Hepatobiliary System

Clinical Features

Gross Pathology

• Noncontributory

Histopathology

Special Stains and Immunohistochemistry

• Immunohistochemistry for hepatitis B core antigen (HBcAg), HBsAg, and hepatitis B e antigen (HBeAg)

Other Techniques for Diagnosis

• Electron microscopy: HBsAg in hepatocyte cytoplasm (22-nm spheres and rods)

Differential Diagnosis

• Serologic markers and virologic assays of viral infection are virtually essential to establish or exclude the diagnosis

Clinical Features

• High mortality rate

• Patients often have fever and right upper quadrant tenderness

• Surgical drainage is often required

• Bacterial abscesses are caused by portal spread of extrahepatic infection with Staphylococcus aureus, Salmonella typhi, and Treponema pallidum (syphilis)

• Parasitic abscesses are caused by Entamoeba histolytica, Echinococcus species, malaria, Leishmania species, Ascaris lumbricoides , and liver flukes (e.g., Clonorchis sinensis, Fasciola hepatica , and Opisthorchis viverrini )

Gross Pathology

• Bacteremic spread through arterial or portal system: multiple, soft, grossly necrotic lesions

• Bacteremic spread by direct extension or trauma: solitary, large, soft, grossly necrotic lesions

Histopathology

Special Stains and Immunohistochemistry

• Gram stain: helps highlight bacteria

• Warthin-Starry, Dieterle stain, or T. pallidum immunohistochemistry: syphilis

• Giemsa stain to identify amastigotes: leishmaniasis

• Direct examination for Echinococcus species scolices and liver flukes

Other Techniques for Diagnosis

• Culture or nucleic acid tests may help identify organism

Differential Diagnosis

• See earlier discussion for specific infection characteristics

Clinical Features

• Clinical history important (e.g., ingesting an agent known to cause liver disease)

• An appropriate time interval between exposure and onset of disease

• A histologic lesion known to be associated with the suspect drug

• Resolution of the lesion after withdrawal

• Can be acute or chronic

• Correlation with laboratory testing (e.g., acetaminophen level) may be helpful

• Drug-specific clinical presentations and literature references are available from LiverTox ( http://livertox.nlm.nih.gov/ )

Histopathology

• Different agents may result in different liver injury patterns, such as the following:

  • Zone 3 hepatocellular necrosis: acetaminophen

  • Mimicking acute viral hepatitis: antituberculous drugs, anesthetics, herbal medicine, nonsteroidal antiinflammatory drugs

  • Cholestasis with duct damage and duct loss: amoxicillin and clavulanic acid (Augmentin)

  • Vanishing bile duct: chlorpromazine, amoxicillin and flucloxacillin, haloperidol, temozolomide

  • Microvesicular steatosis: valproic acid, tetracycline, nucleoside analogues, salicylate (Reye syndrome)

  • Hypertrophic hepatic stellate cells and perivenular and pericellular fibrosis: hypervitaminosis A

  • Sinusoidal obstruction syndrome/veno-occlusive disease: pyrrolizidine alkaloids or chemotherapeutic agents associated with bone marrow transplantation

  • Steatohepatitis-like: amiodarone, tamoxifen, methotrexate

  • Hepatitis with features of autoimmune hepatitis: anti-TNFα immunomodulators, immune checkpoint inhibitors

• Drug toxicity should always enter the differential diagnosis when abundant eosinophils or epithelioid granulomas are present or when hepatitis and cholestasis are both present

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Nonspecific symptoms including malaise, anorexia, weight loss, and tender hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase

• About 20% to 25% of heavy drinkers develop alcoholic steatohepatitis

Gross Pathology

• Early: large, soft, greasy, yellow liver

• Late: shrunken, mottled, red-brown liver with bile staining

• End-stage: cirrhosis

Histopathology

• Steatosis

• Zone 3 injury pattern

• Ballooning degeneration ( Figure 7.3A )

  

• Lobular inflammatory infiltrates, especially rich in neutrophils

• Mallory-Denk bodies and megamitochondria (see Figure 7.3B )

• Perivenular and pericellular fibrosis (see Figure 7.3C )

• Bile ductular reaction

• Sclerosing hyaline necrosis

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Clinical history is essential

Clinical Features

• A manifestation of the metabolic (insulin resistance) syndrome

• Risk factors: central obesity, hyperglycemia, type II diabetes, arterial hypertension, and hypertriglyceridemia

• Nonalcoholic steatohepatitis (NASH) is the progressive lesion of nonalcoholic fatty liver disease (NAFLD), which may progress to cirrhosis and liver failure

• Histologically, NASH is almost identical to alcoholic steatohepatitis but occurs in individuals who do not have significant alcohol history

Gross Pathology

• Early: large, soft, greasy, yellow liver

• Late: shrunken, mottled, red-brown liver with bile staining

• End-stage: cirrhosis

Histopathology

• Nonspecific steatosis in NAFLD

• Predominantly macrovesicular fatty change

• Typically starts in a zone 3 centrilobular pattern

Special Stains and Immunohistochemistry

• Immunohistochemical stains for ubiquitin and p62 have been developed to identify Mallory-Denk bodies.

• Rearrangement of the intermediate filament cytoskeleton in ballooned hepatocytes can be demonstrated by the loss of cytoplasmic keratin 8/18 immunostaining and may be evaluated as a marker for the more objective detection of hepatocellular ballooning in NASH.

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Clinical history is essential

Clinical Features

• Onset typically occurs during third trimester of pregnancy

• Bleeding, nausea and vomiting, jaundice, and occasionally coma

• Usually resolves after delivery

Gross Pathology

• Greasy, small, pale-yellow liver

Histopathology

• Microvesicular steatosis ( Figure 7.4 )

  

• Canalicular and intrahepatocytic cholestasis may occur

• Portal tract inflammation may be prominent

Special Stains and Immunohistochemistry

• Oil red O (on frozen-section slide) demonstrates microvesicular fat droplets.

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Clinical history is essential

Clinical Features

• Abnormal accumulation of iron in liver, pancreas, myocardium, and other organs

• Hereditary: homozygous recessive, loss of function in the HFE gene

• Acquired: multiple transfusions, Bantu hemosiderosis (alcoholic beverages brewed in iron drums in sub-Saharan Africa)

• Most often presents in men older than 40 years

• Liver is the most severely affected organ

• Classic triad: cirrhosis, skin pigmentation, and diabetes mellitus (not as common now owing to early diagnosis and treatment)

• Patients may also have abdominal pain, cardiac dysfunction, and atypical arthritis

• Laboratory studies show increased serum iron and ferritin

• Increased risk for developing HCC

Gross Pathology

• Enlarged liver with dark-brown pigmentation

• Ultimately leads to cirrhosis with persistent dark-brown pigmentation

Histopathology

• Early: hemosiderin granules in cytoplasm of periportal hepatocytes

• Middle:

  • Progressive iron deposition in lobules and eventually bile duct epithelium and Kupffer cells, resulting in hepatocyte necrosis, portal inflammation, and portal and bridging fibrosis ( Figure 7.5A )

    

  • Lobular inflammation typically absent

• Late: fibrous septa develop over years with progression to cirrhosis with intense hemosiderin pigmentation

Special Stains and Immunohistochemistry

• Prussian blue stain for iron highlights increased iron deposition (see Figure 7.5B )

Other Techniques for Diagnosis

• Hepatic iron index (HII): biochemical quantitation of hepatic iron in fresh tissue or paraffin block calculated as micromoles of iron per gram dry weight divided by patient’s age

  • Homozygotes: HII greater than 2 (may be greater than 40)

  • Heterozygotes: less than 2

  • Normal individuals: less than 1

• Nucleic acid testing for germline loss-of-function variants in the HFE gene, most commonly C282Y and/or H63D

Differential Diagnosis

Clinical Features

• Abnormal accumulation of copper in liver, brain, eyes, and other organs

• Variable age of onset

• Autosomal recessive, mutations in the ATP7B gene encoding a copper transporter

• Laboratory findings include decreased serum ceruloplasmin, increased hepatic copper, increased urinary excretion of copper

• Serum copper levels not helpful

• Most commonly presents with acute or chronic liver disease

• Neuropsychiatric symptoms are also frequent at presentation secondary to involvement of basal ganglia

• Kayser-Fleischer rings are diagnostic (green-brown deposits of copper in Descemet membrane in limbus of cornea)

Gross Pathology

• Liver eventually becomes cirrhotic

Histopathology

• Excessive copper granules in hepatocytes can only be seen with special stain ( Figure 7.6 )

  

• Mild to moderate fatty change

• Focal hepatocyte necrosis

• Glycogen vacuoles in hepatocyte nuclei

• Mallory-Denk bodies in periportal hepatocytes

• Acute and chronic hepatitis

• Cirrhosis following chronic hepatitis

• Rarely, massive liver necrosis

Special Stains and Immunohistochemistry

• Rhodanine stain for copper positive

• Orcein stain for copper-associated protein positive

Other Techniques for Diagnosis

• Quantitation of hepatic copper in fresh tissue or paraffin block (more than 250 μg copper/1 g dry liver), typically with mass spectrometry

• Sequencing of ATP7B gene

Differential Diagnosis

Clinical Features

• Variable age of onset

• Autosomal recessive disease caused by mutations of the SERPINA1 gene on chromosome 14

• Absent or decreased α ₁ -antitrypsin activity results in unchecked activity of neutrophilic elastase leading to pulmonary emphysema (destruction of elastic fibers supporting alveolar spaces)

• The most common variant protein (E366K) associated with liver disease is abnormally folded, resulting in impaired transport to the Golgi and accumulation in the endoplasmic reticulum of hepatocytes

• In some patients, there is liver disease without pulmonary emphysema owing to functional mutant forms that inhibit neutrophil elastase but that are not appropriately degraded in hepatocytes

• Clinical hepatic presentations range from:

  • Neonatal hepatitis with cholestatic jaundice

  • Young adults with recurrent attacks of hepatitis that either resolve or lead to chronic hepatitis and cirrhosis

  • Middle-aged to older adults with cirrhosis after a clinically silent course

• Increased risk for HCC, especially in homozygous patients

• Successful liver transplantation is curative

• Augmentation therapy with intravenous α ₁ -antitrypsin delays the natural course of lung disease, but does not impact liver disease

Gross Pathology

• Noncontributory

Histopathology

• Round to oval, variably sized eosinophilic globules most concentrated in periportal hepatocytes

• Otherwise variable histologic features

  • Neonatal hepatitis with or without cholestasis

  • Chronic hepatitic picture

  • Cirrhosis

Special Stains and Immunohistochemistry

• Eosinophilic globules are positive for periodic acid–Schiff (PAS) and resistant to diastase digestion ( Figure 7.7 )

  

• Immunohistochemistry for α ₁ -antitrypsin highlights eosinophilic globules

Other Techniques for Diagnosis

• Serum α ₁ -antitrypsin quantitation (<85 mg/dL is highly predictive)

• Serum protein electrophoresis with reduction in alpha-1 band (not specific)

• Identification of common variant proteins by mass spectrometry, or genetic variants by allele-specific PCR or sequencing of SERPINA1

• Identification of mutant proteins by isoelectric focusing

  • About 75 variants identified and named alphabetically according to migration on isoelectric gel

• Normal genotype is PiMM

• PiZZ is the most clinically significant genotype and shows the highest association with carcinoma

• Patients with PiMZ genotype have 50% normal α ₁ -antitrypsin and 50% mutant form

• Other mutant alleles include S (reduced levels of α ₁ -antitrypsin but no clinical disease unless inherited in combination with another mutation) and null (no detectable protein)

Differential Diagnosis

• Other types of chronic hepatitis include viral, drug, and autoimmune hepatitis, but they do not demonstrate the PAS-positive and diastase-resistant globules that are characteristic of α ₁ -antitrypsin deficiency

Clinical Features

• Young and middle-aged women (female-to-male ratio of 7:3)

• Often associated with extrahepatic autoimmune disorders such as rheumatoid arthritis, thyroiditis, Sjögren syndrome

• Hyperglobulinemia

• Characterized by serum autoantibodies, classically ANA, ASMA, soluble liver antigen (SLA), and anti-LKM1

• Negative viral serologic/virologic markers

• Responsive to immunosuppressive therapy

Gross Pathology

• Noncontributory

Histopathology

• Significant portal and periportal inflammatory infiltrate with lymphocytes and plasma cells (prominent plasma cells are the hallmark) ( Figure 7.8 )

  

• Marked lobular inflammatory infiltrate with prominent plasma cells deep in the parenchyma

• Increased lobular acidophil/apoptotic bodies

• Prominent interface hepatitis

• Bridging/confluent necrosis is common

• Severe hepatocellular injury with hepatitic rosette formation and syncytial giant hepatocytes

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Most commonly occurs in middle-aged women

• Serum AMA positive in more than 90% of cases

• Insidious onset, with pruritus being the most common presenting symptom and jaundice developing later

• Elevated serum alkaline phosphatase, with hyperbilirubinemia developing later

• Chronic and progressive, with cirrhosis developing only after many years

Gross Pathology

• Early: unremarkable

• Late: finely granular capsule; bile-stained parenchyma

• Ultimately liver becomes cirrhotic (biliary type cirrhosis)

Histopathology

• Variability in stages of lesions (i.e., coexistence of different stages in single specimen)

• Stage I (florid duct lesion) : focal destruction of small and medium-sized bile ducts by granulomatous inflammation; bile duct epithelium irregular and hyperplastic; dense portal tract infiltrate of lymphocytes, macrophages, plasma cells, and eosinophils ( Figure 7.9 )

  

• Stage II (ductular reaction) : disappearance of small bile ducts; scarring of medium-sized bile ducts; proliferation of bile ductules in portal tracts; inflammation and interface hepatitis of adjacent periportal hepatic parenchyma

• Stage III (scarring) : small and medium-sized ducts scarce; little inflammation in fibrous septa or parenchyma; lymphoid aggregates with or without PASD-positive material representing residual basement membrane material in areas where ducts have been lost

• Stage IV (cirrhosis) : cirrhosis, often with a jigsaw pattern

Special Stains and Immunohistochemistry

• Noncontributory