Medical Liver Flashcards
Zones of Liver
Zone 1
* Periportal
* Oxidative metabolism
* Gluconeogenesis
* Ureagenesis
Zone 2
* Transitional
* Mixture of functions
Zone 3
* Pericentral
* Glycolysis
* Liponeogenesis
* Xenobiotic metabolism
Special stains used in liver biopsy
Masson’s Trichrome:
* blue = type 1 collagen
* red = hepatocytes
* highlights portal tracts
* highlights reactive fibrosis as result of liver injury
* highlights pericellular/perisinusoidal fibrosis
* staging chronic liver diseases
* highlights Mallory Denk bodies
* highlights giant mitochondria
Reticulin Stain:
* silver impregnation
* stains reticulin fibres –> type 3 collagen
* appear black
* normal –> ECM in space of disse
* assessment of architecture of hepatic plates
* expansion in regenerative and neoplastic conditions
* compression of plates in nodular regenerative hyperplasia
* collapse of the reticulin framework in necrosis
Perl’s Stain:
* Detects iron
* soluble –> ferritin (not seen), insoluble –> hemosiderin (appears granular)
* Haemosiderin –> coarse blue granules, Ferritin –> faint blue cytoplasmic blush
* haemochromatosis –> iron in cytoplasm, initially periportal hepatocytes
* secondary iron overload –> iron in Kupffer cells
* Modified Scheuer grading scheme –> Grade 0 to 4 (granules visable at 400, 250, 100, 25, 10 or naked eye
Victoria Blue:
* distinguishes elastic-rich septa of cirrhosis from elastic-poor capsular tissue/scar tissue.
* helps distinguish bridging necrosis and fibrosis
* collapsed liver parenchyma in necrosis does not have elastic fibres
* elastin depostition preceeds collagen fibre deposition in early fibrosis
* stains ground glass HBsAg containing hepacytes in chronic hep B
Rhodanine:
* detects copper-binding protein –> evaluate for Wilson Disease
* copper excreted in bile and accumulates with chronic biliary disease –> biliary vs non-biliary disease
Orcein:
* stains for copper-assocciated protein
* cola-coloured, perinuclear, coarsely granular appearance
* can be seen in chronic cholestatic disorders
Congo red:
* stains amyloid
Oil Red O:
* highlights presence of a fat globules
* used to evaluate pre-transplant donor liver biopsies
Sirius Red:
* stains type 1 and type 3 collagen –> Found in portal tract
* used to assess degree of fibrosis
CD34:
* marker of endothelial cells
* but sinusoidal endothelium does not normally express this marker
* cells surrounding trabeculae of HCC –> CD34 positive
* helps distinguish cirrhotic nodule from well-differentiated HCC (diffuse positivity)
Acute hepatitis
Causes:
* Hepatitis virus: A, B, C, D, E
* Other viruses: CMV, EBV, HSV, YFV, VZV
* Drugs
* Autoimmune
* Pregnancy related
Acute viral hepatitis
- Elevated serum alanine aminotransferase and aspartate aminotransferase (ALT, AST) tests
- WITHOUT previous history of liver disease
Clinical:
* range from mild asymptomatic infection to fatal fulminant hepatic failure
* Serology confirms diagnosis
* Biopsy not usually necessary –> rule out secondary contributing factors/atypical clinical presentation
Micro:
* lobular disarray
* Ballooning degeneration of cells
* Scattered acidophil bodies (Councilman)
* Hepatocyte dropout
* Lobular and sinusoidal inflammatory cell infiltrate
* Kupffer cell hyperplasia
* Zonal and bridging necrosis
* Trichrome shows no significant fibrosis
Types of hepatocellular necrosis
Apoptosis/Acidophil/Councilman Body:
* Necrosis of single cells
* No inflammation
* Acute hepatitis (Viral/autoimmune/drug)
Focal/Spotty:
* Necrosis involving small clusters of hepatocytes
* Accompanied by aggregates of lymphocytes
* Hepatitis (Viral/autoimmune/drug)
Zonal:
* Centrizonal/Zone 3 –> Ischaemia, Veno-occlusive diease, Drugs
* Periportal/Zone 1 (aka piecemeal, necrosis, interface hepatitis) –> hepatitis (Viral/autoimmune/drug)
Confluent:
* Localized/multilobular
* Fulminant hepatitis, localised ischaemia, transarterial embolisation
Bridging/Submassive/Massive:
* submassive: 30-60% parenchyma necrosis, often with portal sparing
* massive: 60-70%
* Fulminant hepatitis (Viral/autoimmune/drug), acute allograft failure
Drug / toxin induced hepatitis
- Liver injury associated with exposure to certain drugs or toxins
- Can be intrinsic or predictable when they are dose dependent (e.g., acetaminophen)
- Can be idiosyncratic and unpredictable when they are dose independent (e.g., isoniazid)
Micro:
* Fulminent necrosis, zonal necrosis, prominent eosinophils, granulomas,
* Severe steatohepatitis mimicking alcoholic hepatitis: Amiodarone, phenytoin
* Massive centrilobular necrosis: acetaminophen
Hepatotoxic Drug Patterns
Hepatocellular:
* ALT > two fold rise
* ALP normal
* ALT:ALP ratio high >5
Examples:
* HAART
* Acetaminophen
* Allopurinol
* Amiodarone
* NSAID
Cholestatic:
* ALT normal
* ALP > two fold rise
* ALT:ALP ratio <2
Examples:
* Anabolic steroid
* Chlorpromazine
* Clopidogrel
* Erythromycin
* Hormonal contraception
Mixed:
- ALT > two fold rise
- ALP > two fold rise
- ALT:ALP ratio < 2 - 5
Examples:
* Amitriptyline
* Enalapril
* Carbamazepine
* Sulfonamide
* Phenytoin
Chronic Hepatitis
Common causes:
* hepatitis virus B and C
* Granulomatous hepatitis
* Drug induced hepatitis
* Autoimmune hepatitis
* Wilson’s disease
* Parasitic infestation
Definition:
* perisistant elevation of serum liver enzymes (AST and ALT) for >6 months
Micro:
* Chronic inflammatory cells around the portal tract
* Interface hepatitis
* Fibrosis
Hepatitis A virus
- Virus Type: ssRNA virus (Picornavirus family, Enterovirus genus)
- Transmission: Fecal-oral route (contaminated food, water, or direct contact with an infected person)
- Incubation Period: 15–50 days (average 28 days)
- Chronicity: Does not cause chronic infection; the infection is usually self-limited.
- Severity: Usually mild, but can cause fulminant hepatitis in rare cases, particularly in individuals with pre-existing liver disease.
- Prevention:
Vaccine: - Yes (highly effective).
- Post-exposure Prophylaxis: Hepatitis A immune globulin (HAIg) may be used.
Risk Factors: - Poor sanitation, contaminated drinking water, travel to endemic regions.
- Chronic Disease: No chronic carrier state.
Micro:
* periportal inflammation and necrosis, ballooning degeneration, apoptosis
* Cholestasis and increased portal and periportal plasma cells are relatively specific for hepatitis.
* Acidophil bodies or cytolysis are present
Hepatitis B virus
- Virus Type: ds DNA virus (Hepadnaviridae family)
- Transmission: Bloodborne (through sexual contact, sharing needles, perinatal transmission)
- Incubation Period: 45–160 days (average 120 days)
- Chronicity: Can lead to chronic infection (more likely in infants and young children).
Chronic HBV infection can lead to cirrhosis, hepatocellular carcinoma (HCC), and liver failure. - Severity:
Acute infection is severe in some cases, and chronic infection can cause long-term liver damage. - Prevention:
Vaccine: Yes (highly effective). - Post-exposure Prophylaxis: Hepatitis B immune globulin (HBIG) and the hepatitis B vaccine.
Risk Factors: - IV drug use, unprotected sex, healthcare workers, infants born to infected mothers, individuals from endemic regions.
- Chronic Disease: Chronic carrier state is common, with potential for cirrhosis and liver cancer.
- Diagnosis is based on the detection of hepatitis B surface antigen (HBsAg) and IgM hepatitis B core antibody; HBV DNA is present in the initial phase of the infection
- Anti-HBsAg confers long-term immunity
Micro:
* Ground glass appearance (of the central part of the cytoplasm) of hepatocytes when HBsAg is elevated or in active viral replication
* Nuclei of hepatocytes may contain large amounts of core protein and have a pale, homogenous appearance on H&E sections, described as sanded
* Portal infiltrate –> lymphocytes
* +/- interface hepatitis
* Coinfection with HDV –> relatively high necroinflammation
IHC:
* Reticulin stain is useful in the early stage to evaluate for parenchymal loss
* HBsAG (cytoplasmic) / HBcAG (nuclear): double staining technology staining infected cells showing colocalization of the 2 antibodies
* Masson trichrome stain: stains increased collagen accumulation and is an indicator of fibrosis
* HBV ground glass hepatocytes –> Shikata orcein and Victoria blue
Hepatitis C virus
- Virus Type: ss RNA virus (Flaviviridae family, Hepacivirus genus)
- Transmission: Bloodborne (primarily through sharing needles, transfusions, sexual contact, or from mother to child)
- Incubation Period: 14–180 days (average 45 days)
- Chronicity: In most cases, chronic infection develops (70-85% of cases).
Chronic HCV infection can lead to cirrhosis, hepatocellular carcinoma (HCC), and liver failure.
Severity: Chronic infection leads to significant liver complications, including cirrhosis and liver cancer. - Prevention:
Vaccine: No vaccine available. - Risk Factors:
IV drug use, blood transfusions prior to screening, healthcare workers, high-risk sexual behavior, tattoos, and body piercings.
Micro:
* Lymphoid aggregates or follicles with or without germinal centres
* Focal mild macro vesicular steatosis
* Damaged interlobular bile ducts
* Portal fibrous expansion, periportal fibrosis, bridging fibrosis to cirrhosis
Hepatitis D Virus
- Virus Type: RNA virus (Deltavirus family)
- Transmission: Bloodborne (requires co-infection with HBV for replication, so it is usually transmitted in similar ways to HBV)
- Incubation Period: 30–60 days
- Chronicity: Can lead to chronic infection, often exacerbating liver damage in individuals already infected with HBV.
It can accelerate liver damage and increase the risk of cirrhosis and liver cancer. - Severity: More severe than HBV alone, with a higher risk of cirrhosis and liver cancer.
Prevention: - Vaccine: Indirectly through the hepatitis B vaccine (since HDV requires HBV for replication).
No separate HDV vaccine. - Post-exposure Prophylaxis: Treatment of HBV infection reduces the risk of HDV co-infection.
- Risk Factors:
High-risk behaviors associated with HBV infection (IV drug use, unprotected sex). - Chronic Disease: Common in co-infected individuals (HBV + HDV), and the infection tends to progress rapidly to cirrhosis and liver failure.
Hepatitis E Virus
- Virus Type: RNA virus (Hepeviridae family)
- Transmission: Fecal-oral route (contaminated water is the primary source, especially in developing countries)
- Incubation Period: 15–60 days (average 40 days)
- Chronicity: Rarely chronic, but can cause severe acute liver failure in certain populations (e.g., pregnant women).
In general, self-limiting, but the infection can be severe in pregnant women, potentially leading to fulminant liver failure. - Severity:
Typically self-limiting, but in pregnant women, it can cause severe disease and high mortality. - Prevention:
- Vaccine: Yes, but only available in China and not widely used globally.
No specific post-exposure prophylaxis. - Risk Factors:
Poor sanitation, contaminated drinking water, and living in endemic areas (e.g., parts of Asia, Africa, and the Middle East). - Chronic Disease: Rarely chronic; more common in immunocompromised individuals.
Virus Summary Table and Risks
Following a single hollow needlestick innoculum
* HIV –> 0.9%
* Hep B –> 30%
* Hep C –> 3%
- Wearing glovers reduces risk by x10-100
- Mucus membrane or broken skin splash –> risk is 0.09% for HIV, higher for Hep B
Autoimmune hepatitis
- Diagnosis is based on combination of clinical, laboratory and histological features
- Most patients have nonspecific symptoms: fatigue (85%), anorexia, nausea, weight loss, jaundice, pruritus, amenorrhea
- 25 - 34% are asymptomatic
- 25 - 75% have episodes of acute / fulminant hepatitis
- 14 - 44% have concurrent extrahepatic autoimmune disorders, including autoimmune thyroiditis, rheumatoid arthritis, Sjögren syndrome, vitiligo or ulcerative colitis
Types:
Type 1:
* Positive for antinuclear antibody or anti smooth muscle antibody; 10% have other autoimmune disorders. bimodal (10 - 25 years and 45 - 70 years).
Type 2:
* positive for anti liver kidney microsomal antibody or anti liver cytosol type 1 antibody positive; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders. < 15 years
Micro:
* Portal plasma cell rich inflammation (key thing for autoimmune)
* Interface hepatitis, formerly referred to as piecemeal necrosis: portal inflammatory cells eroding through the limiting plate between the portal tract and liver parenchyma
* Emperipolesis: active penetration of lymphocytes into and through a hepatocyte
* Hepatocyte rosettes
* Variable fibrosis (about 10% of autoimmune hepatitis does not show any fibrosis at initial presentation)
* Lobular necroinflammatory activity: usually accompanied by portal and periportal inflammation
Overlap Syndrome:
About 10% of autoimmune hepatitis fits into following scenarios:
* Autoimmune hepatitis / primary biliary cholangitis (PBC)
* Autoimmune hepatitis / primary sclerosing cholangitis (PSC)
Variant syndromes:
* Seronegative autoimmune hepatitis
* Antimitochondrial antibody positive autoimmune hepatitis
* IgG4 associated autoimmune hepatitis
