Pathology of the Liver Flashcards
Which 3 cytosolic hepatocellular enzymes indicate hepatocyte injury?
AST
ALT
LDH
What labs can help determine biliary excretory function? (5)
Substances normally secreted in bile
- serum BR (total and direct only)
- urine BR
- serum bile acids
Plasma membrane enzymes
- ALP
- GGT
What labs/tests can help determine hepatocyte synthetic function? (4)
Proteins secreted into the bloodstream
- serum albumin
- coagulation factors
Hepatocyte metabolism
- serum ammonia
- aminopyrine breath test (hepatic demethylation)
What is the definition of acute liver failure?
Acute liver illness with encephalpathy and coagulopathy that occurs within 26 weeks of initial liver injury in the absence of pre-existing liver disease
What are the major causes of acute liver failure?
Massive hepatic necrosis from drugs or toxins
-acetaminophen ingestion (50%)
Autoimmune hepatitis and Hep. A and B account for the other 50%
What is the clinical course of acute liver failure?
Manifests first with N/V and jaundice, followed by life-threatening encephalopathy and coagulation defects.
What is the pathological/morphological course of acute liver failure?
- The liver typically enlarges at first due to inflammation and edema. ALT/AST are elevated.
- As the process continues and the parenchyma is destroyed, the liver shrinks.
- Jaundice, coagulopathy and encephalopathy can confirm the suspicion of extensive hepatic damage.
What is a sign of significant damage in ALF?
If ALT/AST declines as the parenchyma is destroyed and the liver shrinks
List other possible manifestations of ALF (5)
Changes in bile formation
Hepatic encephalopathy: mental status changes and asterixis; elevated ammonia
Coagulopathies
Portal HTN
Hepatorenal syndrome
What are the 3 most common causes of chronic liver failure worldwide?
Chronic Hep. B
Chronic Hep. C
NAFLD
Which liver enzyme tends to be more elevated in CLF?
ALT>AST
What are the clinical features of CLF?
Approx. 40% of patients with cirrhosis are asymptomatic until the most advanced stages of disease. When symptomatic, they present with non-specific manifestations; anorexia, weight loss, weakness, jaundice, ascites, etc.
What can cause pruritis in a patient with CLF?
Chronic jaundice
What hormone might be elevated in males with CLF? What does it cause?
Hyperestrogenemia - leads to palmer erythema, spider angiomas of the skin, hypogonadism and gynecomastia
What are examples of pre-,intra- and post-hepatic portal HTN?
Pre-: obstruction of the portal v.
Intra-: liver parenchymal disease
Post-: RSHF, constrictive pericarditis, outflow obstruction
Hep. A
Type of virus
Viral family
Route of transmission
Mean incubation period
Frequency of CLD
Diagnosis
Type of virus - ssRNA
Viral family - hepatovirus
Route of transmission - fecal-oral
Mean incubation period - 2-6 wks.
Frequency of CLD - never
Diagnosis - IgM Abs
Hep. B
Type of virus
Viral family
Route of transmission
Mean incubation period
Frequency of CLD
Diagnosis
Type of virus: partial dsDNA
Viral family - hepadnavirus
Route of transmission - parenteral, sexual contact, perinatal
Mean incubation period - 2-26 wks.
Frequency of CLD - 5-10%
Diagnosis - HBsAg or Ab to HBsAg
Hep. C
Type of virus
Viral family
Route of transmission
Mean incubation period
Frequency of CLD
Diagnosis
Type of virus - ssRNA
Viral family - flaviridae
Route of transmission - parenteral, intra-nasal cocaine
Mean incubation period - 4-26 wks.
Frequency of CLD - >80%
Diagnosis - 3rd gen. ELISA for Ab
What is autoimmune hepatitis?
Chronic, progressive hepatitis with autoimmune features
Which patients are at the greatest risk for autoimmune hepatitis?
Caucasians, F>M
DRB1 allele is associated with:
Autoimmune hepatitis
Which patients are most likely to develop type 1 autoimmune hepatitis vs. type 2?
Type 1: middle-aged and older
Type 2: children and teens
Which labs are positive in type 1 autoimmune hepatitis (4) vs. type 2 (1)?
Type 1: + ANA, + SMA, + anti-SLA/LP, + AMA
Type 2: + anti-LKM-1
What morphological changes occur to the liver in acetaminophen injury?
CYP450 toxicity leads to death of hepatocytes in zone 3, while hepatocytes in zone 2 take over metabolic demands and can die, too. In severe, overdoses, the periportal hepatocytes may die and lead to ALF.
What neoplastic lesion can occur to the liver with anabolic steroids and oral contraceptives? What is its course?
Hepatocellular adenoma - benign, but can rupture and cause significant blood loss. 3 sub-types exist and each have their own risk of malignancy.
What can contribute to developing the following neoplasms?
Hepatocellular adenoma
Hepatocellular carcinoma
Cholangiocarcinoma
Angiosarcoma
Hepatocellular adenoma: OC, anabolic steroids
Hepatocellular carcinoma: alcohol, thorotrast
Cholangiocarcinoma: thorotrast
Angiosarcoma: thorotrast, vinyl chloride
What are the 3 stages of progression of alcholic liver disease?
- Hepatic steatosis (fatty liver)
- Alcoholic hepatitis
- Alcoholic steatofibrosis (alcoholic cirrhosis)
What lab findings are associated with hepatic steatosis?
What happens to the size of the liver?
Increased BR and ALP
Hepatomegaly - enlarges
Under what circumstances might hepatic steatosis be reversible?
If the patient abstains from drinking and there is no evidence of fibrosis/cirrhosis
What develops morphologically in alcoholic hepatitis? (3)
Hepatocytes swell (ballooning)
Mallory-Denk bodies (cytoskeleton breakdown) become apparent.
Neutrophils and inflammation appear.
What does the liver look like grossly in alcoholic steatofibrosis?
The liver is brown, shrunken and non-fatty
What liver enzyme tends to be more elevated in alcoholic steatofibrosis?
AST>ALT
Mallory-Denk bodies =
Alcoholic hepatitis
What causes NAFLD primarily?
Metabolic syndrome, obesity
What liver enzyme tends to be more elevated in NAFLD?
ALT>AST
AST>ALT
Alcoholic steatofibrosis (cirrhosis)
ALT>AST
Chronic liver failure
NAFLD
What morphologic change occurs in alcoholic steatofibrosis?
“Chicken-wire fibrosis”: sinusoidal and centrilobular fibrosis begins with sclerosis of the central v. and spreads outward
Which gender have a greater susceptibility for alcholic liver disease? Why?
Which ethnicity tends to be at greater risk?
Females are more susceptible, but men tend to get it more often because there are more male alcoholics. It is thought that this occurs due to the estrogen-dependent response to gut-derived endotoxin (LPS).
AA>W
In order to classify as Metabolic Syndrome, there must be 1 of the following:
And 2 of the following:
1 of the following:
- DM
- impaired glucose tolerance
- impaired fasting glucose
- insulin resistance
2 of the following:
- BP > 140/90
- dyslipidemia
- central obesity
- microalbuminemia
NAFLD is defined as…
A spectrum of disorders that have in common the presence of hepatic steatosis (fatty liver) and do not consume exorbitant amounts of alcohol.
What is the 2-hit pathogenesis for NAFLD?
- Insulin resistance gives rise to hepatic steatosis
2. Hepatocellular oxidative injury resulting in hepatocyte necrosis and inflammatory reactions to it
How does the morphology of NAFLD differ from alcoholic hepatitis?
Looks almost identical to alcoholic hepatitis, except:
-mononuclear cells tend to be more prevalent than neutrophils or Mallory-Denk bodies
What is the progression of NAFLD?
NAFLD can cause isolated fatty liver disease (80%) or NASH.
NASH can go on to cause NASH cirrhosis (11% over 15 years) or HCC directly.
NASH cirrhosis can lead to decompensation (31% over 8 years) or HCC.
Figure 18-23
a-1 ATD pathogenesis
What is unique about the genetics?
What stain is positive?
AR disorder causing decreased a1-AT which allows elastase to accumulate. This causes panacinar emphysema and cirrhosis due to buildup of abnormal proteins.
It is codominant; mutations in the PiZ is most clinically significant.
PAS stain
What mutation and its heredity is associated with Wilson disease? What is its function?
AR mutation in ATP7B - impaired Cu excretion into bile and failure to incorporate Cu into ceruloplasmin.
Where does Cu accumulate in Wilson disease?
Liver, brain and eyes
How does Cu accumulation lead to damage in Wilson disease? (3)
ROS produced by the Fenton reaction
Cu binds sulfhydryl groups of cellular proteins
Cu displaces other metals from hepatic metalloenzymes
What morphological features are classic in extensive Wilson disease?
Mild to moderate fatty change in the liver.
Kayser-Fleischer rings (green to brown deposits of Cu in the cornea) are present if there is eye involvement.
What are the clinical features of Wilson disease? What age does it most often develop?
6-40 y/o
Neurologic involvement presents as movement disorders or rigid dystonia (may appear Parkinson-like) and possible psychiatric involvement.
Hemolytic anemia due to toxicity to RBC membranes.
What lab findings may indicate Wilson disease? (3)
Decreased serum ceruloplasmin
Increased hepatic Cu content
Increased urinary excretion of Cu
Presence of K-F bodies in the eye can also help with diagnosis
Which organs does iron get deposited in Hemochromatosis? What can each cause? (4)
Pancreas - DM
Joints - OA
Heart - CM
Skin - bronzing
Iron causes buildup of ROS. What are 3 manners of cell injury mediated by iron excess?
Lipid peroxidation
Stimulation of collagen formation by activating hepatic stellate cells
ROS interaction with DNA causes cell injury
What is the function of hepcidin?
Hepcidin lowers plasma iron levels, so a deficiency of hepcidin leads to iron overload.
What mutation is most associated with the development of Hemochromatosis?
HFE
Which mutations can lead to severe juvenile hemochromatosis?
HAMP and HJV
What is the most common cause of death in hemochromatosis if left untreated?
HCC
What stain is useful in diagnosing hemochromatosis?
Prussain blue stain
What is an acquired (non-genetic) cause of hemochromatosis?
Recurrent blood transfusions (sickle cell disease, etc.)
What are 2 causes of predominantly conjugated hyperbilirubinemia?
Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)
Impaired bile flow (duct obstruction or autoimmune cholangiopathies)
What are 3 “big picture” causes of predominantly unconjugated hyperbilirubinemia?
Excess BR production
Reduced hepatic uptake of BR
Impaired BR conjugation
(Crigler-Najjar syndrome type I and type II, Gilbert syndrome)
Crigler-Najjar syndrome type I
Inheritance
Defects in BR metabolism
Liver pathology?
Clinical course
Inheritance: AR
Defects in BR metabolism: absent UGT1A1 activity
Liver pathology? None
Clinical course: fatal in neonatal period
Crigler-Najjar syndrome type II
Inheritance
Defects in BR metabolism
Liver pathology?
Clinical course
Inheritance: AD with variable penetrance
Defects in BR metabolism: decreased UGT1A1 activity
Liver pathology? None
Clinical course: generally mild, occasional icterus
Dubin-Johnson syndrome
Inheritance
Defects in BR metabolism
Liver pathology?
Clinical course
Inheritance: AR
Defects in BR metabolism: impaired biliary excretion of BR glucuronides due to mutations in MRP2
Liver pathology? Pigmented cytoplasmic globules
Clinical course: innocuous
Rotor syndrome
Inheritance
Defects in BR metabolism
Liver pathology?
Clinical course
Inheritance: AR
Defects in BR metabolism: possible decreased hepatic uptake/storage; decreased biliary excretion
Liver pathology? None
Clinical course: innocuous
Gilbert syndrome
Inheritance
Defects in BR metabolism
Liver pathology?
Clinical course
Inheritance: AR
Defects in BR metabolism: decreased UGT1A1 activity
Liver pathology? None
Clinical course: innocuous
What is the cause of cholestasis?
Impaired bile formation and bile flow that gives rise to accumulation of bile pigment in the hepatic parenchyma.
It can be caused by extra-hepatic or intra-hepatic obstruction of bile channels, or defects in hepatocytes bile secretion.
What are some clinical signs of cholestasis? (5)
Jaundice
Pruritis
Xanthomas
Malabsorption
Vitamin ADEK deficiencies
What are the lab findings in a patent with cholestasis?
Increased ALP and GGT (enzymes present on apical membranes of hepatocytes and bile duct epithelial cells)
Primary biliary cirrhosis
Age of onset
Gender
Clinical course
Associated conditions
Serology
Radiology
Duct lesion
Age of onset: 30-70 y/o (median is 50 y/o)
Gender: 90% female
Clinical course: progressive
Associated conditions: Sjogren’s (70%), Scleroderma (5%), Thyroid disease (20%)
Serology: 95% + AMA, 50% + ANA, 40% + ANCA
Radiology: normal
Duct lesion: florid duct lesions and loss of small ducts only
Primary sclerosing cholangitis
Age of onset
Gender
Clinical course
Associated conditions
Serology
Radiology
Duct lesion
Age of onset: 30 y/o (median age)
Gender: 70% male
Clinical course: unpredictable, but progressive
Associated conditions: IBD (70%), Pancreatitis (<25%), Retroperitoneal fibrosis
Serology: 65% + ANCA, 6% + ANA
Radiology: strictures and beading of large bile ducts
Duct lesion: inflammatory destruction of extra-hepatic and large intra-hepatic ducts
What are the 2 autoimmune cholangiopathies?
Primary biliary cirrhosis and Primary sclerosing cholngitis
What 2 pathologies can result in impaired blood flow into the liver?
Hepatic a. compromise
Portal v. obstruction and thrombosis
What causes hepatic a. compromise?
Thrombosis or compression of an intra-hepatic branch of the hepatic a. by embolism, neoplasia, etc. can cause necrotic damage to the liver. These liver infarcts are rare, because of the dual blood supply (portal v. and hepatic a.).
Portal v. obstruction and thrombosis can occur extra-, and intra-hepatically. What are the causes of each?
Extra-hepatic: idiopathic (30%), or some degree of obstruction of the portal v. prior to reaching the liver (intra-abdominal sepsis, hypercoagulability, trauma, HCC, cirrhosis, etc.)
Intra-hepatic: portal v. radicles obstructed by acute thrombosis -> lines of Zahn
What is the most common cause of small portal v. branch obstruction (causing impaired blood flow into the liver)?
Schistosomiasis
What are the 3 major manifestations of impaired blood flow into the liver (Hepatic a. compromise, Portal v. obstruction and thrombosis)?
Esophageal varices
Splenomegaly
Intestinal congestion
What is the most common cause of impaired intra-hepatic blood flow?
What are 6 other, less likely, causes?
Cirrhosis
Sickle cell disease DIC Eclampsia Malignancy Peliosis hepatitis - sinusoidal dilation from impeded efflux of hepatic blood Bartonella infection
What are 4 major manifestations of impaired intra-hepatic blood flow?
Ascites (cirrhosis)
Esophageal varices (cirrhosis)
Hepatomegaly
Elevated liver enzymes
What are the 2 major causes of hepatic venous outflow obstruction?
Hepatic v. thrombosis (Budd-Chiari syndrome) and Sinusoidal obstruction syndrome
What is the pathogenesis of Budd-Chiari syndrome?
Obstruction of >/2 major hepatic vv. produces liver enlargement, pain and ascites = Budd-Chiari syndrome
What causes sinusoidal obstruction syndrome?
Toxic injury to the sinusoidal endothelium
What are 5 major manifestations of hepatic v. outflow obstruction?
Ascites
Hepatomegaly
Abdominal pain
Elevated liver enzymes
Jaundice
What is the common cause of nodular regenerative or focal nodular hyperplasia?
Focal or diffuse alterations in hepatic blood supply, arising from obliteration of portal v. radicles and compensatory augmentation of arterial blood supply.
What is the major risk factor for developing hepatic adenomas?
Oral contraceptives
What is a clinical complication of hepatic adenomas?
They can rupture and cause excessive abdominal bleeding
Hepatoblastoma is the most common liver tumor of:
What is a genetic mutation associated with it?
What is the outcome?
Young children (<3 y/o)
WNT pathway, including mutations in APC gene
If untreated, the tumor is usually fatal within a few years, but therapy has raised the 5-year survival to 80%
What are the most important factors in hepatocarcinogenesis?
At what age does it present? What sex is at greater risk?
Viral infections (HBV, HCV) and toxic injuries (aflatoxin, EtOH)
<60 y/o, M>F
What are the 2 most common early mutational events in development of HCC?
B-catenin activation and p53 inactivation
HCC may appear grossly in which forms? (3)
Unifocal mass
Multifocal, widely distributed nodules of variable size
Diffusely infiltrative cancer
Cholangiocarcinoma (CCA) begins where?
What is its prognosis generally?
In the biliary tree, arising from bile ducts within and outside of the liver.
Poor prognosis generally.
What is a Klatskin tumor?
An extra-hepatic form of perihilar tumors from CCA
What are the precursor lesions of CCA?
Biliary intra-epithelial neoplasias (low to high grade, BiIIN-1, -2, or -3 (-3 is highest risk for malignant transformation))
What are some risk factors for CCA? (2)
Liver fluke infections (Opisthorchis, Clonorchis)
Chronic inflammatory disease of bile ducts
Angiosarcoma is mainly associated with which toxins?
Vinyl chloride and Thorotrast
In what population is a hepatic lymphoma most prominent?
What are the 3 important sub-types?
M>F
Diffuse large B-cell lymphomas - most common
MALT lymphomas
Hepatosplenic delta-gamma T cell lymphoma - most common in young males
What 4 primary tumors sites often metastasize to the liver?
Colon
Breast
Lung
Pancreas
Ground glass hepatocyte is present on biopsy. Likely diagnosis?
Hep. B
How do hepatic stellate cells contribute to scar formation in the liver?
Hepatic stellate cells (in the quiescent form) store vitamin A, but in several forms of acute and chronic injury, they can be cativated and converted into highly fibrogenic myofibroblasts.
What are the 2 major mechanisms of liver regeneration?
- Proliferation of remaining hepatocytes
2. Repopulation from progenitor cells
What are 4 unique signs of CLF in males?
Palmer erythema
Spider angiomata
Hypogonadism
Gynecomastia
What is the best predictor of chronicity in HBV?
Age at time of infection (younger patients have higher risk of chronicity)
Hallmark of chronic hepatitis
Portal chronic inflammation
Hallmark of progressive chronic liver damage
Scarring
What is interface hepatitis?
It is a feature of viral hepatitis, as well as AIH and steatohepatitis.
It is associated with a lymphocytic infiltrate into the adjacent parenchyma along with destruction of individual hepatocytes along the edges of the portal tract.
Characteristic feature of chronic viral hepatitis due to HCV
Portal tract expansion by a lymphoid follicle
Major extrahepatic cause of cholestasis in adults is…
LDO - large duct obstruction
“Giant cell transformation” =
Neonatal hepatitis
What is the single most frequenct cause of death from liver disease in early childhood?
What is the definition of it?
What are the 2 forms?
Biliary atresia - complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life.
Fetal: 20%
Perinatal: 80%
+ AMA should make you think…
PBC
+ ANCA should make you think…
PSC
“Onion-skinning”
PSC
What are choledochal cysts?
Congenital dilations of the common bile duct
What is fibropolycytic disease of the liver?
Von Meyenburg complexes
Caroli disease
Caroli syndrome
They are a group of lesions in which the primary abnormalities are congenital malformations of the biliary tree
Von Meyenburg complexes = hamartomas
Caroli disease = simple multiple biliary cysts
Caroli syndrome = Caroli disease + congenital hepatic fibrosis
Most common cause of jaundice in pregnancy is:
Viral hepatitis
Pre-eclampsia and eclampsia
Maternal HTN, proteinuria, edema and coagulation abnormalities (pre-eclampsia)
When hyperreflexia and convulsions occur it is termed eclampsia and can be life threatening
Cholestasis of pregnancy
Onset of pruritis in the 3rd trimester, followed, in some cases, by dark urine and light stools and jaundice
Acute fatty liver of pregnancy can present as..
A spectrum of disorders ranging from subclinical or modest hepatic dysfunction to hepatic failure, coma and death.
Focal nodular hyperplasia definition:
What age?
A single well-demarcated lesion with a central scar that arises spontaneously in an otherwise normal liver.
Young to middle-aged adults
Nodular regenerative hyperplasia definition:
What can develop as a result?
What are 2 associations?
Multiple nodules (looks like cirrhosis) but no fibrous septa.
Portal HTN
HIV, rheumatologic dz
Most common benign neoplasm of the liver:
Which gender is at a bigger risk?
How is it discovered?
Cavenrous hemangioma
F>M
Incidental discovery or a cause of hemorrhage due to subcapsular location
What are the 3 sub-types of hepatic adenomas?
What are the risk for malignancies of each? What morphologic changes occur?
HNF1-ainactivated adeoma - no risk; fatty with no atypia
B-catenin activated adenoma - very high risk; B-catenin and dysplasia
Inflammatory adenoma - small but definite risk; CRP and amyloid A
What are the 2 anatomic variants of Hepatoblastomas?
Epithelial type - composed of fetal or embryonal cells
Mixed epithelial and mesenchymal type - primitive mesenchyme, osteoid, cartilage or striated muscle
What is the fibrolamellar variant of HCC?
Only 5% of cases, but 85% of them occur under age 35. It presents as a single large, hard “scirrhous” tumor with fibrous bands coursing through it.
If + SMA, you should think…
AIH type I
In HCC, what is the clinical importance of large cell and small cell pre-malignant lesions? What disease are they associated with?
Large cell: increased risk for HCC
Small cell: pre-malignant changes
They’re associated with CLD
What is the clinical importance of low grade dysplasia and high grade dysplasia in the development of HCC?
Low grade: suggest an increased risk for HCC
High grade: “most important primary pathway for emergence of HCC in viral hepatitis and alcoholic liver disease”
What morphological change occurs in pre-eclampsia?
Periportal sinusoids contain fibrin deposits associated with hemorrhage into the space of Disse.
What is the primary hepatolithiasis? What does it lead to?
Disorder of intrahepatic gallstone formation that leads to:
- repeated bouts of ascending cholangitis
- progressive destruction of hepatic parenchyma
- increased risk for hepatic neoplasia
