cholecystitis, the gallbladder is usually enlarged and tense, and bright red to green-black . The serosal covering is frequently layered by fibrin and, in severe cases, by exudate. There are no morphologic differences between acute acalculous and calculous cholecystitis, except for the absence of macroscopic stones in the former. In the latter instance, an obstructing stone is usually present in the neck of the gallbladder or the cystic duct.

Acute Cholecystitis :Morphology.
The gallbladder lumen is filled with a cloudy or turbid bile that may contain fibrin and frank pus, as well as hemorrhage. When the contained exudate is virtually pure pus, the condition is referred to as empyema of the gallbladder. In mild cases, the gallbladder wall is thickened, edematous, and hyperemic. In more severe cases, it is transformed into a green-black necrotic organ, termed gangrenous cholecystitis, with small-to-large perforations.

Acute Cholecystitis :Clinical Features
Progressive right upper quadrant or epigastric pain, frequently associated with mild fever, anorexia, tachycardia, sweating, and nausea and vomiting. The upper abdomen is tender. Most patients are free of jaundice Acute calculous cholecystitis may appear with remarkable suddenness and constitute an acute surgical emergency or may present with mild symptoms that resolve without medical intervention.

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

Chronic cholecystitis
Chronic cholecystitis may be a sequel to repeated bouts of mild to severe acute cholecystitis, but in many instances, it develops in the apparent absence of antecedent attacks. It is associated with cholelithiasis in over 90% of cases.

Chronic cholecystitis
The symptoms of calculous chronic cholecystitis are similar to those of the acute form and range from biliary colic to indolent right upper quadrant pain and epigastric distress. Patients often have intolerance to fatty food, belching and postprandial epigastric distress, sometimes include nausea and vomiting.

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

Morphology On histology, the degree of inflammation is variable. Outpouchings of the mucosal epithelium through the wall (Rokitansky-Aschoff sinuses) may be quite prominent. Rarely, extensive dystrophic calcification within the gallbladder wall may yield a porcelain gallbladder, notable for a markedly increased incidence of associated cancer. Xanthogranulomatous cholecystitis is also a rare condition in which the gallbladder is shrunken, nodular, fibrosed and chronically inflamed with abundant lipid filled macrophages. Finally, an atrophic, chronically obstructed gallbladder may contain only clear secretions, a condition known as hydrops of the gallbladder.

Complications: acute and chronic cholecystitis
Bacterial superinfection with cholangitis or sepsis GB perforation & local abscess formation GB rupture with diffuse peritonitis Biliary enteric (cholecystenteric) fistula with drainage of bile into adjacent organs, and potentially gallstone-induced intestinal obstruction (ileus) Aggravation of pre-existing medical illness, with cardiac, pulmonary, renal, or liver decompensation

Carcinoma of Gallbladder
Carcinoma of the GB is slightly more common in women and occurs in 7th decade of life. Gallstones are present in 60 to 90% of cases. Also associated pyogenic and parasitic diseases of biliary tree are common. GB containing stones or infectious agents develop cancer due to irritative trauma and chronic inflammation.

Carcinoma of Gallbladder: Morphology
Carcinomas of the gallbladder exhibit two patterns of growth: infiltrating and exophytic. Infiltrating pattern is more common and appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall. The exophytic pattern grows into the lumen as an irregular, cauliflower mass but at the same time invades the underlying wall.

Carcinoma of Gallbladder: Morphology
Most carcinomas of the gallbladder are adenocarcinomas. Some are well to moderately differentiated; others are infiltrative and poorly differentiated to undifferentiated. Rarely squamous cell carcinomas or adenosquamous carcinoma, carcinoid or mesenchymal. Spread: local invasion of liver, extension to cystic duct, portohepatic lymph nodes, peritoneum, lungs etc.

Disease of exocrine pancreas

Pancreatitis Pancreatitis encompasses a group of disorders characterized by inflammation of the pancreas. The clinical manifestations can range in severity from a mild, self-limited disease to a lifethreatening acute inflammatory process, and the duration of the disease can range from a transient attack to an irreversible loss of function. In acute pancreatitis, gland can return to normal if underlying cause of the pancreatitis is removed. By contrast, chronic pancreatitis is defined by irreversible destruction of exocrine pancreatic parenchyma.

Acute pancreatitis Acute pancreatitis is a group of reversible lesions characterized by inflammation of the pancreas ranging in severity from edema and fat necrosis to parenchymal necrosis with severe hemorrhage. 80% of cases in Western countries are associated with one of two conditions: biliary tract disease or alcoholism. Gallstones are present in 35% to 60% of cases of acute pancreatitis.

Acute pancreatitis Less common causes of acute pancreatitis include the following: Obstruction of the pancreatic duct system eg. periampullary tumors, congenital cystic dilatation of the common bile duct, biliary "sludge," and parasites (particularly Ascariasis lumbricoides and Clonorchis sinensis organisms) Medications. More than 85 drugs have been reported to cause acute pancreatitis. These include thiazide diuretics, azathioprine , estrogens, etc Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states Acute ischemia induced by vascular thrombosis, embolism, vasculitis and shock Trauma, both blunt trauma and iatrogenic injury during surgery or endoscopic retrograde cholangiopancreatography

ETIOLOGIC FACTORS IN ACUTE PANCREATITIS
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 ACUTE PANCREATITIS
Vascular Shock Atheroembolism Polyarteritis nodosa Infectious Mumps Coxsackievirus Mycoplasma pneumoniae

Acute pancreatitis: Morphology
The morphology of acute pancreatitis ranges from inflammation and edema to severe extensive necrosis and hemorrhage. The basic alterations are (1) microvascular leakage causing edema, (2) necrosis of fat by lipolytic enzymes, (3) an acute inflammatory reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of blood vessels with subsequent interstitial hemorrhage. Fat necrosis, as we have seen, results from enzymatic destruction of fat cells. The released fatty acids combine with calcium to form insoluble salts that precipitate in situ.

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

Acute pancreatitis: Clinical Features.
Abdominal pain is the cardinal manifestation of acute pancreatitis. Its severity varies from mild to severe. Full-blown acute pancreatitis is a medical emergency of the first magnitude. These patients usually have the sudden onset of an "acute abdomen" that must be differentiated from diseases such as ruptured acute appendicitis, perforated peptic ulcer, acute cholecystitis with rupture, and occlusion of mesenteric vessels with infarction of the bowel. Characteristically, the pain is constant and intense and is often referred to the upper back. There is leukocytosis, hemolysis, disseminated intravascular coagulation, fluid sequestration, acute respiratory distress syndrome, and diffuse fat necrosis. Peripheral vascular collapse and shock with acute renal tubular necrosis may occur

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

Acute pancreatitis The key to the management is "resting" the pancreas by total restriction of food and fluids and by supportive therapy. Most patients recover fully. About 5% die from shock during the first week of illness. Acute respiratory distress syndrome and acute renal failure are fatal complications. In surviving patients, sequelae include a sterile pancreatic abscess and a pancreatic pseudocyst.

Chronic pancreatitis Chronic pancreatitis is characterized by inflammation of the pancreas with destruction of exocrine parenchyma, fibrosis, and, in the late stages, the destruction of endocrine parenchyma. The chief distinction between acute and chronic pancreatitis is the irreversible impairment in pancreatic function that is characteristic of chronic pancreatitis.

Chronic pancreatitis Chronic pancreatitis. A, Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right), with a sprinkling of chronic inflammatory cells and acinar tissue. B, A higher-power view demonstrating dilated ducts with inspissated eosinophilic ductal concretions in a patient with alcoholic chronic pancreatitis.

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

Chronic pancreatitis Less common causes of chronic pancreatitis include the following: Hypercalcemia, hyperlipidemia. Long-standing obstruction of the pancreatic duct by pseudocysts, calculi, trauma, neoplasms, or pancreas divisum. Tropical pancreatitis, which is a poorly characterized disease seen in Africa and Asia. It has been attributed to malnutrition. Hereditary pancreatitis Idiopathic chronic pancreatitis.

Chronic pancreatitis: Morphology
Chronic pancreatitis is characterized by parenchymal fibrosis, reduced number and size of acini with relative sparing of the islets of Langerhans, and variable dilation of the pancreatic ducts These changes are usually accompanied by a chronic inflammatory infiltrate around lobules and ducts. Grossly: gland is hard, sometimes with extremely dilated ducts and visible calcification

Chronic pancreatitis: Clinical Features
Silent or repeated attacks of abdominal pain, or persistent abdominal and back pain. Attacks may be precipitated by alcohol abuse, overeating (which increases demand on the pancreas), or the use of opiates and other drugs. During an attack of abdominal pain, there may be mild fever and mild-to-moderate elevations of serum amylase. Calcifications can be seen within the pancreas by CT scan and ultrasonography. Complications: Severe pancreatic exocrine insufficiency, chronic malabsorption, diabetes mellitus (due to destruction of islets of Langerhans), severe chronic pain and pancreatic pseudocysts.

PSEUDOCYSTS OF PANCREAS
Pseudocysts are localized collections of necrotic-hemorrhagic material rich in pancreatic enzymes. Such cysts lack an epithelial lining (hence the prefix "pseudo"), and they account for majority of cysts in the pancreas. Pseudocysts usually arise after an episode of acute pancreatitis, or of chronic alcoholic pancreatitis. Traumatic injury to the abdomen can also give rise to pseudocysts

Morphology. Pseudocysts are usually solitary. Pseudocysts can range in size from 2 to 30 cm in diameter. While many pseudocysts spontaneously resolve, they may become secondarily infected, and larger pseudocysts may compress or even perforate into adjacent structures. They can produce abdominal pain and predispose to intraperitoneal hemorrhage or peritonitis.

Pancreatic pseudocyst. A, Cross-section through this previously bisected lesion revealing a poorly defined cyst with a necrotic brown-black wall. B, Histologically, the cyst lacks a true epithelial lining and instead is lined by fibrin and granulation tissue.

CYSTIC NEOPLASMS Only 5% to 15% of all pancreatic cysts are neoplastic (most cysts are pseudocysts). There are of 2 types: 1)serous cystadenoma, are entirely benign, 2)mucinous cystic neoplasms, can be benign, borderline malignant, or malignant.

CYSTIC NEOPLASMS: Serous cystadenomas
Serous cystadenomas are benign cystic neoplasms composed of cuboidal cells surrounding small cysts containing clear, thin, straw-colored fluid.. More common in women in the 7th decade with nonspecific symptoms eg.abdominal pain. May present as palpable abdominal mass. Serous cystadenomas are almost always benign, and surgical resection is curative in majority of patients.

Serous cystadenoma Serous cystadenoma. A, Cross-section through a serous cystadenoma. Only a thin rim of normal pancreatic parenchyma remains. The cysts are relatively small and contain clear, straw-colored fluid. B, The cysts are lined by cuboidal epithelium without atypia.

CYSTIC NEOPLASMS:Mucinous cystic neoplasms
Mucinous cystic neoplasms almost always arise in women usually in the body or tail of the pancreas Present as painless, slow-growing masses. The cystic spaces are filled with thick mucin, and the cysts are lined by a columnar mucinous epithelium with an associated dense stroma similar to ovarian stroma.

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

PANCREATIC CARCINOMA Pancreatic cancer has one of the highest mortality rates of any cancer. It is carcinoma of the exocrine pancreas. It arises from ductal epithelial cells. It occurs in the 6th to 8th decade, blacks more than whites, males more than females, diabetics more than non-diabetics.

PANCREATIC CARCINOMA Morphology
Approximately 60% of cancers of the pancreas arise in the head of the gland, 15% in the body, and 5% in the tail; in 20%, the neoplasm diffusely involves the entire gland. Carcinomas of the pancreas are usually hard, stellate, gray-white, poorly defined masses. Majority of carcinomas are ductal adenocarcinomas. Two features are characteristic: It is highly invasive, and it elicits an intense non-neoplastic host reaction called a "desmoplastic response".

PANCREATIC CARCINOMA Morphology
Peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes are frequently involved. Distant metastases occur, principally to the lungs and bones. Less common variants of pancreatic cancer include acinar cell carcinomas, adenosquamous carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells.

PANCREATIC CARCINOMA: CLINICAL FEATURES
Jaundice, weight loss, pain ,massive metastasis to liver and migratory thrombophelebitis

PANCREATIC CARCINOMA

PANCREATOBLASTOMA Pancreatoblastomas are rare neoplasms that occur primarily in children aged 1 to 15 years. They have a distinct microscopic appearance with squamous islands admixed with undifferentiated cells. These are malignant neoplasms.

PATHOLOGY of DIABETES MELLITIS

THE ENDOCRINE PANCREAS
Normal endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets of Langerhans which contain the following cell types: The β cell produces insulin. The α cell secretes glucagon δ cells contain somatostatin, which suppresses both insulin and glucagon release PP cells contain a unique pancreatic polypeptide. The two rare cell types are D1 cells and enterochromaffin cells. D1 cells elaborate vasoactive intestinal polypeptide (VIP). Enterochromaffin cells synthesize serotonin.

Diabetes mellitus Diabetes mellitus (DM) is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. Diabetes is one of the leading causes of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputation. It is one of the most common noncommunicable diseases.

DIAGNOSIS of DM Blood glucose values are normally maintained in a very narrow range, usually 70 to 120 mg/dL. The diagnosis of diabetes is established by noting elevation of blood glucose by any one of three criteria: A random glucose > 200 mg/dL, with classical signs and symptoms A fasting glucose > 126 mg/dL on more than one occasion An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200 mg/dL 2 hours after a standard carbohydrate load

CLASSIFICATION of DM The vast majority of cases of diabetes fall into one of two broad classes: Type 1 diabetes is characterized by an absolute deficiency of insulin caused by pancreatic β-cell destruction. It accounts for approximately 10% of all cases. Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β-cells ("relative insulin deficiency"). Approximately 80% to 90% of patients have type 2 diabetes.

CLASSIFICATION of DM A variety of monogenic and secondary causes are responsible for the remaining cases. Examples of secondary DM include pancreatitis, pancreatectomy, tumors (pheochromocytoma, pituitary tumors), drugs (corticosteroids), iron overload (hemochromatosis), some genetic disorders( e.g. lipodystrophy). Examples of monogenic forms include maturity onset DM of young, mitochondrial DM, DM associated with insulin gene or insulin receptor mutations.

CLASSIFICATION of DM .1 Type 1 diabetes (β-cell destruction, leads to absolute insulin deficiency) Immune-mediated Idiopathic 2. Type 2 diabetes (insulin resistance with relative insulin deficiency)

CLASSIFICATION of DM 3. Genetic defects of β-cell function Maturity-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 action Defects in proinsulin conversion Insulin gene mutations Insulin receptor mutations

CLASSIFICATION of DM 5. Exocrine pancreatic defects Chronic pancreatitis Pancreatectomy Neoplasia Cystic fibrosis Hemachromatosis Fibrocalculous pancreatopathy 6. Endocrinopathies Acromegaly Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma

CLASSIFICATION of DM 7. Infections Cytomegalovirus Coxsackie virus B
8. Drugs Glucocorticoids Thyroid hormone α-interferon Protease inhibitors β-adrenergic agonists Thiazides Nicotinic acid Phenytoin

CLASSIFICATION of DM 9. Genetic syndromes associated with diabetes Down syndrome Kleinfelter syndrome Turner syndrome 10. Gestational diabetes mellitus

PATHOGENESIS OF TYPE 1 DIABETES MELLITUS
This form of diabetes results from a severe lack of insulin caused by an immunologically mediated destruction of β cells. Most patients depend on insulin for survival; without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma. It was also called "insulin-dependent diabetes mellitus" (IDDM) Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age.

Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined β-cell antigens. As in all autoimmune diseases, genetic susceptibility and environmental factors play important roles in the pathogenesis. The classic manifestations of the disease (hyperglycemia and ketosis) occur after more than 90% of the β cells have been destroyed

More commom than type 1. Pathogenesis is multifactorial. Environmental factors, e.g. sedentary life style and dietary habits, obesity play a major role. Genetic factors are even more important than in type 1 diabetes. Unlike type 1 diabetes, the disease is not linked to genes involved in immune tolerance and regulation, and there is no evidence to suggest an autoimmune basis for type 2 diabetes.

The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and (2) β-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. In most cases, insulin resistance is the primary event, and is followed by increasing degrees of β-cell dysfunction

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Insulin resistance
Insulin resistance is defined as resistance to the effects of insulin on glucose uptake, metabolism, or storage. Insulin resistance is a characteristic feature of most patients with type 2 diabetes. Insulin resistance leads to decreased uptake of glucose in muscle and adipose tissues and an inability of the hormone to suppress hepatic gluconeogenesis.

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Insulin resistance
One of the things associated with insulin resistence is obesity and thereby the link between obesity and diabetes is mediated via effects on insulin resistance

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS β-cell dysfunction
β-cell dysfunction in type 2 diabetes reflects the inability of these cells to adapt themselves to the long-term demands of peripheral insulin resistance and increased insulin secretion. In states of insulin resistance there is hyperinsulinemic state to compensate for peripheral resistance and can often maintain normal plasma glucose for years.

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS β-cell dysfunction
Eventually, β-cell compensation becomes inadequate, and there is progression to overt DM. The underlying basis for failure of β-cell adaptation is not known. It is postulated that adverse effects of high circulating free fatty acids ("lipotoxicity") or chronic hyperglycemia ("glucotoxicity"), may play a role. β-cell dysfunction in type 2 diabetes manifests itself as both qualitative and quantitative defects.

Maturity-Onset Diabetes of the Young (MODY)
2% to 5% of diabetic patients do not fall clearly into either the type 1 or type 2 diabetes phenotype and are said to have "maturity-onset diabetes of the young." In these patients, there is a primary defect in β-cell function that occurs without β-cell loss, affecting either β-cells and/or insulin production.

Maturity-Onset Diabetes of the Young (MODY)
MODY is the outcome of a heterogeneous group of genetic defects characterized by autosomal-dominant inheritance early onset, usually before age 25, as opposed to after age 40 for most patients with type 2 diabetes absence of obesity lack of islet cell autoantibodies and insulin resistance syndrome.

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

PATHOGENESIS OF THE COMPLICATIONS OF DIABETES
Macrovascular disease causes accelerated atherosclerosis in diabetics, resulting in increased risk of myocardial infarction, stroke, and lower-extremity gangrene. Microvascular disease affects the retina, kidneys, and peripheral nerves leading to diabetic retinopathy, nephropathy, and neuropathy, respectively. Diabetes is one of the leading cause of blindness and end-stage renal disease.

PATHOGENESIS OF THE COMPLICATIONS OF DIABETES 1) Formation of Advanced Glycation End Products.
AGEs are formed as a result of nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors with the amino group of both intracellular and extracellular proteins. AGEs have a number of chemical and biologic properties that are detrimental to extracellular matrix components and the target cells of diabetic complications (e.g., endothelial cells):

PATHOGENESIS OF THE COMPLICATIONS OF DIABETES 1) Formation of Advanced Glycation End Products.
1) In case of extracellular matrix components, such as collagen or laminin, the formation of AGEs causes cross-linking between polypeptides, resulting in abnormal matrix-matrix and matrix-cell interactions. These AGE cross-linked proteins are resistant to proteolytic digestion. Thus, cross-linking decreases protein removal while enhancing protein deposition. These AGE-modified matrix components also trap nonglycated plasma or interstitial proteins e.g in large vessels, trapping low-density lipoprotein (LDL), accelerates atherogenesis.

b) increased endothelial permeability
PATHOGENESIS OF THE COMPLICATIONS OF DIABETES 1) Formation of Advanced Glycation End Products 2) Circulating plasma proteins are modified by addition of AGE residues; these proteins, in turn, bind to AGE receptors on several cell types (endothelial cells, mesangial cells, macrophages) resulting in a) release of cytokines and growth factors from macrophages and mesangial cells b) increased endothelial permeability c) increased procoagulant activity on endothelial cells and macrophages d) enhanced proliferation of and synthesis of extracellular matrix by fibroblasts and smooth muscle cells.

Effects of advanced glycation end products
Table Effects of Advanced Glycation End Products (AGEs) Table Effects of Advanced Glycation End Products (AGEs) Table Effects of Advanced Glycation End Products (AGEs) Effects of advanced glycation end products 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 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 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 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 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 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 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 glycation end products
Table Effects of Advanced Glycation End Products (AGEs) Effects of Advanced Glycation End Products (AGEs) Effects of advanced glycation end products 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 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 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 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 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

PATHOGENESIS OF THE COMPLICATIONS OF DIABETES 2) Activation of Protein Kinase C
Intracellular hyperglycemia cause abnormal activation of protein kinase C which triggers multiple pathways that lead to diabetic retinopathy, atherosclerosis etc.

PATHOGENESIS OF THE COMPLICATIONS OF DIABETES 3) Intracellular Hyperglycemia with Disturbances in Polyol Pathways In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose. This ultimately leads to increased cellular susceptibility to oxidative stress.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS
The morphologic changes are related to the late systemic complications of diabetes. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of diabetes, the onset might be delayed.

In most patients, however, morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues. These changes are seen in both type 1 and type 2 diabetes.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS Pancreas
Reduction in the number and size of islets, mostly seen in type 1 DM. An increase in number and size of islets is characteristic of nondiabetic newborns of diabetic mothers (fetal islets show hyperplasia in response to maternal hyperglycemia. Leukocytic infiltration of the islets (insulitis, mostly seen in type 1 DM) EM: show β-cell degranulation , (depletion of stored insulin in the damaged β cells). Amyloid replacement of islets (type 2 DM).

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS Diabetic Macrovascular Disease
The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving aorta, large- & medium-sized arteries. Myocardial infarction, due to atheroma of coronary arteries, is most common cause of death in diabetics. Gangrene of the lower extremities, due to advanced vascular disease, is 100 times more common in diabetics than in nondiabetics.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS Hyaline arteriolosclerosis
Hyaline arteriolosclerosis, the vascular lesion associated with hypertension is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS Diabetic Microangiopathy
A consistent finding is diffuse thickening of basement membranes. The thickening is seen in the capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla. It is also be seen in nonvascular structures as renal tubules, Bowman capsule and peripheral nerves. The material is type IV collagen. Note: despite increase in the thickness of basement membranes, diabetic capillaries are more leaky to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy etc.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATION Diabetic Nephropathy
The kidneys are prime targets of diabetes. Renal failure is second only to myocardial infarction as a cause of death from this disease. It is a major cause of morbidity and mortality. Three lesions are encountered: glomerular, vascular and pyelonephritis.

-Diffuse mesangial sclerosis: in patients with >10 years of DM.
MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATION Diabetic Nephropathy: glomerular lesions 1) There is glomerular capillary basement membrane thickening, diffuse mesangial sclerosis, nodular glomerulosclerosis and/or exudative lesions resulting in progressive proteinuria and chronic renal failure -Diffuse mesangial sclerosis: in patients with >10 years of DM. -Nodular glomerulosclerosis: Also called as Kimmelstiel-Wilson lesion.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATION Diabetic Nephropathy: renal vascular lesions
2) Renal atherosclerosis and arteriolosclerosis constitute part of the macrovascular disease in diabetics. The kidney is one of the most frequently and severely affected organs; Hyaline arteriolosclerosis affects not only the afferent but also the efferent arteriole.

MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATION Diabetic Nephropathy: pyelonephritis,
3) Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules. One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics

Diabetic Ocular Complications. The ocular involvement may take the form of retinopathy, cataract formation, or glaucoma. Diabetic Neuropathy. The central and peripheral nervous systems are not spared by diabetes.

CLINICAL FEATURES OF DIABETES TYPE 1
Type 1 diabetes was traditionally thought to occur primarily in those under age 18 but is now known to occur at any age. The onset is marked by polyuria, polydipsia, polyphagia. Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always raise the suspicion of diabetes.

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

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

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

In the decompensated state, these patients may develop hyperosmolar nonketotic coma, a syndrome associated with severe dehydration resulting from sustained osmotic diuresis in patients who do not drink enough water to compensate for urinary losses from chronic hyperglycemia. Typically, patient is an elderly diabetic who is disabled by a stroke or an infection and is unable to maintain adequate water intake.

CLINICAL FEATURES OF DIABETES TYPE 1& 2
In both forms, it is the long-term effects of diabetes, more than the acute metabolic complications, that are responsible for the overwhelming proportion of morbidity and mortality. In most instances, these complications appear approximately 15 to 20 years after the onset of hyperglycemia. Cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality in long-standing diabetics. Hypertension is approximately twice as frequent in diabetics as in those without the disease. Dyslipidemias

CLINICAL FEATURES OF DIABETES TYPE 1& 2
Diabetic nephropathy:leading cause of end-stage renal disease nephropathy Visual impairment, sometimes total blindness, is a consequences of long-standing diabetes. Diabetic neuropathy can elicit a variety of clinical syndromes, afflicting the central nervous system, peripheral sensorimotor nerves, and the autonomic nervous system. Diabetics are susceptibile to infections of the skin and to tuberculosis, pneumonia, and pyelonephritis. In an individual with diabetic neuropathy, a trivial infection in a toe may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia) that may ultimately lead to death.

PREVENTION primary prevention of type 2 diabetes by lifestyle and dietary alterations secondary prevention of diabetic complications by strict glycemic control has become increasingly recognized. It is also hoped that islet cell transplantation will result in a cure for those afflicted with type 1 diabetes

Type 1 Versus Type 2 Diabetes Mellitus (DM)
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 DM TYPE 2 DM Genetics 30-70% concordance in twins 50-90% concordance in twins Linkage to MHC Class II HLA genes No HLA linkage Linkage to candidate diabetogenic genes (PPARγ, calpain 10)

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 liver β-cell dysfunction and relative insulin deficiency Absolute insulin deficiency

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.

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