Liver, Gallbladder, and Pancreas

Liver, Gallbladder, and Pancreas

The liver maintains the physiologic and metabolic balance of the body. Therefore, disease of the liver may have numerous effects throughout the body: it may cause disturbances in carbohydrate, lipid, amino acid, and vitamin metabolism and interfere with protein synthesis, blood clotting, and detoxification of endogenous and exogenous substances (Table 5-1).

TABLE 5-1

CLINICAL FEATURES OF LIVER FAILURE

Clinical Feature	Pathogenesis
Jaundice	a. Intracellular retention of bilirubin (hepatocyte failure) b. Intercellular and canalicular (bile stasis)
Malabsorption, weight loss, bleeding tendency, muscle wasting	Bile, enzyme, and vitamin deficiency
Edema, muscle wasting	Decreased protein (albumin) synthesis
Spider nevi, palmar erythema, gynecomastia	Disturbed hormone metabolism
Ascites, splenomegaly, varices (gastroesophageal)	Portal hypertension
Hepatic encephalopathy	Toxic metabolites (acetoin, acyloin, ammonia)
Hepatorenal syndrome	Cause unknown (renal vasoconstriction?)

Inflammatory Diseases of the Liver

Viral hepatitis is an acute inflammation of the liver, usually caused by the hepatitis viruses (HAV-HGV), rarely by such other viruses as enteroviruses and herpesviruses (CMV, EBV, HHV-6, or HSV). Symptoms do not develop until the onset of immune reactions against the virus or virus-infected cells, 2 to 26 weeks after infection (incubation period). Bacteria, fungi, and parasites also may cause hepatitis.

Noninfectious causes of liver inflammation include toxic and immunologic disorders of the liver (see Table 5-2). These are discussed together because certain forms of toxic hepatitis may mimic autoimmune disorders or may be mediated through hypersensitivity reactions. A large variety of substances can cause liver damage, and they are associated with an equally large variety of lesions. A selection is shown in Table 5-3.

TABLE 5-2

CHARACTERISTICS OF PRIMARY AUTOIMMUNE DISORDERS OF THE LIVER*

Features	AIH	PBC	PSC
Serology (autoantibodies)	Antinuclear (ANA) Anti–smooth muscle (ASMA) Anti–liver/kidney membrane (LKM) Antiliver (LSP)	Anti–native DNA Antiribosomal Antimitochondrial (AMA) ASMA Anti–bile proteins Antithyroid LSP	ANA Antineutrophils (ANCA) Anti–bile duct epithelia
Genetics	Nonspecific	Female predominance	Male predominance Increased expression: HLA-DR3, HLA-DRW52a, HLA-B8 (DR2,4, DRb12)
Associated diseases	Rheumatoid arthritis Pernicious anemia Cryoglobulinemia Peripheral neuropathy Hemolytic anemia	Raynaud syndrome Thyroid dysfunction Seronegative arthritis Scleroderma Keratoconjunctivitis	Ulcerative colitis Riedel thyroiditis Retroperitoneal fibrosis Orbital pseudotumor (may be complicated by cholangiocarcinoma)

Overlap syndromes combine features of cholestatic and chronic hepatitic forms of diseases, e.g., AIH + PBC, PBC + PSC, or PBC + sarcoidosis.

^*AIH indicates autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

TABLE 5-3

TOXIC HEPATITIS AND ITS LESIONS

Mechanism	Lesion	Exemplary Substances
Direct and indirect toxicity	Hepatocellular necrosis and steatosis	Alcohol, CCl₄, phosphorus methyl-DOPA, tetracyclines
Cholestatic	Hepatocanalicular cholestasis	Steroids
Hypersensitivity	Hepatocellular and hepatocanalicular, necrosis, cholestasis, granulomatous	Erythromycin, chlorpromazine phenytoin
	Vasculitis (panarteritis nodosa type)	Penicillin, allopurinol, sulfathiazole chlorpromazide, diphenylhydantoin, chlorothiazide, methamphetamine
	Sclerosing cholangitis type	Floxuridine
Metabolic	Hepatocellular and hepatocanalicular	Isoniazid, halothane

There are 3 major groups of autoimmune disorders affecting the liver: primary hepatic autoimmune diseases (Table 5-3), liver diseases with secondary autoimmune component, and systemic autoimmune diseases involving the liver.

Metabolic Diseases Involving the Liver

A number of metabolic disorders affect the liver, some of which are consequences of inborn errors of metabolism. Major forms discussed in this chapter are hemochromatosis, Wilson disease (WD), and amyloidosis.

Primary Tumors of the Liver

The most frequent tumors in the liver are metastases, often from the gastrointestinal (GI) tract, the lungs, or the mammary glands. Primary tumors originating in the liver consist of benign hepatic hamartomas and adenomas, bile duct angiomas, and cavernous hemangiomas. Two benign lesions must be distinguished from well-differentiated hepatocellular carcinoma (HCC): hepatocellular adenoma and focal nodular hyperplasia (FNH) of the liver. Adenomas (single or multiple) are well-circumscribed, yellowish masses of liver tissue with a fibrous capsule and histologically lobular architecture devoid of central vein, portal triads, and bile ductules. They occur preferentially in women of reproductive age and seem to be related to the use of oral contraceptives. FNHs, which occur equally in the two sexes, are solitary masses of hypertrophic hepatocellular nodules divided by fibrous septae, with prominent central scarring, large central nutritive vessels, bile ductules and cholestasis, and a pseudocapsule. The most frequent malignant tumors of the liver are HCC and cholangiocarcinoma (CAC). Less frequent are hepatoblastoma (in small children) and hemangiosarcoma.

Cholelithiasis and Cholecystitis

Cholelithiasis (CHL) is the formation of stones in the gallbladder and large bile ducts, usually in extrahepatic locations. CHL occurs in up to 20% of the Western population, approximately four fifths of whom have no symptoms (silent CHL). The prevalence of gallstones increases with age, with most patients being older than 40 years. Females experience CHL approximately twice as often as males, suggesting that a role is played by the endocrine system (increased estrogens, oral contraceptives, obesity, and hypercholesterolemia). Additional risk factors are hyperlipidemia, rapid weight loss, inborn errors of bile acid metabolism, and GI diseases such as Crohn ileitis, pancreatic insufficiency, and mucoviscidosis.

Tumors of the Gallbladder and the Bile Ducts

Papillomas, adenomas, and adenomyomas of deeper (submucosal) glands may occur in the gallbladder. Most remain clinically inapparent except when they cause obstruction (e.g., papillomas in bile ducts or papilla of Vater). The majority of malignant tumors in the gallbladder are adenocarcinomas, which are found in approximately 2% of resected gallbladders. Approximately 5% of malignant tumors in this organ are squamous cell carcinomas.

Acute and Chronic Pancreatitis

Inflammation of the pancreas, usually caused by CHL or alcoholism, is characterized by massive activation of pancreatic enzymes, which, in acute cases, may cause life-threatening autodigestion and shock. Chronic cases cause extensive destruction of pancreatic parenchyma with fibrosis and loss of enzymatic activities.

Cystic Fibrosis (Mucoviscidosis)

Cystic fibrosis (CF) is the most common autosomal recessively inherited disease in children and young adults, with an incidence in Western populations of 1 in 2000 live births. It is caused by variable mutations of the CF gene on chromosome 7 (7q31-32). The primary defect caused by these mutations is in chloride ion channels, which transport chloride ions across epithelial barriers. Deficient chloride ion transport interferes with sodium and water secretion in exocrine glands, resulting in the production of a viscous mucoid material that obstructs glandular ducts in salivary glands, bronchial glands, the pancreas, and others. (See also Fig. 3-3.)

Neoplasms of the Pancreas

Benign tumors of the exocrine pancreas are rare and consist essentially of ductal serous or mucinous cystadenomas. They must be distinguished clinically from inflammatory pseudocysts rather than from carcinoma. Carcinoma of the pancreas is the fourth most common tumor in the Western world, is even more frequent in the Pacific region, and is increasing in incidence. Approximately 23,000 new cases are diagnosed every year in the United States; only approximately 1% of these patients survive 5 years. No clear cause of human pancreatic cancer has been identified. Chronic pancreatitis is a recognized risk factor for carcinoma of the pancreas. Dietary factors, such as high fat and meat intake, may be contributory.

TABLE 5-4

MEMBERS AND CHARACTERISTICS OF THE HEPATITIS VIRUSES*

Name (Molecule)	Family	Transmission	Incubation, weeks	Disease	Carrier	Chronic	Cancer
HAV (ssRNA)	Picorna	Enteral	2–6	Hepatitis, fulminant hepatitis	0	0	0
HBV (dsDNA)	Hepadna	Parenteral	4–26	Hepatitis, fulminant hepatitis, cirrhosis	−1%	−10%	Yes
HCV (ssRNA)	Flavivirus	Parenteral	2–26	Hepatitis, cirrhosis, extrahepatic disorders	−1%	−50%	Yes
HDV (ssRNA)	Subviral satellite (HBV helper)	Parenteral	4–7 (super- infection)	Hepatitis, fulminant hepatitis	−10%	−5%	0
HEV (ssRNA)	Calicivirus	Enteral	2–8	Hepatitis	?	0	0
HGV (ssRNA)	Flavivirus	Parenteral	?	Hepatitis, extrahepatic disorders in drug addicts	−2%	0	?

^*ds indicates double-stranded; ss, single-stranded.

TABLE 5-5

GROSS FEATURES AS RELATED TO THE PATHOGENESIS OF LIVER CIRRHOSIS*

Gross Appearance	Pathogenesis
Diffuse, finely nodular (classic Laennec type: with atrophy)	Post–hepatitis virus cirrhosis
Same with or without fatty infiltration	Post–alcoholic cirrhosis
Diffuse, medium-sized nodular, dark purple (classic Hanot type with hypertrophy)	Chronic congestive (practically only seen in constrictive pericarditis)
Same with severe jaundice (green liver)	Primary biliary cirrhosis or chronic sclerosing cholangitis
Same with “dirty” gray-brown appearance (and similarly pigmented pancreas)	Hemochromatosis, Wilson disease
Diffuse, irregularly nodular, preferentially small- to medium-sized nodular	Autoimmune hepatitis and cirrhosis
Irregular, medium- to large-sized nodular, with jaundice (green liver)	Secondary biliary cirrhosis (i.e., extrahepatic bile duct obstruction)
Same with regular color or with fatty infiltration	“Postnecrotic” cirrhosis of variable etiology (e.g., post-HSV + alcoholic or other toxic influences)

^*HSV indicates herpes simplex virus.

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