Diseases of the liver and pancreas


Alpha-1-Antitrypsin Deficiency



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Alpha-1-Antitrypsin Deficiency

  • Is an autosomal recessive disorder

  • Abnormally low serum levels of major protease inhibitor (“Pi”)

  • Deficiency leads to the development of

  • Pulmonary disease (emphysema)

  • Hepatic disease (cholestasis or cirrhosis)

  • Alpha-1-AT gene is located on human chromosome 14

  • The most common phenotype is PiMM, occurring in 90% of individuals

  • Homozygotes for the PiZZ protein, however, have circulating a1-AT levels that are only 10% of normal levels and are at highest risk for developing clinical disease.

  • Characterized by round-to-oval cytoplasmic globular inclusions of impounded a1-AT in hepatocytes

  • Manifestations include:

  • Neonatal hepatitis without or with cholestasis and fibrosis

  • Childhood cirrhosis

  • Cirrhosis that becomes apparent only late in life when liver scarring is well advanced

  • Hepatocellular carcinoma develops in 2 to 3% of PiZZ adults, usually but not always in the setting of cirrhosis

  • Treatment: For severe hepatic disease is liver transplantation, with restoration of normal a1-AT synthesis and release



Red hyaline globules – cytoplasmic inclusions
Intrahepatic Biliary Tract Disease

  • Secondary Biliary Cirrhosis

  • Primary Biliary Cirrhosis

  • Primary Sclerosing Cholangitis

  • Anomalies of the Biliary Tree

Secondary Biliary Cirrhosis

  • Prolonged obstruction to the extrahepatic biliary tree results in profound alteration of the liver architecture

  • Causes:

  • Impacted gallstone in the CBD (Most common cause)

  • Biliary atresia

  • Malignancies of the biliary tree and head of the pancreas

  • Strictures resulting from previous surgical procedures

  • Changes:

  • Initially, features of cholestasis

  • Reversible with correction of the obstruction

  • Initiation of periportal fibrosis secondary to inflammation

  • Leading to secondary biliary cirrhosis

  • Secondary bacterial infection (“ascending cholangitis”) may contribute to the damage

  • Enteric organisms such as coliforms and enterococci are common culprits.

Morphology

  • End-stage obstructed liver exhibits extraordinary yellow-green pigmentation

  • Accompanied icteric discoloration of body tissues and fluids.

  • Grossly: Liver is hard with a finely granular appearance

  • Microscopically:

  • Large and small bile ducts distended + contain inspissated bile

  • Portal tracts interconnected by inflamed fibrous septa

  • Cholestatic features may be severe

  • Cytoplasmic and canalicular accumulation of bile

  • Extensive feathery degeneration of hepatocytes

  • Formation of bile lakes


Primary Biliary Cirrhosis

  • Is a chronic, progressive, and often fatal cholestatic liver disease

  • Characterized by:

  • Nonsuppurative, granulomatous destruction of medium-sized intrahepatic bile ducts

  • Portal inflammation and scarring

  • Eventual development of cirrhosis and liver failure.

  • It is a focal and variable disease

  • Exhibits different degrees of severity in different portions of the liver

Destruction of bile ductules w/Mononuclear inflammatory infiltrate



Morphology

  • PBC is the prototype of all conditions leading to small-duct biliary fibrosis and cirrhosis

  • Four histologic stages have been described:

  • The florid duct lesion (granulomatous destruction of interlobular bile ducts)

  • Ductular proliferation with periportal hepatitis

  • Scarring, with bridging necrosis and septal fibrosis

  • Cirrhosis

  • Primarily a disease of middle-aged women (Female-to-male predominance 6:1)

  • Age of onset 20 and 80 years - peak 40 to 50 years.

  • May be asymptomatic for years

  • Onset insidious, usually presenting with pruritus

  • Jaundice develops late in the course

  • Hepatomegaly is typical

  • Xanthomas and xanthelasmas arise as a result of cholesterol retention.

  • Serum alkaline phosphatase and cholesterol almost always elevated

  • Hyperbilirubinemia is a late development

  • Signifies incipient hepatic decompensation

  • Striking feature is autoantibodies, especially antimitochondrial antibodies in > 90% of patients

  • Characteristic are ‘M2’ antibodies against mitochondrial pyruvate dehydrogenase

  • Extrahepatic manifestations associated with PBC include the sicca complex of dry eyes and mouth (Sjödogren’s syndrome), scleroderma, thyroiditis, rheumatoid arthritis, Raynaud’s phenomenon, membranous glomerulonephritis, and celiac disease.


Primary Sclerosing Cholangitis

  • Characterized by inflammation, obliterative fibrosis, and segmental dilatation of the intrahepatic and extrahepatic bile ducts.

  • Irregular strictures and dilatations of affected bile ducts leads to characteristic “beading” of a barium column in radiographs of intrahepatic and extrahepatic biliary tree

  • Commonly seen in association with inflammatory bowel disease

  • Chronic ulcerative colitis coexists in approximately 70% of patients

  • Occurs in the third through fifth decades of life

  • Males predominate 2:1

Onion-skin fibrosis in portal region Beaded appearance on cholangiogram



Morphology

  • PSC 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 (“onionskin fibrosis”) is followed by their disappearance, leaving behind a solid, cord-like fibrous scar.

  • In between areas of progressive stricture, bile ducts become ectatic and inflamed, presumably the result of downstream obstruction.

  • As the disease progresses, the liver becomes markedly cholestatic, culminating in biliary cirrhosis.

Clinical Course

  • Asymptomatic patients may come to attention based only on persistent elevation of serum alkaline phosphatase.

  • Alternatively, progressive fatigue, pruritus, and jaundice may develop.

  • Severely afflicted patients exhibit symptoms associated with chronic liver disease, including weight loss, ascites, variceal bleeding, and encephalopathy.

  • Ten-year survival is 50 to 75%

  • Progressive decline is arrested only by liver transplantation


Exam table:



Distinctive pathologic findings of bile ducts:

Periductal fibrosis:

Neonatal Hepatitis

  • Prolonged conjugated hyperbilirubinemia in the neonate is termed as neonatal cholestasis

  • The major conditions causing it are

  • Cholangiopathies, primarily extrahepatic biliary atresia (EHBA)

  • Variety of disorders causing conjugated hyperbilirubinemia in the neonate, collectively referred to as neonatal hepatitis

  • Finding of “neonatal cholestasis” should evoke a diligent search for recognizable toxic, metabolic, and infectious liver diseases

  • Clinical Presentation:

  • Jaundice, dark urine, light or acholic stools, and hepatomegaly.

  • Variable degrees of hepatic synthetic dysfunction may be identified, such as hypoprothrombinemia.

  • Liver biopsy is critical in distinguishing neonatal hepatitis from an identifiable cholangiopathy.

  • The morphologic features of neonatal hepatitis are as follows:

  • Lobular disarray with focal liver cell necrosis

  • Panlobular giant cell transformation of hepatocytes

  • Prominent hepatocellular and canalicular cholestasis

  • Mild mononuclear infiltration of the portal areas

  • Reactive changes in the Kupffer cells

  • Extramedullary hematopoiesis



Circulatory Disorders of Liver

  • Liver Infarction

  • Portal Vein Obstruction and Thrombosis

  • Passive Congestion and Centrilobular Necrosis

  • Peliosis Hepatis

  • Hepatic Vein Thrombosis (Budd-Chiari Syndrome)

  • Veno-Occlusive Disease


Liver Infarction

  • Liver infarcts are rare, thanks to the double blood supply to the liver.

  • However, thrombosis or compression of an intrahepatic branch of the hepatic artery by embolism, neoplasia, polyarteritis nodosa, or sepsis may result in a localized infarct that is usually anemic and pale tan.


Portal Vein Obstruction and Thrombosis

  • May be insidious and well tolerated or may be a catastrophic and potentially lethal event

  • Extrahepatic causes of portal vein obstruction include

  • Massive enlargement of hilar lymph nodes owing to metastatic abdominal cancer

  • Pylephlebitis resulting from peritoneal sepsis (e.g., acute diverticulitis or appendicitis)

  • Propagation of splenic vein thrombosis secondary to pancreatitis

  • Postsurgical thrombosis following upper abdominal procedures

  • Most common intrahepatic cause is cirrhosis of the liver

  • In all cases, retrograde propagation of thrombus or growth of tumor may completely occlude splanchnic inflow to the liver.

  • Abdominal pain

  • Massive ascites and esophageal varices Impairment of splanchnic blood flow often leads to profound bowel congestion and infarction. When the condition is secondary to pylephlebitis, anterograde spread of infection may yield multiple liver abscesses.


Banti’s syndrome

  • Characterized by

  • Splenomegaly

  • Hypersplenism

  • Portal hypertension

  • More aptly termed noncirrhotic or idiopathic portal hypertension

  • Condition arises following subclinical occlusion of the portal vein, usually years after the occlusive event

  • Postulated causes include neonatal omphalitis, dehydration, sepsis, or umbilical vein catheterization for exchange transfusion therapy; hypercoagulable myeloproliferative disorders; biliary tract surgery; peritonitis; and exposure to arsenicals.

  • Prognosis is generally excellent, and clinical outcome relates primarily to the complications of chronic portal hypertension

Passive Congestion and Centrilobular Necrosis

  • Acute and chronic passive congestion of the liver usually reflects acute or slowly developing cardiac decompensation, most commonly right-sided failure.

  • Liver is slightly enlarged, tense, and cyanotic, with rounded edges.

  • On cut section, excessive ooze of blood, and centrilobular areas dusky and soft, surrounded by paler, fatty liver substance in the portal areas (the “nutmeg liver”)

  • Microscopically there is congestion of centrilobular sinusoids.

  • With time, centrilobular hepatocytes become atrophic, resulting in markedly attenuated liver cell cords.

Nutmeg Liver – congestion around central vein



Cardiac Sclerosis

  • Chronic severe congestive heart failure may lead to fibrosis of the liver

  • Due to complication of sustained increased venous backpressure and centrilobular hypoxia.

  • Pattern of liver fibrosis is distinctive - it is mostly centrilobular

  • Scarring of cardiac sclerosis is delicate and subtle and easily missed on both gross and microscopic examination.

  • Liver is slightly reduced in size and has a fine pigskin grain on its external surface.

  • Microscopically there is a subtle increase in fibrous tissue about the central veins, from which delicate strands fan out into the surrounding liver substance.

  • Interconnection of the fibrous strands to produce bridging tracts of fibrous tissue is seen only in extreme examples, usually in association with tricuspid insufficiency.


Peliosis Hepatis

  • Peliosis hepatis is a rare condition

  • Primary dilatation of the sinusoids impeding efflux of hepatic blood.

  • Most commonly associated with exposure to anabolic steroids and rarely oral contraceptives and danazol.

  • Mottled and blotchy areas develop in the liver, consisting of irregular blood-filled lakes ranging from < 0.1to>1 cm

  • Microscopically, the lesions consist of irregular cystic spaces - dilated sinusoids lined by an endothelium

  • There are no intrinsic abnormalities in hepatocytes or hepatic venules.


Hepatic Vein Thrombosis (Budd-Chiari Syndrome)

  • Acute, usually fatal thrombotic occlusion of the hepatic veins.

  • Definition now includes subacute and chronic occlusive syndromes, characterized by hepatomegaly, weight gain, ascites, and abdominal pain.

  • Hepatic vein thrombosis is associated with (in order of frequency)

  • Polycythemia vera

  • Pregnancy

  • Postpartum state

  • Use of oral contraceptives

  • Paroxysmal nocturnal hemoglobinuria

  • Intra-abdominal cancers, particularly hepatocellular carcinoma.

  • All these conditions produce thrombotic tendencies or, in the case of liver cancers, sluggish blood flow.

  • 30% of cases are idiopathic in origin.

  • Untreated the mortality of acute Budd-Chiari syndrome is high.


Tumors of the Liver

  • Benign

  • Cavernous Hemangiomas (most common)

  • Nodular hyperplasia

  • Focal nodular hyperplasia

  • Nodular regenerative hyperlasia

  • Adenomas

  • Malignant

  • Primary

  • Hepatoblastoma

  • Angiosarcoma

  • Hepatocellular carcinoma

  • Cholangiocarcinoma

  • Secondary / Metastatic


Cavernous Hemangiomas

  • The most common benign lesion

  • Appears as discrete red-blue, soft nodules

  • Usually < 2 cm in diameter

  • Often directly beneath the capsule

  • Importance of recognizing these lesions is:

  • Not to mistake them for metastatic tumors

  • Not to perform blind percutaneous biopsies on them


Focal Nodular Hyperplasia

  • Solitary or multiple benign hepatocellular nodules may develop in the liver, in the absence of cirrhosis

  • Appears as a well-demarcated but poorly encapsulated nodule

  • Up to many centimeters in diameter

Gross examination:

  • Is lighter than the surrounding liver and brown to tan (sometimes yellow).

  • Typically, central gray-white depressed stellate scar from which radiate fibrous septa to the periphery

  • Central scar contains arteries which show

  • Fibromuscular hyperplasia

  • Eccentric or concentric narrowing of the lumen.

  • Radiating septa contain foci of intense lymphocytic infiltrates and exuberant bile duct proliferation along septal margins

  • Parenchyma between the septa is composed largely of normal hepatocytes

  • Occurs most frequently in young to middle-aged adults

  • Does not appear to pose a risk for malignancy


Nodular Hyperplasias

Nodular regenerative hyperplasia



  • Is a diffuse, nonfibrosing version of focal nodular hyperplasia, affecting the entire liver with roughly spherical nodules of plump hepatocytes surrounded by rims of atrophic cells

  • Is associated with the development of portal hypertension, with attendant symptoms.

  • Is a nonspecific transformation that may occur in association with such diverse conditions as bone marrow transplantation and primary biliary cirrhosis

Adenomas

  • Benign neoplasms developing from hepatocytes

  • Occur in young women using oral contraceptives

  • Regress on discontinuation

  • Liver cell adenomas have clinical significance for three reasons:

  • Present as an intrahepatic mass - may be mistaken for Hepatocellular Carcinoma

  • Subcapsular adenomas may rupture causing severe intraperitoneal hemorrhage (particularly during pregnancy - under estrogenic stimulation)

  • Rarely they may harbor hepatocellular carcinoma.

Gross Morphology

  • Are pale, yellow-tan, frequently bile-stained nodules

  • Often beneath the capsule.

  • May reach 30 cm in diameter.

  • Although they are usually well demarcated, encapsulation may not be grossly evident

Histologic Morphology

  • Composed of sheets and cords of cells that resemble normal hepatocytes

  • Portal tracts are absent

  • A capsule (delicate collapsed reticulin or well-defined connective tissue) usually separates the lesion from the surrounding parenchyma

A. Gross Pathology

B. Cut Section of Gross Pathology

C. CT of same

D.Normal hepatic tissue on the left side/Adenoma on the right:Disorganized hepatocyte cords Absent normal architecture
Malignant Tumors - Hepatoblastoma


  • Is a tumor usually of young childhood

  • Exhibits two anatomic variants:

  • Epithelial type: Composed of small, compact fetal or smaller embryonal cells, forming acini, tubules, or papillary structures vaguely recapitulating the development of the liver

  • Mixed type: Containing an epithelial element interspersed with foci of mesenchymal differentiation that may consist of primitive mesenchyme, osteoid, cartilage, or striated muscle.

  • Unless successfully resected, both variants are usually fatal within a few years.


Malignant Tumors - Angiosarcoma

  • Resembles those occurring elsewhere in the body

  • It is associated with exposure to vinyl chloride, arsenic, or Thorotrast (once used in radiography as a hepatic contrast medium).

  • The latent period between exposure to the putative carcinogen and the appearance of the neoplasm may be several decades.

  • Are highly aggressive neoplasms

  • Metastasize widely

  • Generally death within a year.


Primary Carcinoma of the Liver

Basically two types of primary liver carcinoma:



  • Hepatocellular carcinoma (HCC) sometimes still called a “hepatoma,” accounts for more than 90% of all primary liver cancers.

  • Cholangiocarcinoma: Composed of bile duct epithelium

Epidemiology

  • Highest numbers of cases of hepatocellular carcinoma are found in Taiwan, Mozambique, and Southeast China

  • Blacks > whites

  • Males > females

  • Global distribution strongly linked to prevalence of HBV infection

In high-incidence regions:

  • HBV carrier state begins in infancy following vertical transmission of virus from infected mothers, conferring a 200-fold increased risk of HCC by adulthood.

  • In these regions, cirrhosis may be absent in 50% of HCC patients

  • Cancer often occurs between 20 and 40 years of age

In the Western world, where HBV is not prevalent:

  • Cirrhosis is present (in 85 - 90% of cases of HCC) along with other chronic liver diseases (including HCV infection and alcohol)

  • Cancer is seldom encountered before age 60.

  • Three major etiologic associations for HCC

  • HBV infection

  • Aflatoxin exposure

  • Cirrhosis.

  • 40% of patients of hereditary tyrosinemia develop this tumor despite adequate dietary control

  • None of the influences related to HCC has any bearing on the development of cholangiocarcinoma

  • Recognized causal influences of this tumor are:

  • Previous exposure to Thorotrast (formerly used in radiography)

  • Invasion of the biliary tract by the liver fluke Opisthorchis sinensis


Hepatocellular Carcinoma

Morphology

  • HCC or cholangiocarcinoma may appear grossly as:

  • Unifocal (usually large) mass

  • Multifocal, widely distributed nodules of variable size

  • Diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver

  • All three patterns may cause liver enlargement (2000 to 3000 gm), particularly the unifocal massive and multinodular patterns.

  • Discrete masses are yellow-white, punctuated sometimes by areas of hemorrhage or necrosis

  • May have a green hue when composed of well-differentiated hepatocytes capable of secreting bile

  • Have a strong propensity for invasion of vascular channels

  • Extensive intrahepatic metastases ensue, and occasionally long, snake-like masses of tumor invade

  • Portal vein (with occlusion of the portal circulation)

  • Inferior vena cava, extending even into the right side of the heart.

Microscopic Features of HCC

  • HCCs range from well-differentiated to highly anaplastic undifferentiated lesions.

  • In well-differentiated and moderately well-differentiated tumors, cells recognizable as hepatocytic in origin are disposed in a trabecular or acinar/ pseudoglandular pattern.

  • Supporting connective tissue is minimal to absent therefore are of soft consistency

  • Bile may occasionally be seen in canalicular spaces or lumens between tumor cells, and bile canaliculi may be present ultrastructurally.



  1. HCC

  2. HCC

  3. HCC

  4. Fibro-Lamellar Carcinoma


-fibro-lamellar carcinoma

-nests and cords of malignant-appearing hepatocytes

-separated by dense bundles of collagen
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