Hepatic Pathology

Galectin-3

((Don't need to know this. All you need to know is that *cirrhosis is reversible*.)) -Basically, is a thing that causes fibrosis. -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 *(promotes stellate cell activation)*

Manifestations of Acute Liver Failure - Jaundice

(yellow skin/sclera) *Overproduction* (unconjugated secondary to Hemolysis) *Impaired excretion* (conjugated secondary to Duct Obstruction and/or Liver Cell Dysfunction) *Physiologic* (newborn deficiency in glucuronyl transferase)

Acute vs Chronic Hepatitis Describe Acute Describe Chronic May evolve through ________ to?

*Acute:* New liver disease/injury -Within 26 weeks of initial injury -Usually heals completely due to hepatic regeneration *Chronic:* Persistent liver disease/injury ->26 weeks *May evolve through fibrosis to:* -Cirrhosis -Complications of cirrhosis -Hepatocellular carcinoma Acute hepatitis is *NOT* acute liver failure. ((Acute liver faiilure is when you have the coagulopathy and mental alteration. Acute hepatitis, you *could just have elevated transaminases or elevated bilirubin.* You could even have coagulopathy, but *without the mental alteration, you do not have liver failure.*)) *IMPORTANT: If you do not see bridging fibrosis (portal to portal), you do not have cirrhosis*

Acute Liver Injury/Acute Hepatitis

*Asymptomatic* (abnormal LFTs only). those with hep C, the vast majority are asymptomatic. May feel like the flu for a while, then goes away, and 10 years later, their diagnosed with chronic liver disease. *Nonspecific constitutional symptoms* ((esp. Hep C. so big spectrum from no symptoms to symptoms)) -Fever -Nausea/vomiting -Fatigue *Physical findings* -Jaundice -Tender liver -Altered mental status/coma (hepatic encephalopathy) -Bleeding, thrombosis *Uncommon* -Headaches, myalgias, arthritis -Rash, urticaria, arthritis

What is the laboratory Assessment of Liver Injury for: Hepatocyte injury? Cholestatic biliary tract dysfunction? Synthetic function?

*Hepatocyte injury* Serum aminotransferases (AST, ALT) *Cholestatic biliary tract dysfunction* Serum bilirubin (direct and indirect) Alkaline phosphatase *Synthetic function* Serum albumin (20 day half life) Coagulation factors (5-48 hrs half life) Generally, if the AST, ALT are markedly elevated, and there's only a small increase in bilirubin, it's most likely hepatocellular injury. Whereas if the bilirubin and alkaline phosphatase are markedly elevated, and only a small amount of transferases, then we think about obstructions.

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*

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, remodeling of the scar tissue can occur and *a return towards architectural normality has been documented even in advanced fibrosis and cirrhosis.* -Galectin-3 and GR-MD-02 play roles. (see their cards)

GR-MD-02

-A complex carbohydrate drug containing terminal galactose residues that *binds to galectin-3 and inhibits its function* -It binds to macrophages and inhibits them, blocking the fibrosis. -Not yet available for humans.

Ballooning Degeneration

-Assoc with steatosis, but here we have more persistant injury and we're getting into a steatal hepatitis. -Cell death here = ballooning degeneration (a form of apoptosis). The cells fill up with fluid, the cytoplasm fragments, clumping of the cytoskeletal proteins. -Frequently assoc with alcohol.

Cholestasis

-Blockage anywhere along the bile transport causes a backflow causing bile plugs in the picture. -Also can get intracytoplasmic cholestasis where the hepatocytes are accumulating bile. -So you can get obstructions with stones blocking the outflow. -Can also get obstruction within the hepatocyte itself (*hepatocyte injury*) from drugs inparticular. -take home: Bile stasis is not always from bile duct obstructoin. It could also be hepatocellular obstructoin from toxins.

Hepatic Portal Circulation

-Branches of the portal veins, hepatic arteries, and bile ducts travel in parallel within *portal tracts,* ramifying variably through *17 to 20 orders of branches.* -All of products of digestion are absorbed from the GI tract → massive antigenic load. These are cleared by the sinusoidal macrophages (*kupfer cells*). and so you don't generally elicit an immune response to them. So some of the diseases are caused by the liver being a little too tolerant, or a little too immunogenic. A lot of the damage to the liver is done by the immune response. (A lot of the viruses we'll talk about (the hepatitis viruses) do not directly injur the liver, it's the immune response to the antigens tht are sitting on top of a hepatocyte or cholangial cell or whatev. So, it's *the immune response that causes injury*) -Liver has *high blood flow* and *low vascular resistance* -*Portal vein* and *hepatic artery* combine to form a *sinusoid*. portal vein is partially oxygenated

Portal Hypertension Prehepatic Causes? Intrahepatic Causes? Posthepatic Causes? Name the mechanisms of Portal Hypertension in cirrhosis Clinical Consequences or Portal Hypertension?

-Increased resistance to Portal Blood Flow Prehepatic Causes -Portal vein thrombosis -Narrowing of the portal vein Intrahepatic Causes -*Cirrhosis*, accounts for *most cases of portal hypertension* -Sinusoidal obstruction Posthepatic Causes -Severe right-sided heart failure -Constrictive pericarditis -Hepatic vein outflow obstruction *Cirrhosis is the dominant cause accounting for most cases of portal hypertension* *Mechanisms of Portal Hypertension in Cirrhosis* -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 -*Portosystemic venous shunts* -Congestive *splenomegaly* -*Ascites* -Hepatic (encephalopathy* -Caput Medusa -*Portacaval Anastomoses --Para-umbilical --Esophageal --Retroperitoneal --Rectal

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/Liver Failure* -Particularly, with Hep C, the patients are pretty much asymptomatic, but more liver cells are dying than being regenerated, and overtime, these patients get significant fibrosis, and even cirrhosis before becoming symptomatic. That's important to be aware of. It can go unnoticed. You don't need symptoms to have underlying liver disease.

Acute liver failure What is it? Defined by? Caused by? Mortality rate? Approach to treatment? Manifestations of Acute Liver Failure?

-Onset of liver failure *within 26 weeks after onset of new liver disease* Defined by: --Evidence of *impaired liver function* --Increased prothrombin time (>1/5) --Encephalopathy (mental alteration) --Around for less than 26 weeks. (Chronic is after) Caused by >80% loss of hepatocytes Mortality rate 40-80% Approach Hospitalize and consider liver transplantation Manifestations -*Jaundice* -Neurologic symptoms ((vary from headache to asterixis (asterixis = they flap their hands like their waving bye bye. Bad sign for liver failure.))) -*Encephalopathy* -Portal hypertension -Hepatorenal syndrome *Jaundice* (yellow skin/sclera) -*Overproduction* (unconjugated secondary to Hemolysis) -*Impaired excretion* (conjugated secondary to Duct Obstruction and/or Liver Cell Dysfunction) -*Physiologic* (newborn deficiency in glucuronyl transferase) *Neurologic symptoms* -Symptoms can include a *asterixis (flapping tremor)* and hyperactive reflexes. *Hepatic encephalopathy* -can range from sleep disturbance → lethargy→ deep somnolence → coma *Portal Hypertension* -Secondary to increased resistance to blood flow through the liver to the vena cava *Hepatorenal syndrome* -Thought to be triggered by *vasodilation in the splanchnic circulation* leading to decreased renal perfusion and glomerular filtration ...evidence of *coagulation abnormality* and any degree of *mental alteration* in a patient without pre-existing cirrhosis and with an illness less than *26 weeks duration*

Pathophysiology of Ascites

-Sinusoidal hypertension -Splanchnic vasodilation and hyperdynamic circulation -Decreased plasma oncotic pressure -Increased aldosterone

Porta hepatis

-Transmits the: ---common hepatic duct ---hepatic artery proper ---hepatic portal vein ---nerves and lymphatics

Portal Inflammation

-When see that area filled with blue cells (mononuclear cells), that's called portal inflammatoin. When it spills out into the adjacent liver parenchyma, we call it *periportal inflammation*. that's assoc with viral hepatitis, drugs, toxins, autoimmune.

Cholestasis 2

-could be assoc with bile duct obstruction. Or it could be seen with very severe hepatocellular injury where you get accumulation of bile excretion as well as uptake.

Anatomic liver lobule

A small pressure difference pushes bood thru the liver. This pressure difference is that between the combo of portal vein and hepatic arteries and the outside of the liver, the hepatic vein. The difference between these 2 areas is about *5-8mmHg* or so. So it's very low. -When it is *>12mm* = that's *portal hypertension*. can cause ascites and liver damage.

Cirrhosis take home messages Classifications? what are the common causes of death/complications in each classification?

Activation of stellate cells is the pivotal event in the initiation and progression of cirrhosis Cirrhosis is potentially reversible Drugs are in development that will reverse cirrhosis. ((We might be out there when they're available)) Important feature of cirrhosis is the loss of parenchyma, known as *parenchymal extinction* 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 Cirrhosis characterized by *diffuse nodular regeneration surrounded* by dense *fibrotic septae* 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.* Classification -As *compensated* or *decompensated* -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 sepsis are the usual causes of mortality in patients with *decompensated cirrhosis.* *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

Child-Turcotte-Pugh Classification

Assessment of Prognosis of Cirrhosis

Histo of Liver Acinus Zone 1 Zone 2 Zone 3

Blood flows from *portal triad to central vein* Zone 1 -Higher oxygen (portal vein and hepatic artery are mixing. portal vein has less O2) -Near portal tract area *-Viral Hepatitis* -Some toxins, drugs Zone 2 Zone 3 -Central vein area -Ischemia here usually *-Metabolic toxins* *-alcohol* -Cytochrome P-450 -Venous outflow obstruction

Liver failure Cause? Fatal sequelae of liver failure includes?

Cause -Liver failure may *follow acute injury* or *chronic injury,* but may also occur as an acute insult superimposed on an otherwise *well-compensated chronic liver disease.* Serious and sometimes *fatal sequelae of liver failure*: -Coagulopathy -Encephalopathy -Portal Hypertension -Bleeding esophageal varices -Hepatorenal syndrome -Portopulmonary hypertension

Liver Metabolic Functions Review

Formation and *excretion* of bile during *bilirubin* metabolism Regulation of carbohydrate *homeostasis* Lipid *synthesis* and secretion of plasma lipoproteins Control of cholesterol metabolism Formation of urea, *serum albumin, clotting factors,* enzymes, and numerous other proteins Metabolism or *detoxification* of drugs and other foreign substances

Liver after hepatocellular Injury can *progress to cirrhosis*

Got it Fibrosis extending between to portal zones (most common) or portal to central vein is called *bridging fibrosis*. have hypertension cause their normal architecture here is destroyed. typical of cirrhosis.

Liver after hepatocellular Injury can *return to normal*

Got it Nice sinusoidal pattern again, 1-2 cells thick.

Structure of a liver lobule Recognize: Bile canaliculi Kupffer cell Liver cell plate Space of Dissee Sinusoids Central vein Portal vein Hepatic artery Bile duct

If hepatic vein wedge pressure (portal → central vein → hepatic vein) rises only *3 to 7 mmHg* above normal, excessive amounts of fluid begin to transude into the lymph and leak through the outer surface of the liver capsule → *Ascites* -different surfaces of hepatocytes are not identical. they do different things.

Acute Hepatitis: Correlation of Clinical Symptoms to Degree of Hepatocyte Necrosis

In general, the symptoms correlate to some degree with the degree of hepatocyte necrosis, which is proportional to the serum levels of AST/ALT.

Microvesicular steatosis What is it? What's it caused by? Histology? How to differentiate this from steatosis?

Is an acute liver failure *without* necrosis. -A different kind of steatosis. -Also is a disruption of fatty acid metabolism. -Is much more serious (life threatening). -Here we have an impaired b-oxidation of the lipids caused by: --*Rey Syndrome* (injury to the mitocondria - b-oxidation of lipids goes haywire, these kids die.) --*Tetracycline toxicity* --*Fatty change of pregnancy* Histology We have little vessicles, or small circles within the cell (look carefully). As opposed to the steatosis where we had big fat globules. This is the histologic change.

Liver Microscopy Review Network of _____________ in the subendothelial space of Dissee stains ___________ Portal Triad consists of?

More than 2 cells thick between sinusoids is generally abnormal. -kupffer = intrasinusoidal -stellate cells = perisinusoidal

Liver Acinus

Portal triads in the periphery. Acinus is the area where 2 portal triads are connecting with the small vessels that branch off.

Histo liver again 2 Reticulin Stain

Reticulin Stain

Histo liver again

See linear patterns of hepatocytes.

List of histological manifestations of hepatic injury

Steatosis Ballooning degeneration Inflammation, cholestasis Hepatocellular injury (reversible) Necrosis and apotosis (cell death) Regeneration Fibrosis Neoplasia

Steatosis

The abnormal retention of lipids Causes: -Non-alcoholic fatty liver -Alcohol -Drugs -Viruses In general, is reversible

Hepatic Sinusoid - about the endothelial layer. What are hepatocytes exposed to?

The endothelial layer is fenestrated and not supported by a basal lamina ("liver sieve"). Hepatocytes are directly exposed to plasma. Pathology impairs this normal diffusion. More than 2 cells thick between sinusoids is generally abnormal.

Hepatic Sinusoid

The union of a hepatic artery and portal vein. Generally, there are only *1-2 hepatocytes lining the sinusoids.* That's important because in liver injury, sometimes you'll see 3, 4, or 5 hepatocytes all grouped together. That's a sign of injury. -Endothelial cells lining sinusoids are fenestrated - i.e. they have holes in the basal lamina. this allows direct communication between the interstitium and the capillary blood flow. The diameter of these fenestrations are controlled intrinsically by the endothelial cells depending on the environmnent. They either widen or constrict. -Doesn't take much to block the sinusoid. In *portal hypertension*, the vast *majority* of the time it's at the *sinusoidal level.* -With cirrhosis secondary to chronic liver injury or alcohol, or virus or whatev, you're getting fibrosis and obliteration of the sinusoid. Sickle cells here can also occlude the sinusoid giving symptoms. -the myofibroblasts also line the sinusoids. These are the key cells for the fibrosis and cirrhosis. They can proliferate, lay down fibrous tissue, and cause obliteration of the sinusoid. -Takes a fair amount of sinusoids to be wiped out before you see symptoms just cause of how many their are.

Causes of Hepatic Injury

This is a summary of what we'll cover: *Infectious* Viral hepatitis *Immune Mediated* Autoimmune hepatitis *Drug and Toxin* Acetaminophen Ethanol *Metabolic* Non-alcoholic fatty liver disease *Genetic* Hemochromatosis Wilson's disease Alpha-1 antitrypsin deficiency *Autoimmune Cholangiopathy* Primary biliary cirrhosis Primary sclerosing cholangitis Hepatitis is inflammation of the liver

MELD score What is it? What is it based on?

Used as a *disease severity index* to help prioritize allocation of organs for transpant. Based on: Creatinine, Bilirubin, and INR It is not a linear relationship to mortality <15 on this scale is not a candidate for transplantation

Liver Fibrogenesis

What causes the fibrosis in the liver is the *myofibroblasts* that hang out *in the sinusoids.* they are activated from acute or chronic injury and begin laying down fibroconnective tissue.

Histo 2 of acinus Zone 1 has? Zone 3 has?

Zone 1 = highest O2 conc. Zone 3 = lowest O2 conc.

Liver histo

blood flows from PV to CV

Acute Hepatitis

bottom right = lobular disarray. If look around, you can't see linear pattern of hepatocytes. There's an increase in mononuclear cells. Sinusoids not forming a linear pattern. Some places, you see 3 hepatocyte nuclei together. -*Lobular disarray* almost always describes acute hepatitis top right = apoptosis. see acidophilic body with red cytoplasm. this is a sign of cell death.

Cirrhosis histo

called regenerating nodules. cirrhosis is diffuse. You don't see half of the liver with it. Rather, the entire liver is affected.

Anatomic Liver lobule 2

central vein takes it to vena cava. blood flows from portal to central. High O2 near portal area, low O2 near central area. So ischemia usually starts near the central area which is where low O2 is present to begin with.

cholestatic disease

disease of the liver caused by bile outflow obstruction

Portal Inflammation with Interface Hepatocyte Injury

interface = the hepatocytes lining up adjacent to the portal zone Chronic active hepatitis: portal zone has inflammation and it spills out and infiltates adjacent hepatocytes, and you see either necrosis or apoptosis. Assoc usually with hep B, sometimes c.