Liver Pathology #2 - Nelson Flashcards
What are the pathologic findings on liver biopsy of alcoholic steatosis and alcoholic hepatitis?
- Alcoholic steatosis:
- macrovesicular steatosis is seen microscopically (large lipid vacuoles)
- Alcoholic hepatitis:
- Liver cell injury: swelling (ballooning degeneration) and necrosis
- Mallory bodies
- Neutrophilic inflammation (often clustered around degenerating hepatocytes, especially those with Mallory bodies)
- Can be accompanied by perivenular and pericellular fibrosis (steatofibrosis, a bad sign, a potential precursor to cirrhosis).
What are mallory bodies?
cytokeratin aggregates
can be seen in other liver diseases such as NAFLD and PBC
What is the typical gross appearance of alcoholic cirrhosis?
- Early:
- enlarged, fatty, and micronodular
- Late:
- liver is shrunken, nonfatty, with variable size of nodules, and cholestasis is usually present
What are the major causes of death in alcoholic cirrhosis?
- Hepatic encephalopathy and coma
- Massive GI tract hemorrhage (esophageal varices)
- Infection
- Hepatorenal syndrome
- Hepatocellular carcinoma (1-6% annual risk)
What is non-alcoholic fatty liver disease?
hepatocyte injury due to insulin resistance leading to hepatocyte lipid accumulation (steatosis) as well as hepatocyte oxidative injury resulting in liver cell necrosis and inflammatory reactions to the damaged hepatocytes
Pathology is similar to alcoholic steatosis and alcoholic steatohepatitis.
(Rash of NASH = non-alcoholic steatohepatitis).
What patient population can get non-alcoholic fatty liver disease?
- patients with:
- metabolic syndrome
- obesity
- type 2 diabetes
- dyslipidemia
- insulin resistance
What is PBC?
- autoimmune cholangiopathy characterized by progressive inflammatory destruction of small and medium sized intrahepatic bile ducts, which may lead to cirrhosis
- extrahepatic bile ducts are spared
What type of patient typically gets PBC?
- Largely a disorder of middle-age females (9:1 F:M, peak age 40-50, range 30-70).
- This disease is most prevalent in individuals of Northern European ancestry.
What symptoms may be exhibited by a patient with PBC?
- insidious onset of fatigue and anicteric pruritis
- increasing bilirubin levels
- portal hypertension
- advanced cases, secondary features emerge:
- xanthomas and xanthelasmas (impaired biliary elimination of cholesterol)
- steatorrhea (decreased excretion of bile acids)
- vitamin D malabsorption-related osteomalacia and osteoporosis
- Eventually, patients can develop liver failure with cirrhosis
- at increased risk for hepatocellular carcinoma.
What is the key diagnostic lab test in PBC?
- elevated alkaline phosphatase and GGT
- (cholestatic injury pattern)
- positive test for AMA
- (antimitochondrial antibodies, particularly AMA-M2)
What are the findings on liver biopsy in PBC?
- loss of bile ducts → used to stage disease
- Stage 1: Portal hepatitis with lymphocytic/granulomatous cholangitis in the portal tracts (florid duct lesion); more commonly, the only bile duct change is loss of intrahepatic bile ducts, along with portal hepatitis and mild portal fibrous expansion.
- Stage II: Periportal hepatitis with periportal fibrosis.
- Stage III: Bridging necrosis with bridging fibrosis.
- Stage IV: Cirrhosis (usually micronodular, with bile stasis).
What is secondary biliary cirrhosis?
Cirrhosis secondary to any disorder causing prolonged extrahepatic bile duct obstruction
What are some possible causes of secondary biliary cirrhosis?
- stones
- tumor
- biliary atresia
- cystic fibrosis
- choledochal cysts
What is PSC?
Autoimmune cholangiopathy characterized by progressive, random, uneven fibroinflammatory obliteration of extrahepatic and intrahepatic bile ducts (fibrosing cholangitis).
What are the key patient populations that PSC occurs in?
- 70% of cases are associated with IBD
- usually ulcerative colitis (4% of patients with ulcerative colitis get PSC)
- Most patients are male with a mean age of 40 years
How you would diagnosis PSC?
- Cholangiography
- demonstrates strictures and dilations of extrahepatic and intrahepatic bile ducts (beaded appearance on cholangiogram)
- Liver biopsy can also be diagnostic
- demonstrating focal fibrosing cholangitis
What is the key pathologic finding on liver biopsy in PSC?
focal fibrosing cholangitis
Define hereditary hemochromatosis.
- inherited disorder of excessive iron absorption
- resulting in the accumulation of iron in tissues → producing organ injury
What is the underlying pathogenesis in hereditary hemochromatosis?
- autosomal recessive disorder
- Several gene defects have been identified →
- which result in decreased synthesis of hepcidin = a protein produced in the liver that regulates intestinal iron absorption
- a deficiency of hepcidin leads to excessive intestinal iron absorption
What are some of the clinical manifestations of the hereditary hemochromatosis?
- Triad = cirrhosis + diabetes + skin pigmentation (so called bronze diabetes)
- this triad is not seen in many patients
- Patients may present with:
- arthralgias
- lethargy
- hypogonadism
- abdominal pain
- cardiomyopathy (CHF)
What are the findings on liver biopsy?
- Increased iron on biopsy
- Periportal iron deposits
- Iron pigment in bile ducts
How is hereditary hemochromatosis diagnosed?
- Best screening test is fasting transferrin saturation
- transferrin saturation is elevated (>45%) → repeat transferrin saturation with serum ferritin
- if both elevated, order HFE gene test
- Liver biopsy is used in those cases where there is uncertainty about the diagnosis or concern about the presence of cirrhosis
What test would you use to screen for hereditary hemochromatosis?
HFE gene test
How is hemochromatosis treated?
- clear excessive iron from the tissues
- using phlebotomy or iron chelating agents
What is secondary hemochromatosis?
Hemochromatosis occurring as the result of non-hereditary accumulation of iron
(for example, multiple blood transfusions)
What are some causes of secondary hemochromatosis?
- Parenteral iron overload (transfusions, iron-dextran injections).
- Ineffective erythropoiesis with increased erythroid activity and increased iron absorption (b-thalassemia, sideroblastic anemia).
- Increased oral intake of iron.
- Chronic alcoholic liver disease (results in redistribution of iron to the liver, not an overall increase in total body iron storage).
How does the liver biopsy of secondary hemochromatosis differ from hereditary hemochromatosis?
iron initially accumulates in the Kupffer cells, not in hepatocytes
Define Wilson’s disease.
Autosomal recessive disorder of copper metabolism, resulting in the accumulation of toxic levels of copper in tissues (liver, brain, eye).
What abnormalities are present on key diagnostic tests in Wilson’s disease?
- Ceruloplasmin levels are typically low
- Urinary 24 hour copper excretion is typically increased
- Overall serum copper levels are usually low, due to the lack of ceruloplasmin
What can be seen on eye exam in Wilson’s Disease?
Ring of copper deposits at the limbus of the cornea (Kayser-Fleischer ring)
When should you consider Wilson’s disease as a diagnostic possibility, and what is typically increased in the liver biopsy?
- Consider Wilson’s disease in the differential diagnosis of liver disease in anyone <30 years of age.
- Liver biopsy demonstrates increased hepatic copper
- copper stains may be negative, so quantitative liver copper can be performed on the biopsy specimen
Define alpha-1-antitrypsin deficiency.
Autosomal codominant disorder characterized by abnormally low levels of alpha-1-antitrypsin → a protease inhibitor (proteases are lysosomal enzymes capable of degrading extracellular tissue proteins; A1AT primarily inhibits neutrophil elastase).
How does the pathogenesis of Alpha-1-antitrypsin deficiency compare/contrast in lung injury and liver injury?
- Liver disease → due to accumulation of alpha-1-antitrypsin in hepatocytes
- Lung/Emphysemal damage due to imbalance of neutrophil elastase and alpha-1-antitrypsin
- Increased risk with smoking
What test would you order to screen for this disease, and what key finding can be seen on liver biopsy?
- Screening test:
- Best first-line diagnostic test is to measure A1AT level
- and if low, determine phenotype
- Liver biopsy:
- cytoplasmic globular inclusions
- A1AT stains eosinophilic (redish/dark pink)
What are the two main categories of drug induced liver injury?
- Direct hepatotoxicity:
- toxic to the liver in a predictable, dose dependent fashion
- these agents will cause hepatocellular injury in all who are exposed
- (e.g. acetaminophen overdose, mushroom poisoning due to Amanita phalloides).
- Unpredictable (idiosyncratic) hepatotoxicity:
- produce liver injury in an unpredictable (idiosyncratic) manner;
- not all who are exposed develop injury.
- These toxic reactions may be related to the rate that the drug may be metabolized in a given individual, or the propensity to develop an immune response to the drug.
- produce liver injury in an unpredictable (idiosyncratic) manner;
Describe chronic passive congestion.
circulatory liver disease → centrilobular congestion
(outflow problem)
Describe centrilobular hemorrhagic necrosis.
circulatory liver disorder → centrilobular congestion with centrilobular necrosis
Describe cardiac sclerosis.
fibrosing reaction following longstanding CPC and/or centrilobular necrosis
(pathology: centrilobular fibrosis)
What are some of the causes of Chronic passive congestion (CPC), Centrilobular hemorrhagic necrosis, and Cardiac sclerosis?
- right sided heart failure
- hepatic vein thrombosis
- left sided heart failure
- shock
- combination of congestion and hypoperfusion leads to centrilobular necrosis
Describe hepatic infarct.
(pathologic findings and causes)
rare secondary condition due to double blood supply
can be seen with arterial occlusion due to vasculitis, embolism, or tumor
Describe Budd-Chiari syndrome.
(pathologic findings and causes)
- Hepatic vein thrombosis → defined as thrombosis of two or more hepatic vein branches
- Classic clinical triad = hepatomegaly + ascites + abdominal pain
- Causes:
- conditions that make blood clots more likely to form, including:
- myeloproliferative disorders
- intra-abdominal malignancy
- chronic inflammatory disease
- infection
- inherited or acquired disorders of blood clotting
- oral contraceptives
- pregnancy
- 10% are idiopathic
- conditions that make blood clots more likely to form, including:
Describe sinusoidal obstruction syndrome.
(pathologic findings and causes)
- Presence of obstructive, nonthrombotic lesions of the small (central) hepatic veins in patients exposed to radiation and/or hepatoxins
- Pathology demonstrates marked narrowing and obliteration of central vein lumens by subendothelial swelling and fibrosis.
- Due to toxic damage to hepatic sinusoidal endothelium, secondary to the cytoreductive agents (e.g. chemotherapy)
Define neonatal cholestasis.
A group of disorders characterized by prolonged conjugated hyperbilirubinemia in the neonate.
Define biliary atresia.
complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life
Define neonatal hepatitis.
- hepatitis occurring in early infancy (1-2 months)
- can be caused by many types of disorders:
- biliary atresia (20%)
- inherited metabolic disorders (e.g. alpha-1 antitrypsin deficiency (15%)
- tyrosinemia
- cystic fibrosis)
- infectious agents (e.g. CMV, many others)
- toxic effects of drugs
- etc.
- 10-15% of cases the cause is unknown (idiopathic neonatal hepatitis)
What are some causes of granulomatous hepatitis?
- Idiopathic (50%)
- Sarcoidosis (22%)
- Drug related (6%)
- Tuberculosis (3%)
- Other (19%)
- PBC, Histoplasmosis, Lymphoma
What do ALT and AST measure?
hepatocellular damage
What do Alkaline Phosphatase and GGT (gamma glutamyl transpeptidase measure?
injury to the bile duct epithelium/canalicular membrane
***markers of cholestasis
What do Albumin, prothrombin time, and certain clotting factors (e.g. factor V levels) reflect?
global hepatic synthesis (function)
***What liver tests are used to determine a specific etiology?***
- Viral hepatitis: serology, nuclear testing DNA/RNA
- Autoimmune hepatitis: ANA, anti-smooth muscle antibodies
- Wilson’s disease: ceruloplasmin
- Alpha-1-antrypsin deficiency: A1AT level, phenotype
- Hemochromatosis: Fe, TIBC, transferrin saturation, genetics
- Primary Biliary Cirrhosis: anti-mitochondrial antibodies (AMA-M2)
Ground glass hepatocytes found on liver biopsy indicate what disease?
chronic viral hepatitis B
Plasma cells found on liver biopsy indicate what disease?
autoimmune hepatitis, PBC
Lymphocytic/granulomatous cholangitis found on liver biopsy indicates what disease?
PBC
Fibrous obliterative cholangitis found on liver biopsy indicates what disease?
PSC
Periportal hepatitis with mild steatosis found on liver biopsy indicates what disease?
chronic viral hepatitis C
Globular hepatocyte inclusions found on liver biopsy indicates what disease?
Alpha-1-Antitrypsin deficiency
Define the HELLP syndrome.
- Hemolysis
- Elevated Liver enzymes
- Low Platelets
Define acute fatty liver of pregnancy.
Disorder of pregnancy characterized by acute onset of liver dysfunction, and severe cases can result in acute hepatic failure and death.
Define intrahepatic cholestasis of pregnancy.
Mild increase in serum conjugated bilirubin
(usually <5mg/dl)
- related to estrogenic hormones along with biliary secretory defects
- slightly increased risk of fetal distress, stillbirths, and prematurity
What are the type of liver abnormalities that can occur in patients receiving a bone marrow (hematopoietic stem cell) transplant?
- liver may be affected by drug toxicity
- sinusoidal obstruction syndrome (veno-occlusive disease)
- acute and chronic graft-vs-host disease (GVHD)
- donor lymphocytes attack epithelial cells of the liver, with resulting hepatitis
- can lead to “vanishing bile ducts” with fibrosis and cirrhosis
What type of liver abnormalities that can occur in patients receiving a liver transplant?
- preservation injury (oxygen radicals in hypoxic organ damage sinusoidal endothelium)
- anastomotic problems
- acute and chronic rejection
- acute rejection → portal hepatitis with lymphocytic cholangitis, as well as endotheliitis involving portal and hepatic vein branches
- chronic rejection → inflammatory damage to both bile ducts and arteries
- (get “vanishing bile duct syndrome” and obliterative arteritis with ischemic necrosis)
How can using “liver function tests,” help one distinguish a hepatocellular injury pattern from a cholestatic injury pattern?
- Hepatocellular injury pattern:
- Abnormal AST and ALT
- disproportionate increase in the serum transaminases compared with ALP (Alkaline phosphatase)
- Cholestatic injury pattern:
- disproportionate increase in ALP compared with the serum transaminases
- primary stimulus for ALP production is bile duct obstruction
What are the two reasons for doing a liver biopsy?
- Determine (if possible) the cause of the liver disease (etiology).
- Determine extent of damage to the liver.
What do grade and stage mean on a liver biopsy performed for chronic hepatitis (e.g. for chronic HCV infection)?
-
Grading:
- based on the amount of lymphocytic piecemeal and lobular necrosis and inflammation present
- (none, minimal, mild, moderate, severe)
-
Staging:
- based on the degree of fibrosis
- (none, portal, periportal, septal (bridging), cirrhosis)
