Ch. 18 1-3 (Dobson) Flashcards
(228 cards)
1
Q
What are the serum measurements for hepatocyte integrity (tells us if there is liver damage, NOT function)?
A
- Aspartate aminotransferase (AST)
- Alanine aminotransferase (ALT)
- Lactate dehydrogenase (LDH)
2
Q
What are the tests that look for biliary excretion function?
A
- Serum bilirubin
- Urine bilirubin
- Serum bile acids
3
Q
What are the tests that look for damage to the bile canaliculus?
A
- Serum alkaline phosphatase
- - Serum gamma-glutamyl transpeptidase (GGT)
4
Q
What are the tests that look for hepatocyte synthetic function?
A
– Serum albumin
– Coagulation factors: PT, PTT, fibrinogen, prothrombin, factors V, VII, IX, and X
– Serum ammonia (hepatocyte metabolism)
5
Q
What are the REVERSIBLE changes in hepatocytes?
A
- Steatosis = accumulation of fat in liver
- - Cholestasis = accumulation of bilirubin in liver
6
Q
Within the lobule, hepatocytes are organized into anastomosing sheets or “plates” extending from portal tracts to the terminal hepatic veins. Between the trabecular plates of hepatocytes are vascular ________.
A
Sinusoids
7
Q
Blood traverses the sinusoids and exits into the terminal hepatic veins through numerous orifices in the vein wall. Hepatocytes are thus bathed on two sides by well-mixed, _______ ______ and _______ ______ blood.
A
Portal venous
Hepatic arterial
8
Q
The sinusoids are lined by fenestrated endothelial cells. Beneath the endothelial cells lies the _______ ______ ______, into which protrude abundant hepatocyte microvilli.
A
Space of Disse
9
Q
Scattered _______ cells of the mononuclear phagocyte system (macrophages) are attached to the luminal face of endothelial cells, and fat-containing myofibroblastic _______ _______ cells are found in the space of Disse.
A
Kupffer
Hepatic stellate
10
Q
Between abutting hepatocytes are _______ ______, which are channels 1 to 2 um in diameter, formed by grooves in the plasma membranes of facing hepatocytes and separated from the vascular space by tight junctions.
A
Bile canaliculi
11
Q
Bile canaliculi drain into the _______ _______ _______ that, in turn, connect to Bile Ductules in the periportal region. The ductules empty into the terminal Bile Ducts within the portal tracts.
A
Canals of Hering
12
Q
Large numbers of _________ are also present in normal liver, comprising as much as 22% of cells other than hepatocytes.
A
Lymphocytes
13
Q
What are the 4 main functions of the liver?
A
- Energy generation and substrate interconversion
- Synthesis and secretion of plasma proteins
- Solubilizing, transport, and storage functions
- Protective and clearance functions
14
Q
T/F. Hepatic damage also occurs secondary to some of the most common diseases in humans, such as heart failure, disseminated cancer, and extra-hepatic infections.
A
True
15
Q
Hyperbilirubinemia or jaundice is defined by elevated levels of bilirubin in the bloodstream. This condition may be classified due to ________, ________, or _______ disorders.
A
Prehepatic
Intrahepatic
Posthepatic
16
Q
This type of bilirubin is attached to albumin and taken to the liver.
A
Unconjugated (Indirect)
***Remember, it is INSOLUBLE!
17
Q
This type of bilirubin is released from the liver into the bile canaliculi to form bile, which is then stored in the gallbladder.
A
Conjugated (Direct)
18
Q
This lab test is particularly sensitive for liver disease. If the level is normal, there is only 1-2% chance of liver disease being present.
A
GGT
19
Q
The levels of AST and ALT are also very useful for the diagnosis of liver disease. An _______ >3000 U/L suggests a severe hypotensive episode causing centrilobular necrosis, a toxic injury such as acetaminophen overdose, or acute viral hepatitis.
A
AST
20
Q
T/F. Chronic diseases of the liver such as alcoholic liver disease and chronic viral hepatitis are typically associated with smaller elevations of transaminases, in the 100-300 U/L range.
A
True
21
Q
Elevated ALT and AST with an AST/ALT ratio >2:1 is classically associated with what?
A
Alcoholic hepatitis
22
Q
Elevated ______ can be seen in both liver and bone disease, whereas a concomitant elevation of ______ and _______ is consistent with cholestatic liver disease.
A
ALP
ALP
GGT
23
Q
While GGT, AST, ALT, and ALP indicate damage to the hepatocytes, _______ and _______ _______ are more reflective of the functional status of the liver.
A
PT (prothrombin time)
Albumin
***This is because both albumin and clotting factors are produced by hepatocytes!
24
Q
Factor VII has a serum-half life of about 4 hours, making the PT a good assessment of a (ACUTE/CHRONIC) change in liver function, whereas albumin is more accurate at assessing a (ACUTE/CHRONIC) change in liver function.
A
Acute
Chronic
25
Assessment of what globulin is useful for determining an acute vs. chronic pathologic liver process?
IgG -- if normal it is acute, if elevated it is chronic
26
For this disease, the liver function pattern shows elevated transaminase levels and variable increases in other enzymes.
Acute Hepatitis
27
For this disease, the liver function pattern shows decreased albumin, elevated IgG (with Beta-Gamma bridging on serum electrophoresis) and elevated PT.
Cirrhosis
28
For this disease, the liver function pattern shows a combination of changes seen in acute hepatitis and cirrhosis patterns.
Chronic Hepatitis
29
For this disease, the liver function pattern shows an elevated ALP and bilirubin.
Cholestasis (Obstructive Liver Disease)
30
In hepatocyte _________, fluid flows into the cell causing it to swell and rupture when osmotic regulation is interrupted. Blebs also form carrying off intracellular debris to extracellular. Macrophages will cluster at these sites of injury.
Necrosis
31
Hepatocyte necrosis is predominant mode of death in what type of injury?
Ischemic/Hypoxic injury
32
Hepatocyte necrosis is a significant part of the response to _______ _______.
Oxidative stress
33
Hepatocyte ________ includes cell shrinkage, nuclear chromatin condensation (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into apoptotic bodies.
Apoptosis
34
What is the term for apoptotic hepatocytes, so named due to their deeply eosinophilic stain?
Acidophil bodies
35
This is the term for apoptotic hepatocytes in yellow fever.
Councilman bodies
36
This type of liver necrosis involves widespread parenchymal loss, and zonal loss of hepatocytes. It may begin as a zone of hepatocyte dropout around the central vein. It produces a space filled with cellular debris, macrophage, and revenants of reticular meshwork. Seen in acute toxic injury, ischemic injuries or viral/autoimmune hepatitis. Also called coagulative necrosis!
Confluent necrosis
37
This type of liver necrosis occurs when vascular insult leads to parenchymal extinction due to large areas of contiguous hepatocyte death, because zone links central veins to portal tracts. There is a collapse of supporting framework that can occur and cirrhosis may result.
Bridging necrosis
38
Hepatocytes are almost stem-cell like in their ability to continue to replicate even in the setting of years of chronic injury, therefore stem cell replenishment is not a significant part of _________ repair.
Parenchymal
39
The principal cell type involved in scar deposition is the...
Hepatic stellate cell
40
In its quiescent form, hepatic stellate cells are a lipid _______ storing cell. However, in several forms of acute and chronic injury, the stellate cells can become activated and are converted into highly fibrogenic _________.
Vitamin A
| Myofibroblasts
41
Regeneration of the liver occurs by what two major mechanisms?
1) Proliferation of remaining hepatocytes
| 2) Repopulation from progenitor cells (canals of Hering)
42
What is the primary intrahepatic stem cell niche?
Canals of Hering
***Severe forms of acute liver failure can activate this!
43
The stimuli for hepatic stellate cell activation are varied and include...
1) Inflammatory cytokines such as TNF-a, produced by Kupffer cells, macrophages, and other cell types
2) Altered interactions with ECM
3) Toxins and ROS
44
It is important to remember that hepatic stellate cell activation and scar deposition is reversible if what happens?
The injurious agent is eliminated!
45
Areas of hepatocyte loss in chronic liver disease, perhaps related to vascular compromise, are transformed into dense _______ _______ through collapse of the underlying reticulin framework and deposition of collagen by myofibroblasts (stellate cells).
Fibrous Septa
46
_______ fibroblasts may also play a role in the scarring that accompanies chronic liver injury in some disorders. Eventually, the fibrous septa encircle surviving hepatocytes and give rise to diffuse scarring (cirrhosis).
Portal
47
In chronic liver disease, surviving hepatocytes replicate in an effort to restore the parenchyma, forming regenerative _________ that are a predominant feature in most cirrhotic livers.
Nodules
48
The most severe form of liver disease is...
Liver failure
49
Liver failure can be acute, due to sudden and massive hepatic destruction, or chronic, following years of insidious progressive liver injury. Which type of liver failure is more common?
Chronic liver failure
50
What percentage of functional capacity is lost before hepatic failure appears?
80-90%
51
When the liver can no longer maintain homeostasis, what offers the best hope for survival?
Liver transplant
52
In liver failure, without a liver transplant, the mortality rate is what percentage?
80%
53
For acute liver failure (ALF), it is associated with __________ and _________ that occurs within 26 weeks (6 months) of the initial liver injury in the absence of pre-existing liver disease. Within this window, knowing the interval between onset of symptoms and liver failure may provide helpful clues to the etiology.
Encephalopathy
| Coagulopathy
54
In the US, 50% of ALF is due to what?
Acetaminophen
***Autoimmune hepatitis, other drugs/toxins, and acute HAV and HBV account for most remaining cases!
55
What is the mnemonic for causes of ALF?
A = Acetaminophen, HAV, Autoimmune hepatitis
B = HBV
C = HCV, Cryptogenic
D = Drugs/toxins, HDV
E = HEV, esoteric causes (Wilson disease, Budd-Chiari)
F = Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)
56
Rarely, ALF is associated with widespread dysfunction of liver cells without obvious cell death, such as in ________ _______ _______ related to fatty liver of pregnancy or in idiosyncratic reactions to toxins (ie, valproate, tetracycline). In these settings, hepatocyte metabolism is severely affected, usually due to __________ dysfunction, preventing the liver from carrying out its normal functions.
Diffuse microvesicular steatosis
| Mitochondrial
57
In states of immunodeficiency, such as untreated HIV, post-transplant immunosuppression, and certain lymphoid malignancies, there are some nonhepatotropic viruses that can cause ALF. What are these viruses?
CMV
HSV
Adenovirus
58
How will a patient present clinically with ALF?
N/V
Jaundice
Pruritus
Elevated LFTs
These progress to life-threatening coagulation abnormalities and hepatic encephalopathy.
59
Why are there life-threatening coagulation abnormalities with ALF?
Because the hepatocytes are involved in the synthesis of most blood coagulation factors, such as fibrinogen, prothrombin (II), Factor V, VII, IX, X, XI, XII, protein C and S, and antithrombin.
***Liver sinusoidal endothelial cells produce Factor VIII and von Willebrand factor!
***Impaired clotting due to lack of production of Vitamin K-dependent factors -- II, VII, XI, X ("1972")
60
What is major sign of hepatic encephalopathy in ALF (due to increased ammonia)?
Asterixis (hand flapping)
61
If ALF is not recognized or treated, what happens?
Leads to multi-organ failure and death
62
What are the sequelae of ALF?
-- Jaundice and icterus
-- Cholestasis = systemic retention of not only bilirubin but other solutes eliminated in bile, can increase risk of life-threatening bacterial infections
-- Hepatic encephalopathy
-- Coagulopathy
-- Disseminated Intravascular Coagulation = liver is responsible for removing activated coagulation factors from the circulation
-- Portal HTN = intrahepatic obstruction most likely; leads to ascites and hepatic encephalopathy
-- Hepatorenal Syndrome = form of renal failure in individuals with liver failure in whom their kidneys are morphologically and functionally normal
63
Chronic liver failure is most often associated with _________, which is just a response to the injury NOT a specific diagnosis.
Cirrhosis
64
Chronic liver failure is the 12th most common cause of mortality in the US. The leading causes of it include...
Chronic HBV
Chronic HCV
NAFLD (Nonalcoholic Fatty Liver Disease)
Alcoholic Liver Disease
65
This is a classification system used to monitor the decline of patients on the path to chronic liver failure. Class A has the fewest points and is well compensated, Class B is partially decompensated, and Class is decompensated. More points is not good!
Child-Turcotte-Pugh classification
66
In chronic liver failure, what percentage are asymptomatic until it has reached advanced stages?
40%
67
Symptoms of Chronic liver failure include the symptoms of ALF plus what?
Portal HTN
68
What are characteristic symptoms of Chronic liver failure?
- - Palmar erythema
- - Spider angiomata
- - Hypogonadism
- - Gynecomastia
Also includes same symptoms as ALF =
- - N/V
- - Jaundice
- - Abnormal LFTs
- - Pruritus
- - Hepatic encephalopathy (asterixis)
- - Coagulation abnormalities
69
Cirrhosis causes ________ in 85% of cases. 500 ml has to present for it to be clinically detectable. It presents with a fluid wave and shifting dullness.
Ascites
***Think Portal HTN!
70
What are the principle sites of shunts due to Portal HTN?
Veins around and within the --
- - Rectum (hemorrhoids)
- - Esophagogastric junction (varices)
- - Retroperitoneum
- - Falciform ligament of liver (involving periumbilical and abdominal wall collaterals)
71
For Portal HTN, long-standing congestion may cause congestive _________. The degree of the enlargement varies widely and may reach as much as 1000 gm, but is not necessarily correlated with other features of portal HTN.
Splenomegaly
72
The massive splenomegaly in portal HTN may secondarily induce _________, which can lead to hematologic abnormalities such as thrombocytopenia and pancytopenia.
Hypersplenism
73
Increased resistance to portal blood flow (portal HTN) may develop in a variety of circumstances, which can be divided into...
Prehepatic
Intrahepatic
Posthepatic
74
What are prehepatic causes of portal HTN?
-- Obstructive thrombosis of Portal V.
-- Structural abnormalities (ie, narrowing) of Portal V. before it ramifies in the liver
75
What are intrahepatic causes of portal HTN?
- - Cirrhosis (most common cause of portal HTN)
- - Schistosomiasis
- - PBC
- - Massive fatty change
- - Malignancy
- - Amyloidosis
etc..
76
What are extra-hepatic causes of portal HTN?
- - Severe right-sided heart failure
- - Constrictive pericarditis
- - Hepatic vein outflow obstruction
77
What are the 4 major clinical consequences of Portal HTN?
- - Ascites
- - Portosystemic shunt formation
- - Congestive splenomegaly
- - Hepatic encephalopathy
78
What are the serious and sometimes fatal sequelae of liver failure?
- - Coagulopathy
- - Encephalopathy
- - Portal HTN
- - Bleeding esophageal varices
- - Hepatorenal syndrome
- - Portopulmonary HTN
79
This type of viral hepatitis is usually benign and self-limited. It does NOT cause chronic hepatitis or lead to a carrier state, and only uncommonly causes ALF (0.1 to 0.3% of patients).
HAV
80
What are the viral characteristics of HAV and how is it spread?
ssRNA
Spread fecal-oral via contaminated water (commonly acquired by travelers)
81
HAV is endemic in countries with poor hygiene and sanitation. In high income countries, the prevalence of seropositivity (indicative of previous exposure) increases gradually with what?
Age -- reaches 50% by 50 yo in US
82
What viral hepatitis can be contracted in high income countries by the consumption of raw or steamed shellfish, which concentrate the virus from seawater contaminated with human sewage?
HAV
83
T/F. Sexual transmission and materna-fetal transmission is common for HAV.
False. Sexual transmission may occur (not common) but maternal-fetal does NOT.
84
Do we screen donated blood for HAV?
No
85
HAV infected individuals have nonspecific symptoms such as fatigue and loss of appetite, and often jaundice. Most recover within 3 months, and disease resolution occurs in nearly all patients by 6 months. ALF occurs in 0.1-0.3% of patients, especially those with _______ _______ _______ due to another etiology.
Chronic liver disease
86
Other uncommon complications of HAV include prolonged ________ and relapse of disease within 6 months of original onset.
Cholestasis
87
What extra-hepatic manifestations of HAV?
-- Rash
-- Arthralgia
-- Immune complex mediated complications (ie, leukocytoclastic vasculitis, glomerulonephritis, and cryoglobulinemia).
88
Is there an effective vaccination for HAV?
Yes
89
This Ab is present for active HAV and signifies infection.
IgM
90
This Ab is protective for HAV, and its presence indicated prior infection or immunization.
IgG
91
HBV infection has varied clinical outcomes, which depends on the age of exposure, comorbid conditions (including exposure to other infectious agents), and host immunity. The major clinical presentations include...
1) Acute hepatitis followed by recovery and clearance of the virus
2) ALF with massive liver necrosis
3) Chronic hepatitis with or without progression to cirrhosis
4) Asymptomatic, "healthy" carrier state
92
Liver disease due to HBV is an enormous global health problem. ______ of the world population have been infected with HBV and _______ people have chronic infection.
1/3 (2 billion)
| 400 million
93
What is the worldwide prevalence for HBV?
Highest (>8%) = Africa, Asia, Western Pacific rim
Moderate (2-7%) = Southern and Eastern Europe
Lower (<2%) = Western Europe, North America, Australia
94
What is the prevalence of HBV in the US?
60,000 new cases each year, and 2 million with chronic infection
95
The mode of transmission of HBV also varies with geographic areas. What are these modes?
High prevalence = Transmission during childbirth accounts for 90%
Intermediate prevalence = Horizontal transmission, especially in early childhood, is predominant
Low prevalence = Unprotected sex and IV drug abuse
***Parenteral transmission!
96
What is the viral characteristics of HBV?
partially dsDNA
97
What is the main determinant of the outcome of the HBV infection for a patient?
Their host immune response to the virus
98
For HBV, high-level viral replication and high production of viral proteins can produce cytopathic changes in infected cells. However, most hepatocyte injury is caused by an attack of ________ cells on infected cells.
CD8+ cytotoxic T cells
99
For HBV, a strong response by virus-specific ______ and ______ ______ producing cells is associated with resolution of acute infection.
CD4+ and CD8+ IFNy
100
This serum marker of HBV appears before the symptoms, peaks during the overt disease, and lasts for about 12 weeks. It is the first serologic marker to rise, if it is present for over 6 months that defines a chronic state of HBV.
HBsAG
101
Is donated blood screened for HBV?
Yes, they test for HBsAG
102
Anti-HBs Ab begins to rise following the resolution of acute disease, generally after the disappearance of HBsAg. What globulin is this?
IgG
***Remeber, ONLY present in resolved stages or immunization. Not present for acute infection or window stage. Present in chronic infection as HBcAb!
103
In some cases, the appearance of anti-HBs Ab is delayed until weeks to months after disappearance of HBsAg. In such instances, the serologic diagnosis can be made by detection of the anti-HBc Ab, which is what globulin?
IgM
***For acute and window periods ONLY, for resolved and chronic stages the anti-HBc Ab is IgG!
104
For HBV, these serology markers are present during acute infection, and may or may not be present during chronic infection. Their presence is indicative of infectivity (whether it can be passed to another person).
HBeAg
| HBV DNA
105
For HBV, Abs to what indicate that the acute disease has peaked and is about wane?
HBeAg Abs
106
T/F. Persistent HBeAg is an indicator of continued viral replication, infectivity, and probably progression to chronic hepatitis. During this, HBeAg Abs are not produced or appear very late in the disease course.
True
107
For HBV, what is the best predictor of chronicity?
Age at time of infection (earlier the age of infection, the more likely for chronicity)
108
T/F. ALF with HBV is common, occurring in approximately 50-60% of acutely infected individuals.
False. ALF with HBV is rare, occurring in approximately 0.1-0.5% of acutely infected individuals.
109
In most cases, HBV infection is self-limited and resolves without treatment. The infection persists and becomes chronic in what percentage?
5 to 10%
110
The risk of chronic infection of HBV is inversely related to age and is greatest (approx. 90%) in infants who are exposed to the virus via what type of transmission?
From their mothers at birth (vertical transmission)
111
Individuals who acquire HBV at birth and who subsequently develop chronic hepatitis are also at greatest risk of developing ________ ________, which is one of the most common and deadliest cancers in parts of the world such as China where perinatal transmission occurs frequently.
Hepatocellular Carcinoma
112
HBV vaccination is highly effective, as it induces a protective ________ Ab response in 95% of infants, children, and adolescents.
Anti-HBs
***This is IgG!
113
In those with chronic HBV, treatment with interferon and antiviral agents such as ________ ________ ________ (entecavir or tenofovir) can slow disease progression, reduce liver damage, and lower the risk of HCC, but complete cure is difficult.
Reverse transcriptase inhibitors
114
In chronic HBV, liver biopsy shows hepatocytes packed with HBsAg that have what appearance?
Finely granular "ground glass" appearance
115
This is the most common cause of chronic viral hepatitis.
HCV
116
HCV rarely causes symptomatic...
Acute hepatitis
117
What are the viral characteristics and modes of transmission for HCV?
ssRNA
Transmission =
- - IV drug abuse (54%)
- - Sexual transmission, especially MSM (36%)
- - Surgery in last 6 months (16%)
- - Needle stick (10% -- 10x greater risk with HIV)
- - Contacts with HCV infected person (10%)
- - Employment in medical field (1.5%)
- - Unknown (32%)
***Parenterally!
118
Acute HCV infection is asymptomatic in about 85% of individuals, and severe acute hepatitis is rare. Persistent infection and chronic hepatitis are the hallmarks of HCV infection, despite the generally asymptomatic nature of the acute illness. Chronic disease occurs in the majority of HCV-infected individuals (80-90%) and _________ eventually occurs in as many as 20% of individuals with chronic HCV (20-30 years).
Cirrhosis
119
What serological test is used to confirm HCV infection?
HCV-RNA = decreased RNA levels indicate recovery, and persistence indicates chronic disease
120
What things are associated with HCV chronic infection progression?
- - Males
- - Older age
- - Alcohol use
- - Immunosuppressive drugs
- - Hepatitis B/HIV co-infection
- - Diseases associated with insulin resistance (obesity, T2DM, metabolic syndrome)
121
Those who develop cirrhosis in chronic HCV, are at risk for development of...
HCC
122
Although the overall risk is small, in the US, HCV is responsible for about ________ of the cases of liver cancer.
1/3
123
Because of the low fidelity of the HCV _______ _______, the virus is inherently unstable, giving rise to multiple genotypes and subtypes (hence why there is no vaccine available).
RNA polymerase
124
This is a unique RNA virus that is dependent for its life cycle on HBV.
HDV (the "delta agent")
125
It is estimated that 5% of HBV-infected individuals are co-infected with _______, which amounts to approximately 15 million people worldwide. Highest prevalence is Amazon basin, central Africa, the Middle East, and the Mediterranean basin.
HDV
126
What are the 2 ways of acquiring HDV?
-- Superinfection upon existing HBV (this is more severe than co-infection)
-- Co-infection of HBV and HDV at the same time
127
This type of viral hepatitis is an enterically transmitted, water-borne infection that occurs primarily in young to middle-aged adults.
HEV
128
______ infection accounts for more than 30% of cases of sporadic acute hepatitis in India, exceeding the frequency of HAV.
HEV
129
HEV does not cause chronic liver disease or persistent viremia in immunocompetent patients. However, acute HEV infection is associated with a mortality rate approaching 20% among who?
Pregnant women
130
HEV infection in pregnant women is associated with ________ ________, which is liver failure with massive liver necrosis.
Fulminant hepatitis
131
Because of the similar transmission mode and the similar high-risk patient population, co-infection of ______ and hepatitis viruses has become a common clinical problem.
HIV
132
In the US, 10% of HIV-infected individuals are co-infected with ______ and 25% with ______.
HBV
| HCV
133
T/F. Chronic HBV and HCV infection are now leading causes of morbidity and mortality for HIV-infected individuals, even those who are on successful anti-HIV therapy.
True
134
In individuals who are untreated or resistant to treatment and who therefore progress to AIDS, ______ ______ is the 2nd most common cause of death.
Liver disease
135
In immunocompetent individuals with HIV infection, the differences in severity and progression of either HBV or HCV may not differ greatly from those who are...
HIV negative
136
Acute and chronic hepatitis changes are similar among viruses and other non-viral entities. What are these features?
Both =
- - Macrophage aggregates
- - Apoptosis
Acute =
- - Ballooning degeneration
- - Cholestasis
Chronic =
- - Portal fibrosis
- - Bridging fibrosis and necrosis
- - Ground-glass cells (HBV)
- - Fatty change (HCV)
137
Chronic hepatitis hallmark is increased _______ chronic inflammation.
Portal
138
The hallmark of progressive chronic liver damage is...
Scarring
139
The defining histologic feature of chronic viral hepatitis is portal lymphocytic, or lymphoplasmacytic, inflammation with ________.
Fibrosis
140
Interface hepatitis, or _______ ______ of the liver is associated with a lymphocytic infiltrate into the adjacent parenchyma and with destruction of individual hepatocytes along the edges of the portal tract. It is a feature of viral hepatitis (especially chronic) as well as autoimmune hepatitis and steatohepatitis.
Piecemeal necrosis
141
Several bacteria can infect the liver directly, including ________ ________ in TSS, ________ _______ in typhoid fever, and ________ ________ in secondary or tertiary syphilis.
Staph aureus
Salmonella typhi
Treponema pallidum
142
Bacteria may also proliferate in the biliary tree, especially when outflow is compromised by partial or complete obstruction. The intra-biliary composition reflects the gut flora, and the acute inflammatory response within the intrahepatic biliary tree is called...
Ascending cholangitis
143
Liver _______ are associated with fever, RUQ pain, and tender hepatomegaly. Bacteria gives rise to these by spreading from extrahepatic sites, through the vascular supply, or from adjacent infected tissues.
Abscesses
***Antibiotics are good for small lesions, but surgical drainage may be required for larger lesions!
144
Bacteria, fungi, helminths, and other parasites/protozoa can involve the liver and biliary tree as localized infection or as part of a _______ disease.
Systemic
145
Parasitic and helminthic infections that can involve the liver include...
- - Malaria
- - Schistosomiasis (Asia, Africa, South America)
- - Strongyloidiasis
- - Cryptosporidiosis
- - Leishmaniasis
- - Echinococcosis
- - Amebiasis
- - Liver flukes (Southeast Asia) = Fasciola hepatica, Opisthorchis species, and Clonorchis sinensis
146
Liver flukes are notorious for causing a very high rate of what cancer?
Cholangiocarcinoma
147
_______ _______ are usually caused by Echinococcal infections. They often have calcifications in their walls which may aid in radiologic diagnosis.
Hydatid cysts
***Clinically do NOT biopsy these! If it opens and spreads it is BAD!
148
This type of liver injury is a major cause of ALF in the US.
Drug or toxin-induced liver injury
149
The pattern of liver injury varies (due to drugs, herbs, supplements, industrial products, etc.) but in most instances the injury is mediated by reactive metabolites generated in the liver. The cytochrome family of enzymes, particularly _______, is involved in most of these metabolic reactions. Since they are more active in the central zone of the lobule, necrosis typically occurs in _______. This is a typical feature of drug-induced liver injury.
CYP450
| Zone 3
150
Based on US Drug Induced Liver Injury Network data, 10% of the patients with drug-induced liver injury die or require liver transplantation, and 17% go on to develop...
Chronic liver disease
151
What associated agents can cause hepatocellular adenoma?
Oral contraceptives
| Anabolic steroids
152
What associated agents can cause hepatocellular carcinoma?
Alcohol
| Thorotrast
153
What associated agents can cause cholangiocarcinoma?
Thorotrast
154
What associated agents can cause angiosarcoma (hepatic)?
Thorotrast
| Vinyl chloride
155
Antimicrobial drugs are the most common culprits in _________ reactions, accounting for nearly one-half of cases. Other commonly implicated agents include cardiovascular drugs, CNS agents, antineoplastic drugs, and analgesics (ie, NSAIDs). A wide variety of herbal and nutritional agents have also been implicated.
Idiosyncratic
156
Liver injury may result from direct toxicity, occur through hepatic conversion of a ________ to an active toxin, or be produced by immune mechanisms, such as by the drug or a metabolite acting as a ________ to convert a cellular protein into an immunogen.
Xenobiotic
| Hapten
157
Exposure to a toxin (herbal, dietary, topical, environmental) or therapeutic agent should always be included in the _______ of any form of liver disease.
ddx
158
A classic, predictable hepatotoxin is __________, now the most common cause of acute liver failure necessitating transplantation in the United States.
Acetaminophen
159
The toxic agent is not acetaminophen itself but rather a toxic metabolite produced by the ________ system in acinus zone 3 hepatocytes. As these hepatocytes die, the zone 2 hepatocytes take over this metabolic function, in turn becoming injured. In severe overdoses, the zone of injury extends to the periportal hepatocytes, resulting in acute hepatic failure.
CYP450
160
This is a major cause of liver disease in most Western countries. It accounts for 5.9% of deaths globally and more often leads to death and disability earlier in life than other forms of chronic liver injury.
Excessive alcohol consumption
161
Only 10-15% of alcoholics develop _________. This depends on quantity and time, gender, ethnicity and genetics, and co-morbidities.
Cirrhosis
162
What happens to a normal liver after severe exposure to alcohol? Is it reversible?
Hepatitis -- liver cell necrosis, inflammation, Mallory bodies, fatty change
Yes can be reversed back to normal liver or to steatosis.
163
What happens to the liver after having repeated hepatitis attacks due to severe alcohol exposure? Is it reversible?
Cirrhosis -- fibrosis, hyperplastic nodules
No cannot be reversed.
164
What happens to a normal liver that is exposed to alcohol? Is it reversible?
Steatosis -- fatty change, perivenular fibrosis, hepatomegaly
Yes can be reversed back to a normal liver.
165
What happens to a steatosis liver that has severe exposure to alcohol? Is it reversible?
Hepatitis -- liver cell necrosis, inflammation, Mallory bodies, fatty change
Yes can be reversed back to steatosis or to a normal liver.
166
What happens to a steatosis liver that has continued exposure to alcohol? Is it reversible?
Cirrhosis -- fibrosis, hyperplastic nodules
No cannot be reversed.
167
What is the ONLY way for a liver that has hepatitis or steatosis to go back to normal?
STOP drinking alcohol!
168
The main enzyme involved in alcohol metabolism is ________ ________, located in the cytosol of hepatocytes. At high blood alcohol levels, however, the microsomal ethanol-oxidizing system also plays an important role. This system involves CYP450 enzymes, mainly ________, located in the SER.
Alcohol dehydrogenase
| CYP2E1
169
Induction of _______ enzymes by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system, which include drugs (acetaminophen, cocaine), anesthetics, carcinogens, and industrial solvents.
CYP450
***If P450 enzymes are being used up by alcohol, other meds that use it can easily become toxic!
170
When alcohol is present in the blood at high concentrations, it competes with other ________ substrates and may delay the catabolism of other drugs, thereby potentiating their effects.
CYP2E1
171
What are the 3 forms of alcohol related liver disease?
1) Steatosis
2) Steatohepatitis
3) Steatofibrosis/Cirrhosis
172
What are the clinical features of Steatosis?
- - Hepatomegaly with minimal symptoms
| - - Mildly elevated bilirubin and ALP
173
What are the clinical features of Steatohepatitis?
- - Tender hepatomegaly
- - (+/-) Cholestasis
- - Hyperbilirubinemia
- - Mallory bodies
- - ***AST>ALT (2:1)*** and elevated ALP
174
What are the clinical features of Steatofibrosis/Cirrhosis?
-- Labs reveal hepatic dysfunction if enough liver tissue left
-- Hypoproteinemia
-- Coagulation abnormalities
175
These are a characteristic finding in alcoholic steatohepatitis. They are intracellular eosinophilic aggregates of intermediate filaments in ballooning hepatocytes.
Mallory (Denk) bodies
176
What is the metabolite of alcohol that causes the damage to the liver in alcoholic hepatitis?
Acetaldehyde
177
In advanced alcohol-related liver disease, what are the common proximate causes of death?
1) Hepatic coma
2) Massive GI hemorrhage
3) Intercurrent infection (predisposed to infx)
4) Hepatorenal syndrome after bout w/ hepatitis
5) HCC
178
(ACUTE/CHRONIC) alcoholism exerts its effects mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued.
Acute
179
(ACUTE/CHRONIC) affects not only the liver and stomach, but virtually all other organs and tissues as well.
Chronic
180
T/F. Chronic alcoholics suffer significant morbidity and have a shortened lifespan, related principally to damage to the liver, GI tract, CNS, cardiovascular system, and pancreas.
True
181
What vitamin is often deficient in chronic alcoholics? Leading to peripheral neuropathies and Wernicke-Korsakoff.
Thiamine (Vitamin B1)
182
This is a metabolic liver disease that is acquired. It is the most common cause of chronic liver disease in the US, affecting 3-5% of the population (30% projected by 2030).
NAFLD (Nonalcoholic fatty liver disease)
183
This disease is defined as the presence of hepatic steatosis (fatty liver) in individuals who do NOT consume alcohol or do so in small quantities and who do not have another cause of secondary hepatic fat accumulation.
NAFLD
184
What are the WHO criteria for diagnosis of the metabolic syndrome?
One of =
- - Diabetes mellitus
- - Impaired glucose tolerance
- - Impaired fasting glucose
- - Insulin resistance
Two of =
- - BP > 140/90
- - TGs > 1.695 and HDL <0.9 (male), <1.0 (female)
- - Waist-hip ratio >0.9 (male), >0.85 (female), or BMI >30
- - Microalbuminuria: Urinary albumin excretion >20 or albumin:Cr >30
185
Over 80% of NAFLD cases have an isolated _______ ______, which has none to very minimal progression to cirrhosis and no increased risk of death compared with the general population.
Fatty liver
186
NAFLD can also develop into ________, which is NAFLD with inflammation. It almost completely overlaps in its histologic features with alcoholic hepatitis.
NASH (Nonalcoholic Steatohepatitis)
187
About 11% of NASH patients will develop ________ over 15 years, but with significant variability. About 31% of these patients will then need __________ or about 7% will develop ________.
Cirrhosis
Transplantation
HCC
188
It is possible for NASH without cirrhosis to develop directly into...
HCC
189
Determination of the extent of fibrosis is important for clinical management. Fibrosis typically develops around the central vein as a fine "spider web" of pericellular collagen deposition. Also referred to as a _______ _______ pattern.
Chicken wire
190
Progression of fibrosis usually manifests as ________ fibrosis, followed by ________ fibrosis and cirrhosis. Cirrhosis is often subclinical for years, and when established the steatosis or ballooned hepatocytes may be reduced or absent.
Periportal
| Bridging
191
More than 90% of cases labeled as "cryptogenic cirrhosis" are thought to be due to ________.
NASH ("burned out NASH")
192
Pediatric NAFLD differs significantly from adult NAFLD. Typically, children show more diffuse steatosis and _______ rather than central fibrosis, and ballooned hepatocytes may not be present.
Portal
193
NAFLD is asymptomatic except for signs and symptoms associated with ________ ________.
Metabolic Syndrome
194
Early _______ is asymptomatic except for elevated LFTs and nonspecific complaints of malaise and RUQ fullness/discomfort.
NASH
195
This is an inherited or acquired metabolic disorder that is caused by excessive iron absorption in parenchymal organs such as the liver and pancreas, followed by heart, joints, and endocrine organs.
Hemochromatosis
196
Hemochromatosis has a primary and secondary form, what are these?
Primary = Hereditary (issues with the iron absorption mechanism)
Secondary = Overconsumption of iron (via transfusions usually)
197
The total body iron pool ranges from 2-6 g in normal adults, with about 0.5 g being stored in the liver (98% is in hepatocytes). In severe hemochromatosis, the total iron pool may exceed _______, more than 1/3 of which accumulates in the liver.
50 g
198
Because there is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. In _________ hemochromatosis, regulation of intestinal absorption of dietary iron is abnormal, leading to net iron accumulation of 0.5 to 1 gm/year. The disease typically manifests after 20g of stored iron has accumulated.
Hereditary (Primary)
199
Mechanisms of liver injury due to hemochromatosis include...
1) Lipid peroxidation via iron-catalyzed free radical reactions.
2) Stimulation of collagen formation by activation of hepatic stellate cells.
3) Interaction of ROS and iron itself with DNA.
***Lead to lethal cell injury and predisposition to HCC.
200
The main regulator of iron absorption is the protein ________, encoded by the ________ gene and produced and secreted by the liver.
Hepcidin
| HAMP
201
The adult form of hemochromatosis is usually caused by mutations of the _______ gene, who product is involved in intestinal iron uptake by its effects on hepcidin levels.
HFE
202
The most common HFE mutation is a ________ to ________ substitution at amino acid _______, which is largely confined to Caucasian populations of European origin.
Cysteine
Tyrosine
282
***Called C282Y
203
The principal manifestations of hemochromatosis include...
- - Hepatomegaly
- - Abnormal skin pigmentation
- - Deranged glucose homeostasis or DM
- - Cardiac dysfunction
- - Atypical arthritis
204
In some patients, the presenting complaint of hemochromatosis is related to _________. It is more often a disease of males and rarely becomes evident before age 40.
Hypogonadism (amenorrhea in females and impotence and loss of libido in males)
205
In hemochromatosis, what is the classic tetrad included with cirrhosis? Develop later in the disease and death may result from cirrhosis or cardiac disease.
1) Hepatomegaly
2) Abnormal skin pigmentation
3) DM
4) Cardiac dysfunction
206
High levels of dietary iron stimulate an increase in hepcidin synthesis, which suppresses the absorption of iron by decreasing the expression of _________, a membrane-bound iron-transporting protein channel. Conversely, low levels of iron keep hepcidin levels low, which stimulates the absorption of iron due to elevated levels of ________.
Ferroportin
Ferroportin
***Hepcidin and Ferroportin/Iron absorption inversely proportional, while Ferroportin and Iron absorption are directly proportional!
207
Screening for hemochromatosis involves demonstration of very high levels of ______ ______ and _______, exclusion of secondary causes of iron overload, and liver biopsy (quantitative hepatic iron) if indicated. However, newly available genetic testing has made the live biopsy no longer necessary for diagnosis.
Serum iron
| Ferritin
208
T/F. It is not important to screen family members of probands for hemochromatosis. It is not common among multiple family members.
False. It is important to screen family members!
209
What stain is used in diagnosing hereditary hemochromatosis and makes the hepatocellular iron appear blue?
Prussian blue stain
210
The second and third most abundant microelements in the body are ______ and ______, respectively. They both serve as cofactors for the activity of many enzymes.
Zn
| Cu
211
This is an autosomal recessive disorder caused by a gene mutation that results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin (transporter for copper).
Wilson disease
212
What gene is mutated in Wilson disease?
ATP7B
213
Wilson disease affects approximately 9000 patients in the US. It is marked by the accumulation of toxic levels of _______ in many tissues and organs, principally the liver, brain, and eye (also kidney, bones, joints, and parathyroid glands).
Copper
214
Copper can also be toxic to RBC due to damage caused by oxidants produced by free copper, causing...
Hemolytic anemia
215
The clinical presentation of Wilson disease is extremely variable. The age at onset ranges from ______ to ______ years old. Some patients present with acute or chronic liver disease. Neurologic involvement may lead to movement disorders or rigid dystonia. May also have psychiatric symptoms.
6 to 40 (average age is 11)
216
The biochemical diagnosis of Wilson disease is usually based on the presence of decreased serum __________, increased hepatic ________ content (the most sensitive and accurate test), and increased _________ excretion of copper (the most specific test). Sequencing of the ________ gene is now available for cases in which results of biochemical tests are indeterminate.
Ceruloplasmin
Copper
Urinary
ATP7B
217
This disease is an autosomal recessive disorder of protein folding.
Alpha1-Antitrypsin deficiency
218
Alpha1AT deficiency leads to the development of ________ ________, because the activity of destructive proteases is not inhibited. The liver disease is a result of the accumulation of the misfolded protein in hepatocytes.
Pulmonary emphysema
219
The major function of Alpha1AT is the inhibition of proteases, particularly ________, ________, and ________, which are normally released from neutrophils at sites of inflammation.
Elastase
Cathepsin G
Proteinase 3
220
The most common clinically significant mutation for Alpha1AT deficiency is _____. People homozygous for the ______ protein have circulating Alpha1AT levels that are only 10% of normal. These individuals are at high risk for developing clinical disease.
PiZ
| PiZZ
221
The wild-type allele for Alpha1AT is ______, which is in 90% of people. Expression of alleles can also be co-dominant, and, consequently ______ heterozygotes have intermediate plasma levels of Alpha1AT.
PiMM
| PiMZ
222
Among people of northern ________ descent, the PiZZ state affects 1 in 1800 live births.
European
223
Because of its early presentation with liver disease, Alpha1AT deficiency is the most commonly diagnosed inherited hepatic disorder in...
Infants and children
224
Alpha1AT deficiency occurs due to a point mutation of _______ to _______. The mutant polypeptide (Alpha1AT-Z) is abnormally folded and polymerized, creating endoplasmic reticulum stress and triggering the unfolded protein response (UPR), a signaling cascade that may lead to apoptosis.
Glu342
| Lys342
225
Neonatal presentations of Alpha1AT tend to be associated with hepatitis and rapid progression to cirrhosis, along with _______ _______ (10-20% of newborns).
Cholestatic jaundice
226
In adolescence, Alpha1AT presents with...
- - Hepatitis
- - Cirrhosis
- - Pulmonary disease
227
In middle to late life, Alpha1AT presents with...
Cirrhosis with or without HCC
228
Morphologically, to diagnose Alpha1AT deficiency, ________ stain is used after diastase digestion of the liver, which highlights the characteristic magenta cytoplasmic granules.
PAS (Periodic Acid-Schiff)
