Pancreatic Pathology 18

INFLAMMATION OF THE PANCREAS

1 . Acute pancreatitis is an acute inflammation arising from injury to the exocrine portion of the pancreas. The etiology is diverse, and includes gall­ stones, alcohol, hypercalcemia, drugs, shock, infections, trauma, and scor­ pion stings. Pancreatic acinar cell injury results in activation of pancreatic enzymes and enzymatic destruction of the pancreatic parenchyma.

a.Clinical features. Acute pancreatitis typically presents with stabbing epigastric abdominal pain radiating to the back; it may also present with shock. Laboratory studies show elevation of serum amylase and lipase. Complications include acute respiratory distress syndrome (ARDS); disseminated intravascular coagulation (DIC); pseudocyst; pancreatic calcifications; and hypocalcemia. Severe cases have a 30% mortality rate.

b.On pathologic examination, the pancreas grossly shows focal hem­ orrhage and liquefication accompanied by chalky, white-yellow fat necrosis of adjacent adipose tissue. Microscopically, the tissue shows liquefactive necrosis of the pancreatic parenchyma with acute inflam­ mation and enzymatic fat necrosis. Necrosis of blood vessels causes hemorrhage.

2.Chronicpancreatitis refers to chronic inflammation, atrophy, and fibrosis of the pancreas secondary to repeated bouts of pancreatitis. Many patients are middle-age male alcoholics. On pathologic examination, the pan­ creas is grossly firm, white, and fibrotic. Microscopically, there is extensive fibrosis with parenchymal atrophy and chronic inflammation. Clinically, chronic pancreatitis can produce abdominal pain, pancreatic insufficiency and malabsorption, pancreatic calcifications, pseudocyst, and secondary diabetes mellitus (late complication) .

DIABETES MELLITUS

1.Diabetes mellitus is a chronic systemic disease characterized by insulin deficiency or peripheral resistance, resulting in hyperglycemia and nonen­ zymatic glycosylation of proteins.

2.The diagnosis is established by demonstrating fasting glucose >126 mg/

dL on at least two separate occasions or by a positive glucose tolerance test. HbAlc :2: 6.5 percent.

3.Insulin-dependent diabetes mellitus (IDDM), also called type 1, juvenile onset diabetes, and brittle diabetes, represents 10% of cases of diabetes. It affects children and adolescents, usually younger than age 20. Risk factors include Northern European ancestry and specific HLA types (DR3, DR4, and DQ).

a.The pathogenesis is a lack of insulin due to autoimmune destruction of p cells (type IV hypersensitivity reaction). Patients are absolutely depen­ dent on insulin to preventketoacidosis and coma. It is thought that this form of diabetes is caused by an autoimmune reaction triggered by an infection (Coxsackie B virus) in a genetically susceptible individual.

Clinical Correlate

Acute Respiratory Distress Syndrome:

ARDS is a life-threatening complication of acute pancreatitis due to release of phospholipase which circulates through the bloodstream and damages alveolar capillary membranes in the lungs.

Clinical Correlate

Measurement of glycosylated hemoglobin (HbAlc) is an excellent measurement of long-term exposure to hyperglycemia.

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USMLE Step 1 • Pathology

Clinical Correlate

Sulfonylureas enhance insulin secretion only in type 2 diabetes.

Clinical Correlate

Diabetic nephropathy: The first laboratory abnormality in diabetic nephropathy is a positive microalbuminuria. ACE inhibitors are often used in diabetic nephropathy because they reduce proteinuria

levels and slow the progression ofthe nephropathy.

b. Clinical features. Insulin-dependent diabetes mellitus can present with polydipsia, polyuria, and polyphagia; dehydration and electrolyte imbalance; metabolic ketoacidosis; and coma and potentially death. Treatment is with insulin.

c. Microscopically, lymphocytic inflammation involves the islets of Langerhans (insulitis), leading to loss of cells and fibrosis ofthe islets.

4. Non-insulin-dependent diabetes mellitus (NIDDM, also called type 2, adult onset diabetes) represents 90% of cases of diabetes and affects obese individuals, both children and adults. Approximately 10 million people in the United States are affected (half are undiagnosed), and the incidence increases with age. Risk factors include obesity, increasing age, and genetic predisposition.

a.The pathogenesis involves relatively reduced insulin secretion; periph­ eral insulin resistance is the term used for reduced tissue sensitivity to insulin due to decreased numbers ofinsulin receptors on the cell mem­ branes.

b.Clinicalfeatures. Non-insulin-dependent diabetes mellitus is frequent­ ly asymptomatic, but it can present with either polydipsia, polyuria, and polyphagia, or with hyperosmolar nonketotic diabetic coma. Treatment is with diet and weight loss, oral antidiabetic drugs, and sometimes insulin (more common in long-standing cases).

c.Microscopically, the changes are nonspecific, and can include focal atrophy and amyloid deposition in islets (hyalinization).

5.Vascular pathology. Diabetes is a major risk factor for atherosclerosis and

its complications, including myocardial infarction (most common cause of death), stroke (CVA), and peripheral vascular disease. The vascular disease can lead to atrophy ofskin and loss ofhair ofthe lower extremities, claudi­ cation, nonhealing ulcers, and gangrene oflower extremities. Microvascular disease is also a problem, and is characterized microscopically by diffuse thickening ofbasement membranes and hyaline arteriolosclerosis.

6. Diabetic nephropathy includes renal artery atherosclerosis and hyaline arteriolosclerosis of afferent and efferent arterioles.

a.It can cause diffuse glomerulosclerosis, which can present with nephrotic syndrome and which is characterized microscopically by increased mesangial matrix, mesangial proliferation, and thickened basement membranes.

b.Diabetes can also cause nodular glomerulosclerosis (Kimmelstiel­ Wilson disease), which can produce nephrotic syndrome and which is characterized microscopically by nodular PAS(+) deposits of mesangial matrix and thickened basement membranes.

c.Other conditions. Diabetic nephropathy also includes pyelonephritis and necrotizing papillitis, and renal failure.

1 78 MEDICAL

7.Diabetic retinopathy. The nonproliferative phase of diabetic retinopathy is characterized by microaneurysms, retinal hemorrhages, and retinal exudates. The proliferative phase is characterized by neovascularization. The final fibrosis phase has vitreous humor fibrosis and detachment of the retina. Diabetics also have an increased rate of cataracts and glaucoma.

8.Diabeticneuropathy can cause peripheral neuropathy, neurogenic bladder, and sexual impotence.

Used with permission.

Figure 18-2. Diabetic retinopathy with hemorrhages, venous beading, and looping of vessels

Chapter 18 • Pancreatic Pathology

Clinical Correlate

Diabetic nephropathy is the most common reason for renal transplantation in adults.

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Chapter 18 • Pancreatic Pathology

Chapter Summary

•In acute hemorrhagic pancreatitis, pancreatic acinar cell injury results in activation of pancreatic enzymes and enzymatic destruction ofthe pancreatic parenchyma. Acute hemorrhagic pancreatitis can be seen in a variety of clinical settings, notably associated with gallstones or alcohol use. Chronic pancreatitis is a chronic inflammation ofthe pancreas with atrophy and fibrosis secondary to repeated bouts of pancreatitis.

•Diabetes mellitus is a chronic systemic disease characterized by insulin deficiency or peripheral resistance, resulting in hyperglycemia and non-enzymatic glycosylation of proteins.

•Insulin-dependent diabetes mellitus usually develops in children and adolescents and is related to lack of insulin secondary to autoimmune destruction of beta cells. Non-insulin-dependent diabetes mellitus is usually a disease of obese adults and is much more common than insulin-dependent diabetes mellitus.

•Both types of diabetes may lead to long-term complications including atherosclerosis, myocardial infarction, stroke, peripheral vascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy.

•Pancreatic islet cell tumors may secrete insulin, gastrin, glucagon, somatostatin, or vasoactive intestinal peptide.

•Pancreatic carcinoma is the fifth most common cause of cancer death in the United States and has a very poor prognosis.

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Gallbladder and	1 9
Biliary Tract Pathology

GALLSTONES (CHOLELITHIASIS)

1. Cholesterolstones are composed of mostly cholesterol monohydrate. The incidence increases with age. Risk factors include female gender, obesity, pregnancy, oral contraceptives, and hormone replacement therapy (HRT). Native American Pima and Navajo Indians have an increased incidence of cholesterol gallstones.

2.Pigmentedbilirubinate stones are composed of calcium salts and uncon­ jugated bilirubin. Risk factors for developing pigmented bilirubinate stones are chronic hemolytic anemias, cirrhosis, bacterial infection, and parasites (Ascaris or Clonorchis [Opisthorchis] sinensis).

3.Clinical features of gallstones. Gallstones are frequently asymptomatic but can cause biliary colic (right upper quadrant pain due to impacted stones). Diagnosis is by ultrasound. Complications include cholecystitis, choledocholithiasis (calculi within the biliary tract), biliary tract obstruc­ tion, pancreatitis, and cholangitis.

INFLAMMATORY CONDITIONS

1.Acute cholecystitis is an acute inflammation of the gallbladder, usu­ ally caused by cystic duct obstruction by gallstones. Acute cholecystitis can present with biliary colic, right upper quadrant (RUQ) tenderness on palpation, nausea and vomiting, low-grade fever, and leukocytosis. Complications include gangrene of the gallbladder, perforation and peri­ tonitis, fistula formation and gallstone ileus (small bowel obstruction by a large gallstone).

2.Chronic cholecystitis is ongoing chronic inflammation of the gallblad­ der, usually caused by gallstones. Microscopically, the gallbladder shows chronic inflammation and Rokitansky-Aschoff sinuses. A late complication is calcification of the gallbladder ("porcelain gallbladder").

3.Ascendingcholangitis is bacterial infection ofthe bile ducts ascending up to the liver, usually associated with obstruction of bile flow. The presen­ tation is with biliary colic, jaundice, high fever, and chills. The infecting organisms are usually gram-negative enteric bacteria.

Note

Formation of cholesterol stones involves the precipitation of cholesterol from supersaturated bile.

Clinical Correlate

Murphy's Sign

This is inspiratory arrest in response to palpation ofthe RUQ during deep inspiration.

MISCELLANEOUS CONDITIONS

1 . Cholesterolosis refers to an accumulation of cholesterol-laden macro­ phages within the mucosa of the gallbladder wall. Gross examination shows yellow speckling of the red-tan mucosa ("strawberry gallbladder"), and microscopic examination shows lipid-laden macrophages within the lamina propria.

2.Hydrops of the gallbladder (mucocele) occurs when chronic obstruc­ tion of the cystic duct leads to the resorption of the normal gallbladder contents and enlargement of the gallbladder by the production of large amounts of clear fluid (hydrops) or mucous secretions (mucocele).

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Clinical Correlate

Courvoisier law: An enlarged palpable gallbladder is more likely to be caused by obstruction due to malignancy than by stones.

"Porcelain gallbladder'': Calcification ofthe gallbladder due to chronic inflammation; high association with carcinoma.

BILIARYTRACT CANCER

1.Gallbladder cancer is frequently asymptomatic until late in the course. When the tumor does present, it may be with cholecystitis, enlarged pal­ pable gallbladder, or biliary tract obstruction (uncommon). X-ray may show a calcified "porcelain gallbladder." Microscopically, the tissues show adenocarcinoma. The prognosis for gallbladder cancer is poor, at only about 1% survival at 5 years.

2.Bile ductcancer. Bile duct carcinoma is defined as carcinoma of the extra­

hepatic bile ducts, while cholangiocarcinoma is carcinoma of the intra­ hepatic bile ducts. Klatskin tumor is a carcinoma of the bifurcation of the right and left hepatic bile ducts. Risk factors for bile duct cancer include Clonorchis (Opisthorchis) sinensis (liver fluke) in Asia and primary sclerosing cholangitis. Bile duct cancer typically presents with biliary tract obstruction. Microscopic examination shows adenocarcinoma arising from the bile duct epithelium. The prognosis for bile duct cancer is poor.

© Gloria Jicha: Tripier Army Medical Center. Used with permission.

Figure 19-1 . X-ray showing calcified (porcelain) gallbladder

184 MEDICAL

Chapter 19 • Gallbladder and BiliaryTract Pathology

Chapter Summary

•Gallstones can take the form of cholesterol stones or pigmented bilirubinate stones.

•Cholesterol stones are composed of mostly cholesterol monohydrate and have as risk factors female gender, obesity, pregnancy, exogenous female hormones, increasing age, and genetics.

•Pigmented bilirubinate stones are composed of calcium salts and unconjugated bilirubin and have as risk factors chronic hemolytic anemias, cirrhosis, bacteria, and parasites.

•Gallstone disease is frequently asymptomatic, or may cause right upper quadrant pain due to impacted stones. Complications include cholecystitis, choledocholithiasis, biliary tract obstruction, and cholangitis.

•Acute cholecystitis is an acute inflammation ofthe gallbladder that is usually

caused by cystic duct obstruction by gallstones. Complications of acute cholecystitis include gangrene ofthe gallbladder, peritonitis, and gallstone ileus.

•Chronic cholecystitis is ongoing chronic inflammation ofthe gallbladderthat is usually caused by gallstones.

•Ascending cholangitis is a bacterial infection ofthe bile ducts ascending up to the liver and is usually associated with obstruction of bile flow.

•Cholesterolosis is a clinically insignificantyellow-speckling ofthe gallbladder mucosa.

•Hydrops ofthe gallbladder occurs when chronic obstruction ofthe cystic duct leads to the resorption ofthe normal gallbladder contents and enlargement ofthe gallbladder, with production of large amounts of clear fluid (hydrops) or mucous secretions (mucocele).

•Gallbladder cancer has a very poor prognosis because it is frequently asymptomatic until late in the course. Bile duct cancer also has a poor prognosis.

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Clinical Correlate

The prothrombin time (PD, not the partial thromboplastin time (PTD, is used to

assess the coagulopathy due to liver disease.

d. Rotor syndrome is an autosomal recessive conjugated hyperbilirubi­ nemia that is similar to Dubin-Johnson syndrome, but without liver pigmentation. There are no clinical consequences.

5. Biliarytractobstructionmayhave multipleetiologies,includinggallstones; tumors (pancreatic, gallbladder, and bile duct); stricture; and parasites (liver

flukes-Clonorchis [Opisthorchis] sinensis). The presentation can include

jaundice and icterus; pruritus due to increased plasma levels of bile acids; abdominal pain, fever, and chill; dark urine (bilirubinuria); and pale clay­ colored stools. Laboratory studies showed elevated conjugated bilirubin, elevated alkaline phosphatase, and elevated 5'-nucleotidase.

6. Primary biliary cirrhosis (PBC) is a chronic liver disease of unknown etiology (autoimmune) that is characterized by inflammation and granu­ lomatous destruction of intrahepatic bile ducts. Females have 10 times the incidence of primary biliary cirrhosis as compared to males; the peak incidence is age 30 to 65 years.

a. Clinicalfeatures. The presentation ofbiliarycirrhosis includes obstruc­ tive jaundice and pruritus; xanthomas, xanthelasmas, and elevated serum cholesterol; fatigue; and cirrhosis (late complication). Most patients have another autoimmune disease (scleroderma, rheumatoid arthritis or systemic lupus erythematosis).

b. Diagnostic studies. Laboratory studies show elevated conjugated bilirubin, elevated alkaline phosphatase, and elevated 5'-nucleotidase.

Antimitochondrial autoantibodies (AMA) are present in more than 90% of cases. Microscopically, lymphocytic and granulomatous inflam­ mation involves interlobularbile ducts.

7. Primary sclerosing cholangitis (PSC) is a chronic liver disease of unknown etiology characterized by segmental inflammation and fibrosing destruction of intrahepatic and extrahepatic bile ducts.

a. Clinically, the male to female ratio is 2:1; peak age 20 is 40 years. Most cases of PSC are associated with ulcerative colitis. The presentation is similar to PBC. Complications include biliary cirrhosis and cholangio­ carcinoma.

b. Diagnosticstudies. Microscopically, there is periductal chronic inflam­ mationwith concentric fibrosis around bile ducts and segmental stenosis ofbile ducts. Cholangiogram shows "beaded appearance" ofbile ducts.

CIRRHOSIS

1. Cirrhosis is end-stage liver disease characterized by disruption ofthe liver architecture by bands of fibrosis which divide the liver into nodules of regenerating liver parenchyma.

2. Causes of cirrhosis include alcohol, viral hepatitis, biliary tract dis­ ease, hemochromatosis, cryptogenic/idiopathic, Wilson disease, and a-1-antitrypsin deficiency.

3.Grosspathology. Micronodular cirrhosis has nodules <3 mm, while mac­ ronodular cirrhosis has nodules >3 mm; mixed micronodular and mac­

ronodular cirrhosis can also occur. At the end stage, most diseases result in a mixed pattern, and the etiology may not be distinguished based on the appearance. The mechanism bywhich cirrhosis is produced is fibrosis produced by the Ito cell (hepatic stellate cells).

4.Cirrhosis has a multitude of consequences, including portal hyperten­ sion, ascites, splenomegaly/hypersplenism, esophageal varices, hemor­ rhoids, caput medusa, decreased detoxification, hepatic encephalopathy, spider angiomata, palmar erythema, gynecomastia, decreased synthesis, hypoalbuminemia, decreased clotting, and hepatorenal syndrome.

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Chapter 20 • Liver Pathology

VIRAL HEPATITIS

1. Hepatitis viruses. Viral hepatitis can be asymptomatic, or it can present with malaise and weakness, nausea and anorexia, jaundice, or dark urine. Laboratory studies show markedly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Diagnosis is by serology.

Clinical Correlate

Non-HepatitisViruses Which May

Infect the Liver

•Epstein-Barr virus (EBV)­ infectious mononucleosis

2.Acute viral hepatitis is defined to be viral hepatitis with signs and symp­

toms for <6 months. It can be caused by any of the hepatitis viruses. • Cytomegalovirus (CMV)

Microscopically, the liver shows lobular disarray, hepatocyte swelling (bal­ loon cells), apoptotic hepatocytes (Councilman bodies), lymphocytes in portal tracts and in the lobule, hepatocyte regeneration, and cholestasis.

3.Chronicviralhepatitis is the term used for viral hepatitis with signs and symptoms for >6 months. It can be caused by hepatitis viruses B, C, and D. Microscopically, chronic persistent hepatitis shows inflammation confined to portal tracts. Chronic active hepatitis shows inflammation spilling into the parenchyma, causing interface hepatitis (piecemeal necrosis of limiting plate). Hepatitis B often has "ground glass" hepatocytes (due to cytoplasmic HBsAg).

•Herpes

•Yellow fever

Table 20-2. The Hepatitis Viruses

Common Virus	Hepatitis A		Hepatitis B		Hepatitis C	Hepatitis D	Hepatitis E
Name	(HAV)		(HBV)		(HCV)	(HOV)	(HEV)
Common	"Infectious"		"Serum"		"Post-transfusion"	"Delta"	"Enteric"
disease name					or "non-A, non-B"
Virus	Picornavirus		Hepadnavirus		Ravivirus	Defective	Hepevirus naked
	naked capsid RNA		enveloped DNA		enveloped RNA	enveloped circular	capsid RNA
						RNA
Transmission	Fecal-oral		Parenteral, sexual		Parenteral, sexual	Parenteral, sexual	Fecal-oral
Severity	Mild		Occasionally severe		Usually	Co-infection with	Normal patients:
					subclinical	HBV occasionally	mild; pregnant
						severe; super-	patients: severe
						infection with HBV
						often severe
Chronicity or	No		Yes		Yes (high)	Yes	No
carrier state	Acute hepatitis		• Acute hepatitis		• Chronic	• Acute hepatitis	Acute hepatitis
Clinical diseases
			• Chronic hepatitis		hepatitis	• Chronic
			•	Cirrhosis	• Cirrhosis	hepatitis
			•	Hepatocellular	• HCC	• Cirrhosis
				carcinoma (HCC)		• HCC
Laboratory	Symptoms and		Symptoms and		Symptoms and	Anti-HOV ELISA
diagnosis	anti-HAV lgM		serum levels of		anti-HCV ELISA
			HBsAg, HBeAg, and
			anti-HBc lgM
Prevention	Vaccine, hygiene		Vaccine				Hygiene

MEDICAL

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Chapter 20 • Liver Pathology

ALCOHOLIC LIVER DISEASE

1.Fatty change (steatosis) is reversible with abstinence. The gross appear­ ance is of an enlarged, yellow, greasy liver. Microscopically, the liver initially shows centrilobular macrovesicular steatosis (reversible) that can eventually progress to fibrosis around the central vein (irreversible).

2.Alcoholic hepatitis is an acute illness that usually follows a heavy drink­ ing binge. Alcoholic hepatitis is clinically variable; some patients have no symptoms while others develop right upper quadrant pain, hepatomegaly, jaundice, malaise, and/or anorexia. Fulminant liver failure may also occur. The prognosis can be poor, since each episode has a 20% risk of death, and repeated episodes increase the risk of developing cirrhosis.

a.Microscopically, the liver shows hepatocyte swelling (ballooning) and necrosis, Mallory bodies (cytokeratin intermediate filaments), neutro­ phils, fatty change, and eventual fibrosis around the central vein.

3.Alcoholic cirrhosis develops in 15% of alcoholics, and is typically a rnicronodular cirrhosis. It is the most common disease requiring liver transplantation in adults.

©cdc.gov. Used with permission.

Figure 20-1 . Alcoholic Cirrhosis, Liver

METABOLIC LIVER DISEASE

1.Wilson's disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism resulting in the accumulation of toxic levels of copper in various organs. The diagnosis is established by demonstrating decreased serum ceruloplasmin levels, increased tissue copper levels (liver biopsy), and increased urinary copper excretion. The treatment includes copper chelators (D-penicill mine); liver transplantation is curative.

a.Genetics. The disease is autosomal recessive, and the WD gene (ATP7B on chromosome 13) codes for a hepatocyte canalicular copper-transporting ATPase. Damage to the gene leads to a decreased biliary excretion of copper. Wilson's disease presents in childhood or adolescence with liver disease.

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USMLE Step 1 • Pathology

In a Nutshell

Protease-Antiprotease Imbalance

•a-1-antitrypsin is an important protease inhibitor.

•It is responsible for inhibiting neutrophil elastase.

•It also inhibits trypsin, chymotrypsin, and bacterial proteases.

Clinical Correlate

a-1-antitrypsin deficiency is the most common genetic disease requiring liver transplantation in children.

b.Distribution ofdisease. Wilson's disease affects the liver (fatty change, chronic hepatitis, and micronodular cirrhosis), cornea (Kayser-Fleischer rings [copper deposition in Descemet's membrane] ), and brain (neuro­ logical and psychiatric manifestations, movement disorder).

2.Hemochromatosis is a disease of increased levels of iron, leading to tissue injury. Hereditary (primary) hemochromatosis is a recessive disorder of the HFE gene on chromosome 6p. The most common mutation of the HFE gene is the C282Y mutation, which increases small-intestine absorption of iron. Secondary hemochromatosis can follow transfusions for chronic ane­ mias. Hemochromatosis affects 5 times as many males as females, and the disease is common in people of Northern European descent.

a.Clinical features. Hemachromatosis can cause micronodular cirrhosis and hepatocellular carcinoma (200 times the normal risk ratio); second­ ary diabetes mellitus; hyperpigmented skin ("bronzing"); congestive heart failure and cardiac arrhythmias; and hypogonadism. The diag­ nosis is established by demonstrating markedly elevated serum iron and ferritin or increased tissue iron levels (Prussian blue stain) on liver biopsy. Treatment is with phlebotomy.

3. a-1-antitrypsin deficiency is an autosomal recessive disorder character­ ized by production of defective a-1-antitrypsin (al-AT), which accumu­ lates in hepatocytes and causes liver damage and low serum levels of al -AT.

a.Genetics. al-AT is produced by the Pi gene (chromosome 14). More than 75 gene variants are described. PiM is the normal, most common form (90%). Most other variants also produce normal al-AT levels. PiS deficiencyvariant causes mildly reduced levels. PiZdeficiencyvariant causes markedly reduced levels. Homozygous PiZZ have severe reduc­ tions (15% of normal) in enzyme levels.

b.Clinicalfeatures.a-1-Antitrypsin deficiencyaffects the liver (micronod­ ular cirrhosis and an increased risk of hepatocellular carcinoma) and lungs (panacinar emphysema). Microscopically, PAS positive, eosinophilic cytoplasmic globules are found in hepatocytes. Treatment involves smoking abstinence/cessation to prevent emphysema. Liver transplantation is curative.

4.Reye syndrome is a rare, potentially fatal disease that occurs in young chil­ dren with viral illness (varicella or influenza) treated with aspirin. The dis­ ease mechanism is unknown; mitochondrial injury and dysfunction play an important role. Reye syndrome causes hepatic fatty change (microvesicular steatosis) and cerebral edema/encephalopathy. There is complete recovery in 75% of patients, but those that do not recover may have coma, permanent neurologic deficits, and death. Treatment is supportive.

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Chapter 20 • Liver Pathology

© cdc.gov. Used withpermission.

Figure 20-2. Reye Syndrome

5.Nonalcoholicfattyliver diseaseis a disease of lipids accumulating in hepa­ tocytes that is not associated with heavy alcohol use. It occurs equally in men and women, and is strongly associated with obesity, hyperinsulinemia, insulin resistance, and type 2 diabetes mellitus. The pathogenesis involves lipid accumulation in hepatocytes that can progress to steatohepatitis (NASH-nonalcoholic steatohepatitis) and finally cirrhosis. Nonalcoholic fatty liver disease is a diagnosis of exclusion.

HEMODYNAMIC LIVER DISEASES

1 . Budd-Chiari syndrome (hepatic vein thrombosis) refers to occlusion of the hepatic vein by a thrombus, often resulting in death. While a few cases are idiopathic, there is much more often an underlying process predispos­ ing for the thrombosis, which may include polycythemia vera, pregnancy, oral contraceptives, paroxysmal nocturnal hemoglobinuria, or hepatocel­ lular carcinoma. Budd-Chiari syndrome causes abdominal pain, hepato­ megaly, ascites, and death. Microscopically, the liver shows centrilobular congestion and necrosis.

2.Chronic passive congestion of the liver refers to a "backup of blood" into the liver, usually due to right-sided heart failure. Grossly, the liver char­ acteristically has a nutmeg pattern of alternating dark (congested central areas) and light (portal tract areas) liver parenchyma. Microscopically, the liver shows centrilobular congestion. Complications include centrilobular necrosis, which is an ischemic necrosis of centrilobular hepatocytes. Long­ standing congestion can lead to centrilobular fibrosis, which can eventually become cardiac cirrhosis (sclerosis) .

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LIVERTUMORS

1.Hemangiomais the most common primary tumor ofthe liver. This benign vascular tumor typically forms a subcapsular, red, spongy mass. It is often asymptomatic and detected incidentally.

2.Hepatic adenoma (liver cell adenoma) affects young women and is related to oral contraceptive use. Subcapsular adenomas may rupture, causing an intraperitoneal hemorrhage. Microscopically, the tissue resembles normal liver except for the lack of portal tracts. The tumor may regress after oral contraceptives are discontinued.

3.Hepatocellular carcinoma (HCC) is the most common primary malig­

nant tumor ofthe liver in adults. The incidence is higher in Asia and Japan than in the United States. Risk factors include cirrhosis, hepatitis B and C viruses, alcohol, af!atoxin Bl. HCC has a tendency for hematogenous spread and invasion of portal and hepatic veins. The tumor marker is cx.-fetoprotein (AFP). The fibrolamellar variant affects younger age, has fibrous bands, and has a better prognosis.

4.Metastatic tumors are the most common tumors found within the liver. Common primary sites include colon, breast, and lung. Metastatic tumors tend to occur as multiple well-circumscribed masses.

Chapter Summary

•Jaundice produces yellow skin and sclera and occurs with bilirubin levels >2-3 mg/dl.

•Increased red blood cell turnover, due to either hemolytic anemia or ineffective

erythropoiesis, causes an unconjugated hyperbilirubinemia and may predispose for pigmented bilirubinate gallstones.

•Physiologic jaundice of the newborn is a transient unconjugated hyperbilirubinemia due to the immaturity of the liver.

•Gilbert syndrome and Crigler-Najjar syndrome are inherited causes of unconjugated hyperbilirubinemia due to bilirubin glucuronosyltransferase deficiency or absence. Gilbert disease is completely benign. Type I Crigler-Najjar syndrome is fatal in infancy secondary to kernicterus and type II Crigler-Najjar syndrome causes jaundice.

•Dubin-Johnson syndrome is a benign autosomal recessive disorderthat causes conjugated hyperbilirubinemia secondary to decreased bilirubin excretion due to a defect in the canalicular transport protein. A distinctive feature of Dubin­ Johnson syndrome is black pigmentation ofthe liver. Rotor syndrome is similar to Dubin-Johnson syndrome but does not have the liv$r pigmentation.

•Biliary tract obstruction can be due to gallstones, tumors, stricture, or parasite, and can present with jaundice, pruritus, abdominal pain, bilirubinuria, and pale stools.

•Primary biliary cirrhosis is a chronic liver disease of probable autoimmune etiology that is characterized by inflammation and granulomatous destruction of intrahepatic bile ducts.

•Primary sclerosing cholangitis is a chronic liver disease of unknown etiology characterized by segmental inflammation and fibrosing destruction of intrahepatic bile ducts.

(Continued)

194 MEDICAL

Chapter 20 • Liver Pathology

Chapter Summary (cont'dJ

•Cirrhosis is an end-stage liver disease due to many etiologies characterized by disruption ofthe liver architecture by bands offibrosis that divide the liver into nodules of regenerating liver parenchyma. Complications of cirrhosis include portal hypertension, ascites, hypersplenism, esophageal varices, hemorrhoids, caput medusae, hepatic encephalopathy, spider angiomata, palmar erythema, gynecomastia, hypoalbuminemia, decreased clotting factors, and hepatorenal syndrome.

•Acuteviral hepatitis can be due to any ofthe hepatitis viruses. Chronic viral hepatitis can be caused by hepatitis viruses B, C, and D. Hepatitis viruses vary in the nature ofthe virus and the manner in which they are spread. Hepatitis A virus is spread by the fecal-oral route and usually causes mild acute hepatitis. Hepatitis B virus is spread parenterally and by sexual contact and may cause acute hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis C is spread by the parenteral and sexual routes and may cause acute hepatitis, chronic hepatitis,

cirrhosis, and hepatocellular carcinoma. Hepatitis D is a defective virus that requires Hepatitis B as a coinfection or superinfection to produce severe disease, which maytake the form ofacute hepatitis, chronic hepatitis, or cirrhosis. Hepatitis E virus is spread by the fecal-oral route and causes acute hepatitis that may be severe in infected pregnant women.

•Amebic liver abscess is due to infection with Entamoeba histolytica and requires antibiotics and surgical drainage for therapy.

•Alcoholic liver disease can produce steatosis, alcoholic hepatitis, or alcoholic cirrhosis.

•Wilson disease is a genetic disorder of copper metabolism resulting in accumulation oftoxic levels of copper leadingto liver disease, Kayser-Fleischer corneal rings, and neurologic and psychiatric manifestations.

•Hemochromatosis is characterized by increased levels of iron that can deposit into tissues, leading to cirrhosis, hepatocellular carcinoma, diabetes mellitus, bronze skin, congestive heart failure, cardiac arrhythmias, and hypogonadism.

•Alpha-1-antitrypsin deficiency is an autosomal recessive disorder characterized by production of defective alpha-1-antitrypsin, which accumulates in hepatocytes

and causes liver damage and low serum levels of alpha-1-antitrypsin.

•Reye syndrome is a potentially fatal disease that occurs in young children with viral illnesses treated with aspirin. It can cause liver steatosis and cerebral edema.

•Nonalcoholic fatty liver disease is highly associated with obesity and type 2 diabetes mellitus leading to hepatic lipid accumulation, nonsteatohepatitis, and can progress to cirrhosis in 10-30% of patients.

•Budd-Chiari syndrome is occlusion of the hepatic vein by a thrombus, often resulting in death.

•Chronic passive congestion ofthe liver is a "backup of blood" into the liver, usually due to right-sided heart failure, and may, in long-standing cases, lead to cirrhosis (sclerosis).

•Benign tumors ofthe liver include hemangiomas and hepatic adenomas. Malignant tumors include hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, and metastatic tumors.

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