DIGITAL LIVER HISTOPATHOLOGY LIBRARY
Edited by: Kevin E. Bove MD
Alagille Syndrome: Sequence of the basic pathological lesion in liver of patientsFIGURE 1. The panels in the illustration are from liver biopsy specimens in infants and are arranged to suggest that destruction of small bile ducts is a progressive process that injures and obliterates small interlobular bile ducts, resulting in obstructive cholestasis.
Alpha-1 Antitrypsin Deficiency: Diagnostic imagesFIGURE 1. A: Diatase-resistant inclusions are prevalent in hepatocytes but rare in carcinomatous nodule (*). (PAS+ stain after diatase treatment). B and C: Storage material in hepatocytes is demonstrable by peroxidase immunostain in paraffin section and fluorescein-conjugated antibody in frozen section. D: Alpha-1 Antitrypsin protein accumulates in endoplasmic reticulum of hepatocytes. (Electron Microscopy)
Alpha-1 Antitrypsin Deficiency: 5 week old infantFIGURE 2. A: Neonatal hepatitis with giant cell transformation and focal cholangiopathy. B: Storage globules are readily demonstrated; this is not always the case in affected young infants. (PAS- Diastase stain);
Alpha-1 Antitrypsin Deficiency: Cholangiopathy in InfantsFIGURE 3. A: Mild pericholangitis. B: Ductular cholestasis. C and D: Destructive cholangitis.
Alpha-1 Antitrypsin Deficiency: Cirrhosis in childFIGURE 4. Cirrhosis in 13 month old child with ZZ phenotype
Pathways for Bile Acid Synthesis
FIGURE 1. Yellow, steroid nuclear defects. Blue, Side chain defects. Green, Peroxisomal disorders.
Bile Acid Synthesis Defect: 3-beta-OH-steroid dehydrogenase deficiency
FIGURE 2. In an infant, pretreatment. A: Early onset (age 6 months). Intrabular cholestasis with prominent giant cell transformation. B. Mild portal inflammation and mild swelling of bile duct epitheium. C: Ductular reaction with mild periportal fibrosis. Trichrome stain. D: Ductular reacton is highlighted by cytokeratin stain.
Bile Acid Synthesis Defect: 5 beta reductase deficiencyFIGURE 3. Neonatal onset. Oral bile acid replacement therapy for 16 months. Lobular cholestasis resolved. Minimal portal fibrosis remains.
Bile Acid Synthesis Defect: 5 oxysterol beta reductase deficiency
FIGURE 4. In two infants, pretreatment. A and B: Liver biopsy at age 5 days. C: Liver biopsy at age 6 weeks.
Bile Acid Synthesis Defect: 3-beta-OH steroid dehydrogenase deficiency
FIGURE 5. Late onset type. All panels show evidence of chronic low-grade ductular reaction accompanied by fibrosis.
Hepatic mDNA depletion: Mitochondrial
FIGURE 1. Acute liver failure in infancy due to mDNA depletion: Notable are non-uniform microvescicular fat, canalicular cholestasis and focal erythropoiesis. Noteworthy are abnormal numbers and ultrastructural appearance of mitochondria in panel D.
Alpers disease: Example #1 - Valproic acid and acute liver failure in an infant
FIGURE 2. Two cases; Infant #1 (A and B) and infant #2 (C and D). Both examples have intralobular cholestasis, focal inflammation, and mild fatty change. Hepatocyte regeneration is prominent in panel A.
Alpers disease: Example #2 - Complex III defect, valproic acid and acute liver failure in an infant
FIGURE 3. Notable features are: A: portal inflammation B and D: microvescicular fat ad mitochondria-laden granular red hepatocytes C: prominent hepatocyte regeneration
Alpers disease: Example #3 - Late stage liver lesion in an infant
FIGURE 4. A: Micronodular cirrhosis. B: Non-uniform micro and macrovesicular fatty change.
PFIC1 is due to mutation in FIC1 gene ATP8B that encodes an aminoacid phospholipid flipase located on the hepatocyte canalicular membrane. The ability to transport bile constituents is impaired across the canaliculuar membrane, and also across the ileal enterocyte membrane where reabsorbtion normally occurs, producing chronic diarrhea. Bile residue in the canalicular lumen often has a distinctive ultrastuctural appearance that facilitates diagnosis. Hepatic fibrosis is mild to absent.
PFIC1: Liver biopsies at 2 and 8 years in one patient. No fibrosis.
FIGURE 1. A: Age, 2 years. Hepatocytes are normal except for vague rosettes and rare canalicular bile plug. Bile duct in portal area is normal. B: Focal cytoplasmic swelling, rare necrotic hepatocyte C: Age, 8 years. Fibrosis is absent. Trichrome stain. D: Focal cytoplasmic swelling and rare canalicular bile plug
PFIC1: Coarse granular "Byler bile" in a dilated canaliculus, example #1
FIGURE 2. Electron Microscopy reveals unusual quality of canalicular bile
PFIC1: Byler bile in canaliculus, example #2
Electron Microscopy reveals unusual quality of canalicular bile
PFIC1: Compare canalicular bile in biliary atresia
FIGURE 4. Note the difference between PFIC1 bile and ordinary bile in biliary atresia
PFIC1: Compare canalicular bile in estrogen-induced cholestasis
FIGURE 5. Note the difference between PFIC1 late and ordinary bile in estrogen induced cholestasis.
PFIC1: Compare canalicular bile in idiopathic neonatal hepatitis
FIGURE 6. Note the difference between PFIC1 late and ordinary bile in idiopathic neonatal hepatitis.
PFIC2 is due to mutations in the gene that codes ABCB11, a transporter of bile acids located in the canalicular membrane know as bile salt export protein (BSEP). Progressive or intermittent cholestasis has extremely varied outcomes.
PFIC2: Non-diagnostic liver biopsy in young infant
FIGURE 1. A: Normal bile duct and minimal hepatocyte change. B and C: Lobular cholestasis with rare multinucleate giant cell. D: Mild ductular reaction. Cytokeratin immunstain.
PFIC2: Presentation in an infant with rapid progression
FIGURE 2. A: Age 2 months. Severe lobular cholestasis with prominent giant cell transformation of hepatocytes and extr-medullary hematopoiesis. Interlobular bile ducts are normal. B: Age 16 months. Liver explant. Persistent giant cell transformation with prominent lobular fibrosis. Trichrome stain.
PFIC2: Presentation in an infant with slow progression
FIGURE 3. A: Age 8 months. Mild lobular cholestasis with scattered small multinucleate hepatocytes and mild pericellular fibrosis. CV,central vein. P, portal zone. B: Age 9 years. No significant change. Minor pericellular and central lobular fibrosis. Trichrome stain.
PFIC3 is due to mutations in the MDR3 gene that codes for ABCB4, a transporter of phospholipid across the canalicular membrane. Absent phospholipid in bile destabilizes bile, unmasking the inherent toxicity of normal bile acids. This results in a disease of the small bile ducts of variable severity and a predilection to develop cholesterol gall stones. Clinical symptoms may be delayed until early adulthood, or pregnancy. A progressive severely destructive cholangiopathy may occur in young children.
PFIC3: Presentation in an infant with profound intrahepatic cholangiopathy and progressive fibrosis
FIGURE 1. A: Hepatocyte swelling, giant cell transformation and rare necrotic hepatocyte. B: Prominent ductular reaction at portal margin. C: Proliferation of ducts and ductules simulates changes of mechanical obstruction, Cytokeratin stain. D: Proliferation of ducts associated with periductal fibrosis.
PFIC3: Presentation in late infancy with rapid progression to biliary cirrhosis
FIGURE 2. A: Cirrhosis with extreme paucity of interlobular bile ducts in explanted liver at age two years. B: Gross photo of explanted liver.
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