Liver Quiz Flashcards
Icterus
yellow discoloration of the sclera due to retention of bilirubin.
Bilirubin metabolism
Reticuloendothelial cells convert heme to bilirubin (85% from breakdown of senescent RBCs, 15% from hepatic heme or marrow RBC precursors).
Bilirubin is transported to the liver complexed to albumin (unconjugated bilirubin). Bilirubin is conjugated with glucuronic acid in liver cells (conjugated bilirubin). Conjugated bilirubin is excreted in bile (brown stools).
Unconjugated vs Conjugated bilirubin
Unconjugated: Water insoluble Bound to albumin Toxic to tissues Not excreted in urine.
Conjugated bilirubin:
Water soluble
Is not tightly bound to albumin when present in serum
Not toxic to tissues
Excreted in urine when present in serum at high levels (bilirubinuria).
Gilbert’s syndrome
Common (3-10%); autosomal recessive or autosomal dominant inheritance
Due to decreased glucuronyltransferase activity (UGT1A1 30% of normal).
Increased unconjugated bilirubin (
Intrahepatic cholestasis
Bile within hepatocytes
Canalicular bile stasis
Feathery degeneration of hepatocytes
Extrahepatic cholestasis (extrahepatic biliary obstruction)
Canalicular bile stasis
Feathery degeneration of hepatocytes
Bile within distended bile ducts, and occasionally “bile lakes”
Portal tract edema
Bile duct proliferation within portal tracts
Extrahepatic biliary obstruction may promote the development of ascending cholangitis, a secondary bacterial infection of the biliary tree
HEPATITIS A
Virus preferentially infects liver cells (hepatotrophic virus).
HAV infection does not cause chronic hepatitis.
Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.
The viremia (virus in the blood) is transient, and because of this, blood products are rarely at risk and donor screening for HAV is not performed (fecal-oral transmission).
Majority of infections are subclinical (asymptomatic).
Some present clinically with acute hepatitis; .1% will develop fulminant hepatitis (acute liver failure) and may die.
Diagnosis is made by successful interpretation of the serologic profile.
Prevent the disease by vaccination.
HEPATITIS B
Virus preferentially infects liver cells (hepatotrophic virus).
HBV infection has the potential to cause chronic hepatitis.
Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.
Virus is present in blood and body fluids (saliva, semen, vaginal secretions).
Transmission is parenteral, sexual/close contact, perinatal.
Diagnosis is made by successful interpretation of the serologic profile, to include nucleic acid testing if necessary (detecting viral DNA).
Prevent the disease by vaccination.
Majority of patients (70%) have asymptomatic infection (subclinical disease); 30% develop clinical acute hepatitis.
The majority of patients (90%) will have infections that resolve.
0.1-0.5% develop acute fulminant hepatitis with liver failure and may die.
Approximately 5% of exposed adults will develop chronic hepatitis. Some of these patients may eventually recover, but some will develop non-progressive chronic hepatitis B, some will develop progressive disease leading to cirrhosis, and some will develop hepatocellular carcinoma. Some individuals (particularly those exposed at childbirth) will develop an asymptomatic “healthy” carrier state.
Carrier state, defined as persistent HBV infection without significant ongoing necroinflammatory disease, typically occurs as a result of exposure at childbirth (perinatal transmission) or exposure as a young child (immune tolerance to HBV).
DELTA HEPATITIS VIRUS
Defective single stranded RNA virus that causes hepatitis only in the presence of HBV. In order to replicate and form complete virions, HDV must be encapsulated by HBV.
HDV can infect an individual with chronic HBV (superinfection) or it can be transmitted simultaneously with HBV (acute coinfection). (Hint: to remember the difference, think that superinfection is an infection “superimposed” on an existing chronic infection).
Infection with HDV and HBV is more severe than HBV alone, with increased mortality in acute hepatitis and increased propensity to develop chronic hepatitis.
In USA, HDV largely restricted to IV drug users.
Diagnosis is made by successful interpretation of the serologic profile, to include nucleic acid testing if necessary (detecting viral RNA).
Prevent the disease by vaccination for HBV.
Acute coinfection of HBV and HDV results in acute hepatitis B + D. This entity is clinically indistinguishable from acute hepatitis B alone. While the acute hepatitis occurring in B + D acute coinfection is usually transient and self-limited, the severity of the acute hepatitis is increased, and there is an increased risk of acute liver failure, particularly in IV drug users (3-4%, compared to .1-.5% with HBV alone).
Rate of progression to chronic hepatitis in acute coinfection is no different than with acute HBV infection without HDV.
HDV superinfection may (1) convert mild chronic HBV hepatitis into acute liver failure (7-10%) (2) cause acute hepatitis to erupt in a healthy, inactive HBV carrier (3) lead to chronic hepatitis (80%, compared to 4% with HBV alone). An inactive HDV/HBV carrier state also exists.
In patients with HBV infection, testing for HDV should be considered in those who have risk factors (intravenous drug users and patients from endemic countries) or in those who present with unusually severe or protracted acute hepatitis, as well as those with acute hepatitis of undetermined origin occurring in a chronic HBV carrier.
HEPATITIS C
HCV is a single stranded RNA virus discovered in 1989.
HCV is spread parenterally (blood, IV drug use), by sexual or close contact, rarely perinatally (32% unknown source).
Virus preferentially infects liver cells (hepatotrophic virus).
Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.
Acute liver failure is rare, developing in only 0.2%. 20% will develop acute hepatitis, which is usually asymptomatic, that resolves. Unfortunately, 80% will develop chronic hepatitis, with 20-30% developing cirrhosis if untreated. Chronic HCV infection accounts for almost half of all chronic liver disease in the USA and the number of cases are expected to triple in the next 20 years. Most patients with chronic viral hepatitis C are asymptomatic, and 30% may have a normal serum ALT.
Virus consists of 6 distinct genotypes and over 50 subtypes; in the USA, infection with genotype 1a is most common, followed by genotypes 1b, 2a, and 2b.
Some patients develop extrahepatic autoimmune manifestations/syndromes (cryoglobulinemia, membranoproliferative glomerulonephritis, thyroiditis).
Antibodies (anti-HCV) develop approximately 10 weeks following infection. Unfortunately, antibodies do not confer recovery or immunity in most patients (virus has a high mutation rate, enabling divergent strains in a single patient to escape from neutralizing antibodies). There is no vaccine.
Presence of antibodies does not distinguish between acute, chronic, or past infection. Diagnosis is established by antibody detection using immunoassays as a screening test, and if positive, active infection is confirmed by measuring viral load using tests that detect and quantitate HCV RNA by PCR; this test can also be used to assess response to therapy. Genotype testing is also performed, as it is used to guide therapy, as well as predict response to therapy. Liver biopsy may also be performed to assess extent of liver damage.
Treatment regimens are in flux, with some very promising therapies that will be “game changing” in terms of clearing the infection. Therapy is based on the genotype, and certain genotypes appear to be more responsive to treatment. Response to treatment can also be dependent on genetic variations near the IL-28B gene in the patient, and also on the presence of certain mutations in the HCV virus. The goal of therapy is to achieve clearance of the infection with a sustained virological response (undetected HCV virus 24 weeks following therapy).
CDC estimates that the prevalence of HCV infection for individuals born between 1945 and 1965 is five times that of other age groups, and that 75% are unaware they are infected because of a lack of symptoms. As a result, the CDC has recommended that all individuals in this age group (aka “baby boomers”) be tested for HCV infection. Initial testing includes HCV antibody screen with reflex to HCV RNA by PCR if the antibody screen is positive.
HEPATITIS E
Virus preferentially infects liver cells (hepatotrophic virus).
Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.
HEV is very prevalent in underdeveloped countries, very rare in the USA.
HEV does not cause chronic hepatitis or a carrier state (remember, the viral hepatitis that are “vowels”, A and E, do not cause chronic hepatitis).
While acute viral hepatitis E is generally self-limited, 0.5-3% develop acute liver failure. For reasons that are unknown, pregnant women have high mortality (20%).
Diagnosis is made by considering HEV as a possible cause of acute hepatitis, and successful interpretation of the serologic profile.
According to UpToDate, a vaccine has been developed for HEV but is not commercially available.
CLINICAL SYNDROME OF ACUTE VIRAL HEPATITIS
Incubation phase: variable, dependant on viral type.
Preicteric prodrome: nonspecific, constitutional symptoms (malaise, fatigue, nausea, loss of appetite, arthralgias etc.); elevated serum levels of liver enzymes (ALT: alanine aminotransferase; AST: aspartate aminotransferase).
Icteric (jaundice) phase: jaundice is not always present (anicteric hepatitis); conjugated hyperbilirubinemia mainly; dark urine (bilirubinuria).
Convalescence (recovery) vs. acute liver failure vs. chronic hepatitis (with or without progression to cirrhosis) vs. “healthy” carrier.
PATHOLOGY OF ACUTE VIRAL HEPATITIS
In general, same pathology regardless of viral type. Patients with acute viral hepatitis seldom undergo liver biopsy.
Major finding is that of lobular hepatitis, which includes:
Diffuse liver cell degeneration (cellular swelling - ballooning degeneration) with focal hepatocellular necrosis and apoptosis (with apotosis, one can see so called councilman bodies, and with necrosis, get loss and disappearance of hepatocytes, so called “dropout necrosis”). In severe cases, confluent necrosis can be seen.
Kupffer cell hyperplasia and hepatocellular regeneration.
Mononuclear inflammation (predominantly lymphocytes) within portal tracts and lobules (hence the term lobular hepatitis).
“Lobular disarray”
Variable hepatocellular and canalicular cholestasis.
MASSIVE HEPATIC NECROSIS
Massive acute hepatocellular necrosis, with or without lobular and portal inflammation, can be caused by a variety of agents such as acute viral hepatitis, drug or toxin induced hepatitis (acetaminophen overdose causes 50%), vascular liver diseases, autoimmune hepatitis, Wilson’s disease.
Patients clinically suffer acute liver failure; if the patient survives, they may not get cirrhosis (the acute toxic agent causes no fibrosis, and as the reticulin framework of the liver is intact, the liver can regenerate without much architectural distortion).
Pattern of necrosis may suggest etiology:
Focal random necrosis, inflammatory infiltrate: viral hepatitis, autoimmune hepatitis. Zonal necrosis, non-inflammatory: drugs, ischemia.
PERINATAL Hep INFECTION
Infants born to mothers with an active HBV infection (positive for HBsAg and HBeAg) have a 70-90% chance of acquiring perinatal HBV infection.
More than 90% of infected infants will become chronic HBV carriers.
25% of these carriers will eventually die of cirrhosis or hepatocellular carcinoma.
All pregnant women should be screened for HBsAg.
Treatment of newborns born to HBsAg positive mothers with hepatitis B immune globulin (HBIG) and hepatitis B vaccine is 85-95% effective in preventing the development of the HBV chronic carrier state, when administered within 2-12 hours after birth.
AUTOIMMUNE HEPATITIS
Liver injury due to a T-cell-mediated autoimmune pathogenesis; there is a female predominance, with negative viral hepatitis markers, elevated serum IgG and gamma globulin levels, and characteristic autoantibodies.
AIH is subclassified into subtypes based on positive titers to various autoantibodies:
Type 1 is defined by anti-nuclear (ANA), anti-smooth muscle actin (SMA), and anti-soluble liver antigen/liver-pancreas (anti-SLA/LP) antibodies. Type 2 is defined by anti-liver/kidney microsome-1 (anti-ALKM-1) and/or antibodies to a liver cytosol antigen (ALC-1).
Type 1 is usually seen in middle age females, type 2 is usually seen in children and adolescents. Type 1 is the most common type seen in the USA, and is associated with HLA DR3.
Liver pathology demonstrates chronic hepatitis with increased plasma cells in the periportal lymphocytic inflammatory infiltrate along with lobular inflammation; patients may also present with a “flare” of fulminant acute hepatitis (acute liver failure).
Diagnosis of AIH is a diagnosis of exclusion with other liver diseases; quantitative “scoring systems” have been developed based on female gender, ratio of alkaline phosphatase to ALT, total serum globulin, autoantibody titers, level of alcohol consumption, lack of markers for other liver diseases such as PBC and viral hepatitis, and findings on liver biopsy.
Treatment of autoimmune hepatitis is with immunosuppressive agents (e.g. steroids).
Some patients with AIH may also exhibit cholangitis (autoimmune cholangitis).
CIRRHOSIS
Hepatic disease of varied etiology characterized by widely distributed (diffuse, not focal) interconnecting fibrous scars with nodular parenchymal regeneration.
Many causes:
Alcoholic liver disease 60-70%
Viral hepatitis (B, D, C) 10%
Biliary diseases 5-10%
Hereditary hemochromatosis 5%
Wilson’s disease, A1AT def. rare
Cryptogenic cirrhosis (Non-Alcoholic Fatty Liver Disease) 10-15%
Stellate cells in the space of Disse proliferate as a result of injury and become activated into fibrogenic myofibroblasts; other fibrocytic cells (such as portal fibroblasts) also cause fibrosis.
Cirrhosis was once thought to be irreversible, when there were no reliable ways to cure any of the chronic liver diseases, and thus there were no opportunities to see if cirrhosis could regress. Although it is uncommon, fully established cirrhosis may regress (hepatocytes secrete metalloproteinases which can break apart fibrotic scars – “remodeling of the fibrous scars”).
Many patients with chronic liver disease and cirrhosis are asymptomatic until late in the course of the disease. Patients with cirrhosis may die from progressive liver failure, complications of portal hypertension, or hepatocellular carcinoma.
Hepatic failure
fibrosis destroys and impairs the normal vascular interconnections in the liver, resulting in decreased hepatic perfusion.
Hepatic failure may be the result of acute liver failure, or more commonly, chronic liver failure.
Acute liver failure is defined as an acute liver illness associated with encephalopathy and coagulopathy that occurs within 26 weeks (half a year) of the initial liver injury in the absence of pre-existing liver disease.
Acute liver failure is typically secondary to massive hepatic necrosis (usually acute viral hepatitis A or B, drug, toxin, AIH). Acute liver failure may also occur without overt necrosis (Reye’s syndrome, acute fatty liver of pregnancy). Most common cause of acute liver failure is acetaminophen overdose (50% of cases).
Chronic liver failure is most commonly due to chronic liver disease associated with cirrhosis; however, not all cases of cirrhosis lead to chronic liver failure and not all end-stage chronic liver disease is cirrhotic. Some individuals with compensated advanced liver disease can develop acute liver failure (this is called acute-on-chronic liver failure).
Portal hypertension
due to increased resistance to portal blood flow as a result of fibrosis of sinusoids and central veins, as well effects from parenchymal nodules. Arterial to portal anastomoses also occur within the fibrotic liver, increasing portal pressure. Hyperdynamic splanchnic circulation is also present.
Posthepatic, intrahepatic, and prehepatic causes, but cirrhosis is the most common cause (see next slide).
Key manifestations/complications may include:
Ascites (fluid in peritoneal cavity, most common cause is cirrhosis) Portosystemic shunts, occurring in areas where systemic and portal circulation share similar capillary beds (e.g. bleeding Esophageal Varices) Splenomegaly (congestive) Hepatic Encephalopathy
REYE’S SYNDROME
Reye’s syndrome is rare acute postviral illness characterized by liver injury (microvesicular steatosis) and encephalopathy.
In addition to microvesicular steatosis, widespread mitochondrial injury is present. It is believed that some patients with Reye’s syndrome actually have inborn errors of metabolism (fatty acid oxidation disorder).
Reye’s syndrome usually occurs in children and teenagers following a viral infection, with 90-95% having received salicylates (aspirin); 25% of patients with Reye’s syndrome will suffer profound encephalopathy and less commonly liver failure.
Incidence of Reye’s syndrome has dramatically decreased following discontinuation of aspirin for febrile illness.
PORTAL VEIN THROMBOSIS
Extrahepatic causes:
Intra-abdominal sepsis leading to pylephlebitis (septic thrombophlebitis of the portal vein, often caused by acute appendicitis, acute diverticulitis, or other intrabdominal infection). Inherited or acquired hypercoagulable disorders (e.g. post surgical thrombosis, myeloproliferative syndromes). Trauma Pancreatitis or pancreatic cancer (propagation of splenic vein thrombosis).
Intrahepatic causes:
Cirrhosis Invasion of portal vein by hepatocellular carcinoma.
Complications of portal vein thrombosis include portal hypertension. As the obstruction is often presinusoidal (i.e. before the liver), ascites does not typically occur.
Hepatic stellate cells
Hepatic stellate cells are storage sites of lipids, especially esterified vitamin A. When stellate cells are activated, they lose vitamin A stores and deposit collagen in the Space of Disse.
Hepatic pit cells
Hepatic pit cells are liver associated lymphocytes. These natural killer cells protect against viruses and tumor cells.
Hepatic endothelial cells
Hepatic endothelial cells are “leaky”: perforated by fenestrae and no basement membrane.
Kupffer cells
Kupffer cells are endocytic, phagocytic macrophages. Source of inflammatory mediators that contribute to liver injury.
What does the liver convert?
The liver converts excess protein and carbohydrates to blood proteins, glucose, and VLDL.
Phase I and II reactions
Phase I reactions add hydroxyl groups to substrates.
Phase II reactions add sulfate, methyl groups, glutathione, or glucuronate to the hydroxyl group.
Cytochomre P450
Cytochomre P450 enzymes are important phase I metabolizing enzymes.
all use NADPH; all use O2
overlapping substrate specificity
expression induced by their substrates
Sulfotransferases use ______ as a sulfur donor.
Sulfotransferases use PAPS as a sulfur donor.
Ethanol and Cyp2E1
Ethanol incudes Cyp2E1
alcohol damage to the liver
Acetaldehyde angers kupffer cells, which set off stellate cells
Glycogen storage diseases labs
Glycogen storage diseases: Fasting hypoglycemia.
PGM1
interconverts glucose 1-phosphate and glucose 6-phosphate.
What does the liver do with excess carbohydrates?
Excess carbohydrate is converted to fatty acids and packaged as triacylglycerol in VLDL particles by the liver. IDL and LDL particles can be recycled by the liver.
What does the liver do with excess nitrogen?
Excess nitrogen that results from amino acid catabolism must be converted to urea for excretion. One of urea’s nitrogens comes from free ammonia and the other comes from aspartate.
Excess nitrogen is transported from peripheral tissues to the liver in the form of the amino acid glutamine.
The liver has a high requirements for products of the pentose phosphate pathway.
NADPH powers biosynthetic and detoxification reactions. Nucleotides are used for nucleic acids and cofactors.
Wnt
central vein endothelial cells secrete Wnt
Differences in Wnt regulated gene expression create a ‘safe zone’ for free ammonia to be a substrate for the urea cycle, without free ammonia being released into the general circulation.
