Liver Path 1 part 2 Flashcards
Acute vs Chronic Hepatitis
Time Course
Acute: New liver disease
within 26 weeks of initial injury
Usually heals completely due to hepatic regeneration
Chronic: Persistent liver disease
> 26 weeks
May evolve through fibrosis to:
Cirrhosis
Complications of cirrhosis
Hepatocellular carcinoma
acute hepatitis is NOT acute liver failure
Symptoms of Acute Hepatitis
Asymptomatic (abnormal LFTs only)
Nonspecific constitutional symptoms
- Fever
- Nausea/vomiting
- Fatigue
Physical findings
- Jaundice
- Tender liver
- Altered mental status/coma (hepatic encephalopathy)
- Bleeding, thombosis
Uncommon
- Headaches, myalgias, arthritis
- Rash, urticaria, arthritis
Acute Hepatitis: Correlation of Clinical Symptoms
to Degree of Hepatocyte Necrosis
mild hepatitis- asymptomatic, under 500 AST/ALT
Moderate hepatitis: fatigue, nausea, moderate jaundice, normal PT- over 1,000 AST/ALT
Acute liver failure- fatigue, nausea, vomiting, abd pain, severe jaundice, elevated PT, coma/ death
ALT and AST
Aminotransferases
AST: liver, muscle, RBC: Enzyme in amino acid metabolism.
ALT: primarily Liver; glutamate and pyruvate metabolism in the alanine cycle
Chronic Liver Disease
Liver injury tests (AST/ALT) tend to be low to moderate but persist for months/years
Daily symptoms often mild or even absent
Hepatic regeneration occurs but may or may not equal injury
Long-term: new symptoms may arise due to liver dysfunction and/or as consequences of cirrhosis
Numerous etiologies of Chronic Liver Disease
Hepatitis C is called “the silent epidemic.”
Three-quarters of people infected with hepatitis C don’t know they have it because they can have no symptoms for years.
There are usually no symptoms of cirrhosis in its early stage
Autoimmune hepatitis can present insidiously or be rapidly progressive
Up to 10 percent of all children in the nation have non-alcoholic fatty liver disease. NAFLD is the leading cause of chronic liver disease in childrenand adultsin the United States.
(Obesity major cause of NAFLD)
Histological Manifestations of Liver Injury
Inflammation (Portal tracts, Interface between portal tracts and parenchyma, Within the parenchyma), cholestasis
Hepatocellular injury (Ballooning degeneration, Steatosis, Cholestasis, Inclusions) (reversible)
Necrosis (the cell swells due to defective osmotic regulation. This form of injury is the predominant mode of death in ischemic/hypoxic injury and a significant part of the response to oxidative stress.) and apotosis (cell death) (an active form of “programmed” cell death (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into acidophilicapoptotic bodies.)
Regeneration
Fibrosis
Neoplasia
Hepatic Injury–> Limited Repertoire of Responses :
Degenerative, but potentially reversible changes, (steatosis) and bilirubin (cholestasis).
When injury is not reversible, hepatocytes die principally by two mechanisms
necrosis or apoptosis.
Steatosis- causes
Non-alcoholic
fatty liver
Alcohol
Drugs
Viruses
Steatosis- def’n, how it comes about
Steatosis is abnormal accumulation of triglycerides in the liver.
EtOH, NASH, Drugs
Defects in fatty acid metabolism are responsible for pathogenesis of fatty liver disease, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased
Hepatocytes are distended by single large fat droplets, which displace the cell nucleus to the side. As fat is dissolved during routine tissue processing, a clear space only remains. (H&E).
Steatosis is very common and once thought to be indicative of excess alcohol. It is now known that steatosis and steatohepatitis are commonly found in patients with type 2 diabetes mellitus, obesity and the metabolic syndrome. Can progress to fibrosis and cirrhosis
This whole spectrum has been referred to asnon-alcoholic fatty liver disease(NAFLD) and the hepatitis subset asnon-alcoholic steatohepatitis(NASH).
Microvesicular steatosis - causes
Reye Syndrome
Tetracycline toxicity
Fatty change of pregnancy
Numerous drugs including
Ectasy
Aflatoxins
Acute liver failure WITHOUT necrosis
Microvesicular steatosis
generally a serious condition with hepatic dysfunction and coma and one which is often associated with impaired β-oxidation of lipids.
Associated with aspirin use in children (Reye syndrome)
Alcoholic hepatitis
which many hepatocytes are markedly ballooned, with rounded plasma membrane contours, cleared-out cytoplasm and clumped strands of intermediate filaments (some of which would qualify as Mallory–Denk bodies).
Interspersed among the ballooned hepatocytes are neutrophils and lymphocytes cells and fibrous tissue.
Mild injury to hepatocytes, cholangiocytes, or the endothelium and mesenchyme may be met with complete recovery of the organ.
There may also be complete recovery of the liver following massive hepatocellular death provided that inflammatory and fibrogenic pathways are not initiated.
What does acute hepatitis look like?
lobular disarray
Apoptosis = active form of cell death: cytoplasmic shrinkage, cell membrane blebbing, chromatin condensation), nuclear fragmentation , and cellular fragmentation into small membrane-bound ‘apoptotic bodies’
These characteristic changes (Apoptosis) are the result of activation of caspases and endonucleases Hep C, apoptosis recent cell death, apoptotic bodies cleared quickly
In the liver, hepatocellular apoptotic bodies have long been referred to as
acidophilic bodies or Councilman bodies.
Identification of apoptotic bodies indicates
current and ongoing hepatocellular apoptosis, since apoptotic hepatocytes are engulfed within a matter of hours by Kupffer cells or other macrophages.
good indicator of cholestatic liver disease
Alkaline phosphatase
Hepatocellular Biliary Injury: Cholestasis
Necrosisper seis not necessarily a feature of cholestatic liver disease, but hepatocellular apoptosis with appearance of acidophilic bodies is often present, attributed to the * direct toxic effect of retained bile acids on hepatocytes.
Pigmentation includes * accumulation of bilirubin and its glucuronides in hepatocytes, inspissated bile in swollen canaliculi, and bile regurgitation into the sinusoidal space with phagocytosis by Kupffer cells.
Such pigmentation occurs predominantly in the * perivenular region of the hepatic lobule, as does dilatation of bile canaliculi.
During severe cholestasis of long duration, bilirubin deposition and * canalicular dilatation may extend into the * periportal region.
A patient with distended bile canaliculus
Theyellow-green globular materialseen within small bile ductules in the liver is bilirubin pigment. This is hepatic cholestasis.
A problem with excretion of bile, or an obstruction to flow of bile, could cause this appearance.
This patient would exhibit jaundice
Portal Inflammation
Chronic viral hepatitis. Mononuclear portal inflammation is variable; lymphoid aggregates, sometimes with germinal centers, are common in hepatitis C.
Different forms of peri- portal chronic inflammation sometimes the mononuclear inflammatory cells will infiltrate the bile duct epithelium as seen in some autoimmune diseases and sometimes a chronic inflammatory cells can cause the hepatocytes adjacent to the portal zone to be injured and show early signs of necrosis
this is called piecemeal piecemeal necrosis, correlates with active cellular injury while in other cases there is just increased numbers of inflammatory cells without obvious cell injury.
Interface hepatitis in chronic viral hepatitis.
Previously referred to as ‘piecemeal necrosis’, this lesion can often be observed at low power, evidenced by irregular contours of a portal tract containing a dense mononuclear cell infiltrate eroding the limiting plate of hepatocytes in a piecemeal fashion.
Liver After Hepatocellular Injury: Progression to Cirrhosis
This trichrome stain of the liver demonstrates bridging fibrosis.
While regeneration may be viewed as a beneficial step to recovery, a central and perhaps defining detrimental process in progressive chronic liver disease is fibrosis.
However, if the hepatic injury persists, liver regeneration may fail to restore lost tissue and matrix deposition becomes more extensive, akin to the formation of scar in the liver.
As chronic liver disease advances, excess type I and III collagens are laid down not only in portal tracts but also in the lobule, creating both fibrous septal tracts and severe alterations to sinusoidal ultrastructure.
Liver Fibrogenesis
Hepatic stellate cells, residing in the space of Disse, normally are quiescent, fat-storing cells (Vitamin A). Ito cells
In several forms of acute and chronic injury, the stellate cells can become activated and are converted into highly fibrogenic myofibroblasts.
If injury persists, scar deposition begins, often in the space of Disse.
This is particularly important in alcoholic and nonalcoholic fatty liver diseases, but is also a generalized mechanism of scar formation in other forms of chronic liver injury.
What makes HSCs undergo the transition from a quiescent to activated
state.
multiple injurious insults and/or exposure to
inflammatory cytokines such as platelet-derived growth
factor (PDGF), transforming growth factor (TGF)-β,
tumor necrosis factor (TNF)-α, and interleukin (IL)-1
HSC activation is a pivotal event in
initiation and
progression of hepatic fibrosis and a major contributor
to collagen deposition[30,31]. Activation of HSCs is characterized
by cell proliferation and migration, contraction
after transforming into myofibroblasts, generation of a
large amount of collagen and other extracellular matrix
(ECM), ultimately leading to liver fibrosis
strongest known inducer of fibrogenesis in hepatic fibrosis
TGF-beta
Given the critical role of
TGF-β1 in the pathogenesis of liver cirrhosis, specific
blockade of TGF-β1/Smad3 signaling has shown some
therapeutic value for liver fibrosis
Current Thinking on Cirrhosis
Activation of stellate cells is the pivotal event in the initiation and progression of cirrhosis
Animal and clinical evidence has confirmed that any degree of fibrosis and even cirrhosis are potentially reversible by reasonable therapeutic strategies
In clinical circumstances where an effective treatment for the underlying insult is available, remodelling of the scar tissue can occur and a return towards architectural normality has been documented even in advanced fibrosis and cirrhosis.
Galectin-3
is a protein that binds to terminal galactose residues on glycoproteins and is highly expressed in macrophages
Mouse experiments have shown that galectin-3 is
a critical protein in fibrogenesis in multiple organs, including liver fibrosis due to toxins and NASH
**GR-MD-02 is a complex carbohydrate drug containing terminal galactose residues that binds to galectin-3 and inhibits its function
The key features of stellate cell activation are:
(1) robust mitotic activity in areas developing new parenchymal fibrosis
(2) a shift from the resting-state ‘lipocyte’ phenotype to a transitional myofibroblast phenotype
(3) increased capacity for synthesis and secretion of extracellular matrix.
It is predominantly the cytokines secreted by activated Kupffer cells and other inflammatory cells that stimulate the stellate cells to divide and to secrete large amounts of extracellular matrix.
End result of myofibroblast activation.
cirrhosis
parenchymal extinction
the loss of parenchyma due to microscopic areas of ischemia after vascular inflammatory injury and occlusion
Scarring in areas of hepatocyte dropout and collapse of the lobular unit (PV and CV come close together)
Hepatocyte hyperplasia of viable cells elongate the scars into fibrous septae and bridging fibrosis
Parenchymal extinction results from
the presence of widespread imbalance of hepatic blood flow where inflow exceeds the outflow capacity
Cirrhosis is characterized by
diffuse nodular regeneration surrounded by dense fibrotic septae with subsequent parenchymal extinction
and collapse of liver structures causing pronounced distortion of hepatic vascular architecture which leads to increased resistance to portal blood flow and subsequent portal hypertension
Cirrhosis classifications and most common causes of death
compensatedordecompensated
Most common cause of death in compensated cirrhosis is cardiovascular disease, followed by stroke, malignancy, and renal disease.
Complications of portal hypertension, hepatocellular carcinoma, and sepsisare the usual causes of mortality in patients with decompensated cirrhosis.
Most deaths in patients with cirrhosis occur as a result of
hepatic decompensation
Decompensated cirrhosis has complications of variceal hemorrhage, ascites, encephalopathy, jaundice, or hepatocellular carcinoma characterizes.
Compensated cirrhosis does not have the above complications.
Hepatic Venous Wedge Pressure
is a strong independent prognostic indicator in compensated and decompensated cirrhosis in predicting complications and mortality.
The pressure gradient between the portal vein and the inferior vena cava represents the liver portal perfusion pressure
Moreover, HVPG changes parallels changes in histology after effective antiviral therapy and showed a significant HVPG reduction after effective antiviral therapy in patients with advanced chronic HCV hepatitis.
Thus, serial HVPG measurements allow evaluating progression/regression in chronic hepatitis C and evaluating the response to antiviral treatment.
Child-Turcotte-Pugh Classification
Assessment of Prognosis of Cirrhosis
points for each parameter: encephalopathy, ascites, bilirubin, albumin, PT (see proonged) or INR
Portal Hypertension- prehepatic causes
Increased Resistance to Portal Blood Flow
Portal vein thrombosis
Narrowing of the portal vein
portal hypertension- intrahepatic causes
Cirrhosis, accounts for most cases of portal hypertension
Sinusoidal obstruction
portal hypertension- posthepatic causes
Severe right-sided heart failure
Constrictive pericarditis
Hepatic vein outflow obstruction
Portal Hypertension in Cirrhosis Mechanisms
Increased resistance to portal flow at the level of the sinusoid
Compression of the central vein by perivenular fibrosis and parenchymal nodules
Anastomoses between arterial and portal systems imposing high pressure on a low pressure system
Clinical Consequences of Portal Hypertension
Portosystemic venous shunts
- Congestive splenomegaly
- Ascites
- Hepatic encephalopathy
If obstruction is predominantly intrahepatic the major clinical consequences are
ascites and hepatic encephalopathy
Portosystemic venous shunts develop
wherever the systemic and portal circulation share common capillary beds
Congestive splenomegaly leads to Thrombocytopenia
Hepatic encephalopathy correlates with accumulation of ammonia
Chronic liver failure complications estrogen, etc
Portacaval
Anastomoses
Para-umbilical
Esophageal
Retroperitoneal
Rectal
One of the most common causes for splenomegaly is
portal hypertension with cirrhosis of the liver.
Micronodular cirrhosis from chronic alcoholism is more common in the U.S. than macronodular cirrhosis following hepatitis B or C infection. (Lots of overlap between micronodular and macronodular)
Note that this spleen also shows irregular tan-white fibrous plaques over the purple surface.
This “sugar icing” has the name hyaline perisplenitis. (Significance ?? Multiple episodes of peritonitis)
Pathophysiology
of ascites
Sinusoidal hypertension drives fluid into the space of Disse where lymph flow exceeds thoracic duct capacity
Splanchnic vasodilation and hyperdynamic circulation leads to increased perfusion pressure of interstitial capillaries causing fluid extravasation in peritoneum
Decreased plasma oncotic pressure
Increased aldosterone leads to increased sodium reabsorption and increased intravascular volume
Chronic Liver Failure Syndromes
Hepatopulmonary syndrome
Portopulmonary hypertension
Hepatopulmonary Syndrome:
30% of patients with cirrhosis
Intrapulmonary vascular dilation–> rapid blood flow–> poor Hb oxygenation–> Hypoxia
Unknown pathogenesis
Portopulmonary hypertension
Related to portal hypertension
?Excessive pulmonary vasoconstriction
Dyspnea on exertion (DOE)
* Clubbing of fingers
