Liver Pathology Flashcards
______ is a general term referring to inflammation of the liver
Hepatitis
What are causes of hepatitis?
- infectious: viral, bacterial, fungal, and parasitic organisms; or
- noninfectious: e.g., alcohol, drugs, autoimmune diseases, and metabolic diseases.
What can the term viral hepatitis describe?
either a clinical illness or the histologic findings associated with the disease
What specific viruses can cause viral hepatitis? (5)
1) hepatitis A virus (HAV)
2) hepatitis B virus (HBV)
3) hepatitis C virus (HCV)
4) hepatitis D virus (delta agent) (HDV)
5) hepatitis E virus (HEV)
U.S. viral hepatitis is most commonly caused by what?
HAV, HBV and HCV
(can all result in acute (viral) hepatitis)
Acute infection with HBV and HCV can lead to ______ (viral) hepatitis.
Patients who are chronically infected may go on to develop _______ and ________
- chronic
- cirrhosis
- hepatocellular carcinoma (HCC)
Hepatitis A is transmitted by what?
a picornavirus, hepatitis A virus (HAV)
_____ does not cause chronic hepatitis
HAV
______ the most common cause of viral hepatitis worldwide
Hepatitis A
How is Hepatitis A transmitted?
- fecal-oral route, from person to person
- spread by ingestion of contaminated water and food
A major clinical finding in Hepatitis A is that _______ occurs in > 70% of patients
Jaundice (icterus)
What are serologic markers for hepatitis A?
- IgM antibody against HAV appears in blood at the onset of symptoms and is a reliable marker of acute infection
With hepatitis A, the IgM response usually declines in a few months followed by the appearance of _____ anti-HAV that persists for years, often conferring ______ immunity
- IgG
- lifelong
What is Hepatitis B?
an acute infection of the liver parenchymal cells caused by the hepatitis B virus (HBV)
What are outcomes of HBV infections? (5)
1) acute hepatitis with recovery and clearance of the virus
2) nonprogressive chronic hepatitis
3) progressive chronic disease ending in cirrhosis
4) fulminant hepatitis with massive liver necrosis
5) an asymptomatic “healthy” carrier state (persistence of hepatitis B surface antigen).
HBV-induced chronic liver disease is also an important risk factor for the development of _______
hepatocellular carcinoma (HCC)
Hepatitis B is caused by HBV, a hepadnavirus, and what proteins? (3)
- outer surface coat envelope glycoproteins: hepatitis B surface antigen (HBsAg)
- inner nucleocapsid “core” protein: hepatitis B core antigen (HBcAg)
- precore region designated: hepatitis B e antigen (HBeAg)
Where does HBV exist in people?
exists in the blood and body fluids
What are some ways HBV can be transmitted? (4)
- parenteral route: (needles)
- perinatal transmission
- contact of HBV infectious material with mucous membranes and open skin breaks
- oral intake of HBV infectious material may result in infection
In the US, Hepatitis B transmission is mainly ________
horizontal
What is the best predictor of chronic hepatitis B infection?
Patient age at the time of infection
Massive liver necrosis is a rare finding that may occur with Hepatitis B. When does an individual have the highest risk for this?
highest risk is in patients coinfected with hepatitis D
When does the serological marker HBsAg appear in Hepatitis B?
HBsAg before the onset of symptoms, peaks during symptomatic disease, and then usually declines to undetectable levels in 12 weeks
The detection of _____establishes infection with HBV and implies infectivity
HBsAg
______ appears after the acute disease is over and usually is not detected until a few weeks to several months after HBsAg disappears
Antibodies to HBsAg (Anti-HBs)
How long do Antibodies to HBsAg (Anti-HBs) persist in people?
may persist for life and confers protection
What do the serological markers HBeAg and HBV DNA signify in Hepatitis B?
signify ongoing viral replication
Persistence of ______ is an indicator of progression to chronic hepatitis B
HBeAg
The appearance of antibodies to HBeAg (anti-HBe) implies what?
an acute infection has peaked and is on the wane
When do IgM antibodies to HBcAg (IgM anti-HBc) become detectable in serum in Hepatitis B?
before the onset of symptoms, concurrent with the onset of elevated serum aminotransferase levels (indicative of hepatocyte destruction)
Know how to interpret hepatitis B serology results
see picture/chart in notes
What is Hepatitis C?
an acute liver parenchymal infection caused by hepatitis C virus (HCV)
In Hepatitis C, there are at least _____ major genotypes.
What are most common in USA?
- 6
- 1a and 1b are the most common in the U.S.
Most HCV transmission is ______
_______ accounts for most HCV transmission in the U.S
- parenteral
- Injecting-drug use
HCV infection may stimulate production of what?
cytotoxic T-lymphocytes and cytokines (INF-gamma), which probably mediate hepatic necrosis
When do symptoms of Hepatitis C develop?
develop 7 to 8 weeks after infection (range of 2 to 26 weeks), but 70% to 80% of cases are subclinical
What happens to ~ 10 - 20% of patients after acute hepatitis C infection?
they clear the HCV infection and have complete resolution
Progression to chronic HCV infection is ______ and occurs in ~______% of patients
- common
- 80 - 90
chronic HCV infection, ________ may develop and include a variety of immunologic and lymphoproliferative disorders
extrahepatic manifestations / sequelae
15 - 20% of those patients with chronic HCV will develop _______ over a period of 20 to 30 years;
cirrhosis
The serological marker _______ is detectable in blood for 1 to 3 weeks and is coincident with elevations in serum transaminases in hepatitis C
HCV RNA
In symptomatic acute HCV infection, _____ are detected in only 50 - 70% of patients;
anti-HCV antibodies
In chronic HCV infection, circulating _____ persists in ~ 90% of patients despite the presence of neutralizing antibodies
HCV RNA
Why must testing for HCV RNA be done in hepatitis C?
must be done to confirm the diagnosis of chronic HCV infection
What is a characteristic clinical feature of chronic HCV infection
episodic elevations in serum aminotransferases
What is Hepatitis D virus also called
delta agent
What is Hepatitis D Virus dependent on for its life cycle?
dependent for its life cycle on HBV
Coinfection with _______ is associated with higher rates of severe acute hepatitis and fulminant liver failure
HBV and HDV
How is Hepatitis E Virus (HEV) most commonly transmitted?
by the fecal-oral (water-borne infection) route
A characteristic feature of HEV infection is what?
high mortality rate among pregnant women, approaching 20%
What is Autoimmune hepatitis (AIH)
an immune-mediated, inflammatory liver disease characterized by elevated serum globulin levels (IgG), circulating characteristic autoantibodies, and the typical histology of interface hepatitis, plasma cell rich infiltration, and lobular hepatitis
In Autoimmune hepatitis (AIH), _____ develops in at least 40% of survivors
cirrhosis
What are histologic/morphologic features of autoimmune hepatitis? (3)
- necrosis and inflammation
- plasma cell predominance
- Hepatocyte “rosettes”
What is cirrhosis also called?
End-stage liver disease
What is cirrhosis the end result of?
irreversible hepatocellular injury that is characterized by diffuse transformation of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands.
What is the pathological hallmark of cirrhosis?
development of fibrous scar tissue that replaces normal hepatic parenchyma, leading to blockade of hepatic portal blood flow and disturbance of normal liver function
What do the clinical features of cirrhosis result from? (3)
- hepatic cell (hepatocyte) dysfunction (hepatic insufficiency)
- portosystemic shunting
- portal hypertension
What are common causes of cirrhosis in the US? (6)
- Hepatitis C: 26%
- Alcoholic liver disease: 21%
- Hepatitis C with concurrent alcoholic liver disease: 15%
- Cryptogenic (unknown) causes: 18% (due to nonalcoholic fatty liver disease [NAFLD])
- Hepatitis B (including coincident hepatitis D): 15%
- Miscellaneous: 5%
Up to 40% of patients with cirrhosis have _______ and demonstrate no clinical symptoms
- compensated cirrhosis
What clinical presentation do patients with decompensated cirrhosis have? (3)
- symptomatic complications related to cirrhosis
- hepatic insufficiency (e.g., jaundice or hepatic encephalopathy)
- portal hypertension (e.g., ascites or esophageal variceal hemorrhage
What are signs and symptoms of Cirrhosis involving the skin and eyes? (6)
- Jaundice (icterus) and scleral icterus
- Ecchymosis
- Palmar erythema
- Spider angiomas
- Spider angiomas
- Pruritus
How does cirrhosis affect the liver?
Hepatomegaly:
- the liver is enlarged, palpable, and firm
- Tender hepatomegaly and abdominal pain
How does cirrhosis affect the spleen?
-Splenomegaly / hypersplenism
- portal hypertension and hepatic congestion
Abdominal _____ develops in ~ 60% of patients with cirrhosis, and peripheral _____ is manifested by clubbing of the distal phalanges of the fingers
- ascites
- edema
What are some general signs of cirrhosis?
- Weakness, fatigability, muscle cramps, and weight loss
- Anorexia
- Fetor hepaticus (a characteristic body and breath odor)
What are oral findings of cirrhosis?
- Hemorrhagic changes
- Impaired gustatory function
- glossitis
- loss of tongue papillae
- angular or labial cheilitis
- candidal infection
- bilateral, painless hypertrophy of the parotid glands (sialadenosis)
What are common elevated laboratory findings in cirrhosis? (7)
- Elevated aminotransferases (aspartate & alanine aminotransferase)
- Plasma conjugated bilirubin
- Serum ammonia
- Serum lactate dehydrogenase (LDH)
- Serum alpha-fetoprotein (AFP)
- Serum alkaline phosphatase
- Alpha-2-macroglobulin (A2M)
What are common decreased laboratory findings in cirrhosis?
- Serum albumin
- Platelet count (Thrombocytopenia)
- Depletion of vitamin K
_____ is fairly common in cirrhosis and usually normocytic - normochromic
Anemia
In cirrhosis, reduced ______ synthesis and deficiencies of vitamin K-dependent coagulation factors II (prothrombin) V, VII, IX, and X can result in abnormally elevated _______ and INR and impaired _____ and risk for increased bleeding
- hepatic
- prothrombin time (PT)
- hemostasis
In cirrhosis, reduced hepatic synthesis of fibrinogen leads to what?
hypofibrinogenemia and dysfibrinogenemia
A common symptom of cirrhosis is hepatic failure. What are 3 complications directed associated with this?
- Hepatic encephalopathy
- Hepatorenal syndrome
- Hepatopulmonary syndrome
What are some common complications of cirrhosis?
- Portal hypertension
- Esophageal varices
- Upper gastrointestinal (GI) tract bleeding
- Hepatocellular carcinoma
- Increased risk of systemic infection
- Cardiomyopathy
What can portal hypertension from cirrhosis lead to?
- a large increase in blood flow resistance through the liver (i.e., chronic passive congestion
- increased portal venous inflow and increased resistance to portal blood flow.
What are esophageal varices the direct result of?
increased blood pressure due to portal hypertension
Upper gastrointestinal (GI) tract bleeding may occur from what?
esophageal varices, portal hypertensive gastropathy, or gastroduodenal ulcer
What is the most common fatal complication of cirrhosis?
variceal rupture
(Hemorrhage from ruptured esophageal varices may be massive, resulting in fatal exsanguination)
Up to 5% of patients with cirrhosis are at risk to develop _______ annually
hepatocellular carcinoma
What systemic infection does cirrhosis increase the risk of?
spontaneous bacterial peritonitis
What is Primary Biliary Cholangitis (also called Primary Biliary Cirrhosis) (PBC)
a chronic, variably progressive cholestatic liver disease manifested by fatigue and pruritus
Who is most commonly diagnosed with primary biliary cholangitis (PBC)
PBC has a female-to-male ratio of 9:1
What is primary biliary cholangitis (PBC) characterized by?
autoimmune destruction of intralobular bile ducts leading to portal inflammation, hepatic cell necrosis, fibrosis, and, if left untreated, cirrhosis, liver failure, and death
What is the etiology of primary biliary cholangitis (PBC)
believed to require both a genetic susceptibility as well as an environmental trigger → persistent T-lymphocyte–mediated attack on intrahepatic bile duct epithelial cells
Patients with PBC have a ten-fold increased concentration of PDC-E2-specific _______
cytotoxic CD8+ lymphocytes
What are the serologic hallmark of PBC?
antimitochondrial antibodies (AMAs)
In primary biliary cholangitis (PBC), autoimmune damage to _____ results in bile leaking into liver parenchyma resulting in hepatocyte _______, which can lead to progressive fibrosis and eventual _______
- bile ducts
- necrosis
- cirrhosis
What are the usual presenting symptoms of primary biliary cholangitis (PBC)
Fatigue (50 - 78% of patients) and pruritus (20 -70% of patients)
In primary biliary cholangitis (PBC), _______ is present predominantly on the palm and soles, is worse at night and with constricting garments, and is worse with dry skin and humid weather
Pruritus
Besides fatigue and pruritus, what are other symptoms of primary biliary cholangitis (PBC)? (5)
- Jaundice
- portal hypertension
- hyperlipidemia,
- osteoporosis
- Kayser-Fleischer rings
What autoimmune diseases may primary biliary cholangitis (PBC) be associated with? (3)
- Sjögren’s syndrome
- rheumatoid arthritis
- systemic lupus erythematosus
What is another name for fatty liver disease?
steatosis
What is fatty liver disease (steatosis)?
accumulation of triglycerides and other lipids within the liver cells (hepatocytes)
What is fatty liver disease (steatosis) mainly comprised of?
Alcoholic Liver Disease (ALD) and Non-alcoholic Fatty Liver Disease (NAFLD)
Alcoholic Liver Disease (ADL) 3 morphologic / histologic states associated with alcoholic liver disease. What are they?
- alcoholic steatosis (fatty liver)
- alcoholic hepatitis
- alcoholic cirrhosis
Is Alcoholic Fatty Liver (or Alcoholic Steatosis) permanent or reversible?
reversible with abstinence from alcohol use or may progress to alcoholic hepatitis with continued alcohol use
During Alcoholic Fatty Liver (or Alcoholic Steatosis), ______ accumulates in the liver parenchyma (hepatocytes).
_____ accumulation spreads outward from the central vein to hepatocytes in the mid-lobule and then the _____ regions
- fat
- lipid
- periportal
How would you describe fatty livers with widespread steatosis macroscopically?
enlarged, soft, yellow, and greasy
What takes place during Alcoholic Hepatitis?
Inflammation and swelling of hepatocytes
During Alcoholic Hepatitis, hepatocytes undergo swelling (ballooning) and _____; these features are most prominent in the _____ regions
- necrosis
- centrilobular
During Alcoholic Hepatitis, predominantly _____ infiltration may permeate the lobule and accumulate around degenerating ______
- neutrophilic
- hepatocytes
What do more severe cases of alcoholic hepatitis lead to?
cirrhosis and liver failure
In Alcoholic Cirrhosis, Liver damage is usually considered _____ with regenerative, hyperplastic nodules and progressive hepatic _____
- irreversible
- fibrosis
In Alcoholic Cirrhosis, fibrosis appears first in the _________ region as central vein sclerosis. _______ appears next in the space of Disse.
- centrilobular
- Perisinusoidal scarring
In Alcoholic Liver Disease (ADL), alcohol metabolism is shifted to the production of NADH. This leads to what?
- glycerol phosphate, which combines with the fatty acids and becomes triglycerides, which accumulate within the liver.
In Alcoholic Liver Disease (ADL), when lipid _____ (lipolysis) stops due to alcohol consumption, fats accumulate in the liver and leads to (alcoholic) ______
- oxidation
- fatty liver disease
In Alcoholic Liver Disease (ADL), interleukins with the help of _____ attack the hepatocytes, leading to swelling and ______ of the hepatocytes that is associated with ______ hepatitis
- neutrophils
- inflammation
- alcoholic
What is Non-alcoholic fatty liver disease (NAFLD)?
- a spectrum of diseases based on histopathologic findings
- liver disease occurring in patients who do not abuse alcohol and manifesting histologically by mononuclear cells and/or neutrophils, hepatocyte ballooning, and spotty necrosis
What are two subsets of Non-alcoholic fatty liver disease (NAFLD)?
- Non-alcoholic steatohepatitis (NASH)
- Non-alcoholic fatty liver (NAFL)
In Non-alcoholic steatohepatitis (NASH), patients have progressive disease that can result in ______ and _____. It is characterized by steatosis, lobular inflammation, and hepatocellular (hepatocyte) _____ seen on liver biopsy
- fibrosis
- cirrhosis
- ballooning
Non-alcoholic fatty liver (NAFL) is also known as what?
“isolated fatty liver”
What is Non-alcoholic fatty liver (NAFL) characterized by?
harmless, reversible, non-progressive steatosis and hepatomegaly
NAFL typically does not cause _____ inflammation, fibrosis or hepatocyte ballooning; or cause liver damage, and will almost never progress to ______ .
- liver
- cirrhosis
What are the main risk factors for Non-alcoholic fatty liver (NAFL)
- obesity
- diabetes mellitus
- hypertension
(metabolic syndrome)
_____ and _____ resistance are the most reproducible etiologic factors in the development of NAFLD, and appear to be the two key initiating events for the development of NAFLD
- Obesity
- insulin
What does the development of obesity and insulin resistance in NAFLD increase?
increase the mobilization of free fatty acids from adipose tissue, which are taken up by hepatocytes, and to stimulate the synthesis of fatty acids within hepatocytes
Excessive ______ lipids and their metabolic intermediates _____ insulin resistance in the liver and _____ hepatocytes to the toxic effects of inflammatory cytokines
- intrahepatic
- enhance
- sensitize
Hepatocytes in patients with NASH show evidence of ______ activation
inflammasome
Liver injury resulting from NAFLD mechanisms causes _______ activation, ______ deposition, and hepatic fibrosis, which along with ongoing hepatocyte _____
- stellate (Ito) cell
- collagen
- damage
What are complications of Non-alcoholic Fatty Liver Disease (NAFLD)? (3)
- Cardiovascular disease
- Cirrhosis
- Hepatocellular carcinoma (HCC)
Patients with NAFLD/NASH have an increased risk for what cardiovascular diseases?
- coronary artery disease
- left ventricular hypertrophy
- atrial fibrillation
- cerebrovascular disease [stroke]
What is Hepatocellular Carcinoma (HCC)
(also known as hepatoma) is a primary malignant tumor of the liver
What are the main risk factors for Hepatocellular Carcinoma (HCC)
Chronic HBV infection, chronic HCV infection, alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and cirrhosis
What are secondary risk factors for Hepatocellular Carcinoma (HCC)
- Primary biliary cholangitis, hemochromatosis, alpha-1-antitrypsin deficiency, and autoimmune hepatitis.
- History of excessive alcohol ingestion
- Aflatoxin B1 (a mycotoxin)
Cirrhotic-related HCC patients may present with symptoms of new-onset decompensated ______ and liver failure with _____ being the commonest presentation for HCC
- cirrhosis
- abdominal pain
