Pathology of Hepatitis & Cirrhosis

SMS 2044

Normal Liver

The Liver
The right upper quadrant of the abdomen is dominated by the liver and its companion biliary tree and gallbladder. Residing at the crossroads between the digestive tract and the rest of the body, the liver has the enormous task of maintaining the
body's metabolic homeostasis.

Autopsy
1.5 kg, wedge shape 4 lobes, Right, left, Caudate, Quadrate. Double blood supply Hepatic arteries Portal Venous blood Acini / Portal triad. Lobules central. V

Normal Liver - Infant

CT Upper abdomen - Normal

Normal Liver - Microscopy

N O
FIBROUS TISSUE

Liver Functions:
Metabolism Carbohydrate, Fat & Protein Secretory bile, Bile acids, salts & pigments Excretory Bilirubin, drugs, toxins Synthesis Albumin, coagulation factors Storage Vitamins, carbohydrates etc. Detoxification toxins, ammonia, etc.

GENERAL PRINCIPLES The

liver is vulnerable to a wide variety of metabolic, toxic, microbial, and circulatory insults. liver. In others, the hepatic involvement is secondary, such as cardiac decompensation, extrahepatic infections. alcoholism,

In some instances, the disease process is primary to the often to some of the most common diseases in humans,
and

However, with progression of diffuse disease or strategic

disruption of the circulation or bile flow,

the consequences of deranged liver function become life-threatening.

Damage from toxic or immunologic insult may cause hepatocytes to take on a swollen, edematous appearance (ballooning degeneration) with irregularly clumped cytoplasm and large, clear spaces. Alternatively, retained biliary material may impart a diffuse, foamy, swollen appearance to the hepatocyte (foamy degeneration). Substances may accumulate in viable hepatocytes, including iron, copper, and retained biliary material. Accumulation of fat droplets within hepatocytes is known as steatosis. A single large droplet that displaces the nucleus, are known as macrovesicular steatosis, may be seen in the alcoholic liver or in the livers of obese or diabetic individuals.

FEATHERY DEGENERATION

Cell Death
Virtually any significant insult to the liver may cause hepatocyte destruction. In necrosis, poorly stained mummified hepatocytes remain, most commonly as the result of ischemia (coagulative necrosis). Cell death that is toxic or immunologically mediated occurs via apoptosis, in which isolated hepatocytes become shrunken, pyknotic, and intensely eosinophilic.

 Alternatively, hepatocytes may osmotically swell and rupture, so-called hydropic degeneration or lytic necrosis.

In the setting of ischemia and a number

of drug and toxic reactions, hepatocyte necrosis is distributed immediately around the central vein (centrilobular necrosis).

With more severe inflammatory or toxic

injury, apoptosis or necrosis of contiguous hepatocytes may span adjacent lobules in a portal-to-portal, portal-to-central, or central-to-central fashion (bridging necrosis).

Destruction of entire lobules

(submassive necrosis) or most of the liver parenchyma (massive necrosis) is usually accompanied by hepatic failure. With bacterial infection, macroscopic abscesses may occur.

Hepatitis:
Hepatitis: Inflammation of Liver Viral, Alcohol, immune, Drugs & Toxins Biliary obstruction gall stones. Acute, Chronic & Fulminant - types Viral Hepatitis
Specific Heptitis A, B, C, D, E, & other Systemic - CMV, EBV, other.

Pattern of Viral Hepatitis:

Carrier state / Asymptomatic phase Acute hepatitis Chronic Hepatitis
Chronic Persistent Hepatitis (CPH) Chronic Active Hepatitis (CAH)

Fulminant hepatitis Cirrhosis Hepatocellular Carcinoma

Acute - Hepatitis - Chronic

Acute Hepatitis:
Swelling and Apoptosis Piecemeal or Bridging, panacinar necrosis Inflammation lymphocytes, Macrophages Ground glass hepatocytes HBV Mild fatty change HCV Portal inflammation and Cholestasis

Foreign bodies, organisms, and a variety of drugs may incite a granulomatous reaction.

Signs and Symptoms

Abdominal pain Joint and muscle pain Change in bowel function Nausea, vomiting, anorexia Lethargy, malaise Fever (Hepatitis A) Irritability

More Signs and Symptoms

oJaundice oclay colored stools odark urine oPruritis/urticaria oSkin abrasions oRash

Fulminant Hepatitis:
Hepatic failure with in 2-3 weeks. Reactivation of chronic or acute hepatitis Massive necrosis, shrinkage, wrinkled Collapsed reticulin network Only portal tracts visible Little or massive inflammation time More than a week regenerative activity Complete recovery or - cirrhosis.

Chronic Hepatitis:
Persistent & Active types. CPH/CAH Lymphoid aggregates Periportal fibrosis Necrosis with fibrosis bridging fibrosis. Cirrhosis regenerating nodules.

Acute viral Hepatitis:

Acute viral Hepatitis:

Acute viral Hepatitis:

Acute viral Hepatitis C:

Liver Biopsy CPH:

Jaundice
Yellow discoloration of skin & sclera due to excess serum bilirubin. >than 85 umol/l (5 mg/dL) Conjugated & Unconjugated types Obstructive & Non Obstructive (clinical) Pre-Hepatic, Hepatic & Post Hepatic types Jaundice - Not necessarily liver disease *

Jaundice
Hepatic bile formation serves two major functions. Bile constitutes the primary pathway for the elimination of Second,
secreted bile salts and phospholipid molecules promote emulsification of dietary fat in the lumen of the gut. (icterus), occurs when systemic retention of bilirubin leads to elevated serum levels above 2.0 mg/dL, the normal in the adult being less than 1.2 mg/dL. bilirubin but also other solutes eliminated in bile (particularly bile salts and cholesterol). bilirubin, excess cholesterol, and xenobiotics that are insufficiently water soluble to be excreted into urine.

Thus, jaundice, a yellow discoloration of skin and sclerae

Cholestasis, is defined as systemic retention of not only

Common Causes of Jaundice

Pre Hepatic (Acholuric) - Hemolytic
Unconjugated/Indirect Bil, pale urine

Hepatic Viral, alcohol, toxins, drugs

Liver damage - unconjugated Swelling, canalicular obstruction - Conjugated

Post Hepatic (Obstructive) Stone, tumor

Conjugated/Direct Bil, High colored urine,

Bilirubin metabolism and elimination.

Normal bilirubin production (0.2 to 0.3 g/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins. Extrahepatic bilirubin is bound to serum albumin and delivered to the liver.

Hepatocellular uptake and glucuronidation by glucuronosyltransferase in the hepatocytes generates bilirubin which are water soluble and readily excreted into bile.

Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and reexcretion into bile.

PATHOPHYSIOLOGY OF JAUNDICE
Both un-conjugated bilirubin and bilirubin glucuronides may accumulate systemically and deposit in tissues, giving rise to the yellow discoloration of jaundice. This is particularly evident in the yellowing of the sclerae (icterus). There are two important pathophysiologic differences between the two forms of bilirubin. Un-conjugated bilirubin is tightly complexed to serum albumin and is virtually insoluble in water at physiologic pH.

 This form cannot be excreted in the urine even when blood levels are high. Normally, a very small amount of unconjugated bilirubin is present as an albumin-free anion in plasma. The unbound plasma fraction may increase in severe hemolytic disease or when protein-binding drugs displace bilirubin from albumin.

 In contrast, conjugated bilirubin is

water soluble, nontoxic, and only loosely bound to albumin.

Because of its solubility and weak

association with albumin, excess conjugated bilirubin in plasma can be excreted in urine.

With prolonged conjugated

hyperbilirubinemia, a portion of circulating pigment may become covalently bound to albumin.

This "delta fraction" may persist in

the circulation for weeks after correction of a cholestatic insult, owing to the plasma lifetime of albumin.

 In the normal adult, serum bilirubin levels vary between 0.3 and 1.2
mg/dL

Jaundice

becomes evident when the serum bilirubin levels rise above 2.0 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur with severe disease. and clearance is disturbed by one or more of the following mechanisms:

Jaundice occurs when the equilibrium between bilirubin production (1) excessive production of bilirubin, (2) reduced hepatic uptake, (3) impaired conjugation, (4) decreased hepatocellular excretion,
and

(5) impaired bile flow (both intrahepatic and extrahepatic).

The first three mechanisms produce unconjugated

hyperbilirubinemia, and the latter two produce predominantly conjugated hyperbilirubinemia.

 The morphologic alterations that cause liver failure fall into

three categories:
1. Massive hepatic necrosis. This is most often caused by fulminant viral hepatitis (hepatotropic or nonhepatotropic viruses).
Drugs and chemicals also may induce massive necrosis

1. Chronic liver disease. This is the most common route to

hepatic failure and is the end point of relentless chronic liver damage ending in:

2. Cirrhosis.

Clinical Features
Jaundice is an almost invariable finding. Impaired hepatic synthesis and secretion of albumin leads to hypoalbuminemia, which predisposes to peripheral edema. Hyperammonemia is attributable to defective hepatic urea cycle function. Fetor hepaticus is a characteristic body odor variously described as "musty" or "sweet and sour" and occurs occasionally.

 A coagulopathy develops, attributable to impaired hepatic synthesis of blood clotting factors II, VII, IX, and X. The resultant bleeding tendency may lead to massive gastrointestinal hemorrhage as well as petechial bleeding elsewhere. Hepatic encephalopathy Hepatic encephalopathy is a feared complication of acute and chronic liver failure

Cirrhosis

Cirrhosis

Fibrosis

Regenerating Nodule

CIRRHOSIS, TRICHROME STAIN

Etiology of Cirrhosis
Alcoholic liver disease Viral hepatitis Biliary disease Primary hemochromatosis Cryptogenic cirrhosis Wilsons, 1AT def 60-70% 10% 5-10% 5% 10-15% rare

Pathogenesis:
Hepatocyte injury leading to necrosis.
Alcohol, virus, drugs, toxins, genetic etc..

Chronic inflammation - (hepatitis). Bridging fibrosis. Regeneration of remaining hepatocytes Proliferate as round nodules. Loss of vascular arrangement results in regenerating hepatocytes ineffective.

Cirrhosis Features:
Liver Failure Parenchymal regeneration but why ..??. Portal obstruction, Porta systemic shunts Portal hypertension, Splenomegaly Jaundice, Coagulopathy, hypoproteinemia, toxemia, Encephalopathy,

Micronodular cirrhosis

Ascitis in Cirrhosis

Ascitis in Cirrhosis

Micronodular cirrhosis:

Macronodular Cirrhosis

Liver Biopsy Cirrhosis

Liver Biopsy Cirrhosis:

Nutmeg Liver-Cardiac Sclerosis

Clinical Features
Hepatocellular failure.
Malnutrition, low albumin & clotting factors, bleeding. Hepatic encephalopathy.

Portal hypertension.
Ascites, Porta systemic shunts, varices, splenomegaly.

Cirrhosis Clinical Features

Gynaecomastia in cirrhosis

Porta-systemic anastomosis: Prominent abdominal veins.

MRI Cirrhosis

Complications:
Congestive splenomegaly. Bleeding varices. Hepatocellular failure.

Hepatic encephalitis / hepatic coma.

Hepatocellular carcinoma.

Alcoholic Liver Injury:

Ethyl alcohol : Common cause of acute/Chronic liver disease Alcoholic Liver disease - Patterns
Fatty change, Acute hepatitis (Mallory Hyalin) Chronic hepatitis with Portal fibrosis Cirrhosis, Chronic Liver failure

All reversible except cirrhosis stage.

Alcoholic Liver Injury: Pathogenesis

Acetaldehyde metabolite hepatotoxic Diversion of metabolism fat storage. Oxidation of ethanol NAD to NADH. NAD is required for the oxidation of fat.. Increased peripheral release of fatty acids. Inflammation, Portal bridging fibrosis Stimulates collagen synthesis fibrosis. Micronodular cirrhosis.

Alcoholic Liver Damage

Alcoholic Fatty Liver

Alcoholic Fatty Liver

Alcoholic Fatty Liver

Alcoholic Hepatitis

Normal Liver Histology

CV

PT

Pathogenesis of Hepatic Encephalopathy

BRAIN Porta systemic shunts LIVER

Toxic N2 metabolites From Intestines

Bleeding in Liver disease:

vitamin K in liver gamma-carboxyglutamic acid for coagulation factors II, VII, IX, and X. Liver disease factor VII is the first to go so the defect will appear initially in the extrinsic pathway, i.e., abnormal PT. When severe it affects both pathways.

Conclusions:
Common end result of diffuse liver damage.
(Viral hepatitis, Alcohol, congenital, drugs, toxins & Idiopathic)

Characterised by diffuse loss of architecture. Fibrous bands & regenerating nodules distort and abstruct blood flow. (inefficient function) Hepatocellular insufficiency & portal hypertension. Shrunken, scarred liver, ascitis, spleenomegaly, liver failure, CNS toxicity.

Prevention Teaching
What would you teach?
Adequate sanitation and hygiene Wash hands before eating and after using the toilet Drink only purified or bottled water No sharing of eating utensils, needles, toothbrushes, razors, etc. Use a Choose your tattoo or