Session 28 Liver Pathology

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Lecture Notes

Session 28: Liver Pathology

Alex Simon (MD)

Learning tasks

At the end of this session, students are expected to be able to:

Explain morphological response to hepatic injury.

Explain liver failure.

Explain jaundice and cholestasis.

Explain liver cirrhosis.

Explain portal hypertension.

Explain pathological changes in hepatitis.

Morphological response to Hepatic injury

Degeneration and intracellular accumulation.

Necrosis and apoptosis.

Regeneration.

Inflammation.

Fibrosis.

Cirrhosis.

Ductular reaction.

Refer to Handout 28.1 for additional information on morphological response to hepatic injury.

Major clinical syndromes of liver disease

Hepatic failure.

Cirrhosis.

Portal hypertension.

Cholestasis.

Hepatic failure

The most severe clinical consequence of liver disease is hepatic failure.

It generally develops as the end point of progressive damage to the liver, either through:

Insidious piecemeal destruction of hepatocytes.

By repetitive waves of symptomatic parenchymal damage.

Less commonly, hepatic failure is the result of sudden, massive destruction.

Hepatic failure

Whatever the sequence, 80% to 90% of hepatic function must be lost before hepatic failure ensues.

In many cases, the balance is tipped toward decompensation by intercurrent conditions or events that place demands on the liver.

These include

Systemic infections.

Electrolyte disturbances.

Major surgery.

Heart failure.

Gastrointestinal bleeding.

Patterns of injury that cause liver failure

The patterns of injury that cause liver failure fall into three categories

Acute liver failure with massive hepatic necrosis.

Chronic liver disease.

Hepatic dysfunction without overt necrosis.

Refer to Handout 28.2 for additional information on patterns of injury that cause liver failure.

Characteristic signs of severe Hepatic dysfunction

Jaundice and cholestasis.

Hypoalbuminemia.

Hyperammonemia.

Hypoglycemia.

Palmar erythema.

Spider angiomas.

Hypogonadism.

Gynecomastia.

Weight loss.

Muscle wasting.

Complications of Hepatic Failure

Coagulopathy.

Hepatic encephalopathy.

Hepatorenal syndrome.

Portopulmonary hypertension.

Hepatopulmonary syndrome.

Jaundice

Jaundice is a yellow discoloration of skin and sclerae (icterus).

The most common causes of jaundice are

Hepatitis.

Obstruction to the flow of bile.

Hemolytic anemia.

Jaundice cont…

Jaundice occurs when the equilibrium between bilirubin production and clearance is disrupted

The major responsible mechanisms causing jaundice

Excessive production of bilirubin.

Reduced hepatic uptake.

Impaired bilirubin conjugation.

Decreased hepatocellular excretion.

Impaired intra- or extrahepatic bile flow.

Cholestasis

Cholestasis is defined as systemic retention of not only bilirubin but also other solutes eliminated in bile (particularly bile salts and cholesterol).

Skin xanthomas (focal accumulations of cholesterol) sometimes appear.

Result of hyperlipidemia and impaired excretion of cholesterol.

Elevated serum alkaline phosphatase is the laboratory finding.

Liver cirrhosis

It affects an entire liver.

The normal lobular architecture of the liver is lost and replaced by regenerative parenchymal nodules that are separated from each other by irregular bands of fibrosis.

There is a variable degree of vascular shunting.

Cirrhosis is the condition marked by diffuse transformation of an entire liver into regenerative parenchymal nodules, surrounded by fibrous bands and variable degree of vascular shunting.

Classification of Liver cirrhosis

According to morphology.

Micronodular (less than 3mm).

Macronodular (more than 3mm).

Mixed (micronodular and macronodular).

According to their activity.

Active (continuing hepatocytes necrosis and presence of the inflammation).

Inactive (no above features).

Classification of Liver cirrhosis cont…

According to etiology.

Alcoholic cirrhosis.

Post necrotic cirrhosis.

Biliary cirrhosis.

Pigment cirrhosis.

Cardiac cirrhosis.

Cirrhosis in Wilson’s disease.

Cirrhosis in Alpha-1 antitrypsin deficiency.

Cirrhosis in Autoimmune hepatitis.

Cryptogenic cirrhosis.

Etiology of Liver cirrhosis

The most common causes of cirrhosis are

Chronic alcoholism.

Chronic hepatitis B and C infection.

Other common causes are biliary diseases and hemochromatosis.

After all the known causes have been excluded, about 10% of cases the cause is not know.

This is referred to as cryptogenic cirrhosis.

Pathogenesis of Liver cirrhosis

Major mechanisms that combine to create cirrhosis

Hepatocellular death.

Regeneration.

Progressive fibrosis.

Vascular changes.

Three (3) processes that are central to the pathogenesis of cirrhosis

Death of hepatocytes.

Extracellular matrix deposition.

Vascular reorganization.

Pathogenesis of Liver cirrhosis

Fibrogenesis.

Types I and III collagen and other ECM components are deposited in the space of Disse.

The major source of excess collagen in cirrhosis are the perisinusoidal stellate cells (formerly known as Ito cells), which lie in the space of Disse.

Ito cells are activated by reactive oxygen species, growth factors, and cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxins, and transform into myofibroblasts.

Portal fibroblasts probably also participate in some forms of cirrhosis.

Pathogenesis of Liver cirrhosis cont…

Regenerative nodules.

The cause of compensatory proliferation of hepatocytes to form regenerative nodules is obscure.

Possibly, growth factors, chalones and hormonal imbalance, play a role in regeneration.

Hepatocytes in these nodules derive from two sources

Preexistent, long-lived hepatocytes

Newly formed hepatocytes capable of replication

Pathogenesis of Liver cirrhosis cont…

Vascular changes.

The major vascular lesions that contribute to defects in liver function are

Loss of sinusoidal endothelial cell fenestrations.

Development of portal vein–hepatic vein and hepatic artery–portal vein vascular shunts.

Morphology of Liver cirrhosis

The three (3) main morphological characteristics of cirrhosis are

Bridging fibrous septa in the form of delicate bands or broad scars around multiple adjacent lobules.

Parenchymal nodules containing replicating hepatocytes.

Disruption of the architecture of the entire liver.

Clinical features (Outcomes/ Complications) of Liver cirrhosis

Most cases of ultimately fatal cirrhosis involve one of the following mechanisms

Progressive liver failure.

A complication related to portal hypertension.

The development of hepatocellular carcinoma.

Clinical features (Outcomes/ Complications) of Liver cirrhosis

Others complications are

Infections.

Steatorrhoea.

Haematologic derangements such as bleeding disorders.

Chronic relapsing pancreatitis.

Gallstones.

Cardiovascular complications such as atherosclerosis of coronaries and aorta and myocardial infarction.

Portal Hypertension

Increased resistance to portal blood flow may develop from prehepatic, intrahepatic, and posthepatic causes.

The dominant intrahepatic cause is cirrhosis, accounting for most cases of portal hypertension.

Other less common causes of Portal hypertension

Schistosomiasis.

Massive fatty change.

Diffuse granulomatous diseases (e.g., Sarcoidosis, miliary tuberculosis).

Diseases affecting the portal microcirculation(e.g. nodular regenerative hyperplasia).

Mechanisms causing Portal Hypertension

Portal hypertension in cirrhosis results from increased resistance to portal flow at the level of the sinusoids and compression of central veins by perivenular fibrosis and expanded parenchymal nodules.

Anastomoses between the arterial and portal systems in the fibrous bands also contribute to portal hypertension by imposing arterial pressure on the normally low-pressure portal venous system.

Mechanisms causing Portal Hypertension cont…

Another major factor in the causation of portal hypertension is an increase in portal venous blood flow resulting from a hyperdynamic circulation.

This is caused by arterial vasodilation in the splanchnic circulation, resulting primarily from increased production of nitric oxide (NO) in the vascular bed.

This occurs in response to reduced clearance of bacterial DNA absorbed from the gut that bypasses the Kupffer cells due to intrahepatic shunting of blood from portal to systemic circulation.

Bacterial DNA causes increased production of NO.

Portal Hypertension cont…

The major clinical consequences of Portal Hypertension are

Ascites.

The formation of portosystemic venous shunts.

Congestive splenomegaly.

Hepatic encephalopathy.

Refer to Handout 28.3 for additional information on clinical consequences of portal hypertension.

Hepatitis

It is an inflammation of liver parenchyma

It can be acute or chronic

Acute and chronic forms of hepatitis are distinguished in part by duration and in part by the pattern of cell injury.

Causes of Hepatitis

Infections e.g. Viruses.

Alcohol.

Chemicals and toxins.

Autoimmune cause.

Genetic diseases like Wilson diseases, Cystic fibrosis, Hemochromatosis.

Metabolic cause.

Circulatory insults like ischemia.

Viral hepatitis

Viral hepatitis is caused mainly by

Hepatitis virus A (HAV)

Hepatitis virus B (HBV)

Hepatitis virus C (HCV)

Hepatitis virus D (HDV)

Hepatitis virus E (HEV).

Other viruses which can cause hepatitis are

Epstein-Barr virus (EBV).

Cytomegalovirus.

Herpes simplex.

Yellow fever.

Pathological changes in Hepatitis:Gross changes

On gross inspection

In acute hepatitis appears normal or slightly mottled.

In chronic hepatitis may be normal or include grossly evident focal scarring or, as cirrhosis develops.

At the other end of the spectrum, in massive hepatic necrosis the liver may shrink and become transformed into a limp, red organ covered by a wrinkled, baggy capsule.

Pathological changes in Acute Hepatitis:Histological changes

Hepatocellular injury

Hepatocytes appear swollen with granular cytoplasm which tends to condense around the nucleus (ballooning degeneration).

Apoptotic hepatocytes shrink, become intensely eosinophilic and have fragmented nuclei.

Dropout necrosis in which isolated or small clusters of hepatocytes undergo lysis.

Bridging necrosis is a more severe form of hepatocellular injury in acute viral hepatitis.

Pathological changes in Acute Hepatitis:Histological changes cont…

Inflammatory infiltrate

There is infiltration by mononuclear inflammatory cells, usually in the portal tracts, but may permeate into the lobules.

Kupffer cell hyperplasia

There is reactive hyperplasia of Kupffer cells many of which contain phagocytosed cellular debris, bile pigment and lipofuscin granules.

Pathological changes in Acute Hepatitis:Histological changes cont…

Cholestasis

Biliary stasis is usually not severe in viral hepatitis and may be present as intracytoplasmic bile pigment granules.

Regeneration

As a result of necrosis of hepatocytes, there is lobular disarray.

Surviving adjacent hepatocytes undergo regeneration and hyperplasia.

Pathological changes in Chronic Hepatitis

Smoldering hepatocyte necrosis throughout the lobule may occur in all forms of chronic hepatitis.

In the mildest forms, significant inflammation is limited to portal tracts.

Continued periportal necrosis and bridging necrosis are harbingers of progressive liver damage.

The hallmark of serious liver damage is the deposition of fibrous tissue.

Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septa and hepatocyte regenerative nodules.

Clinical Outcomes of Viral Hepatitis

A number of clinical syndromes may develop after exposure to hepatitis viruses

Asymptomatic acute infection: serologic evidence only

Acute hepatitis: anicteric or icteric

Chronic hepatitis: with or without progression to cirrhosis

Chronic carrier state: asymptomatic without apparent disease

Fulminant hepatitis: submassive to massive hepatic necrosis with acute liver failure

Key points

Steatosis is seen in alcoholic liver disease, Reye syndrome and Acute fatty liver of pregnancy.

80% to 90% of hepatic function must be lost before hepatic failure ensues.

The most frequent cause of liver cirrhosis are chronic hepatitis B and C and alcohol.

The main complications of cirrhosis are related to decreased liver function, portal hypertension, and increased risk for development of hepatocellular carcinoma.

In hepatitis, mononuclear infiltrates predominate in all phases of the disease.

Review questions

Explain five (5) main patterns of morphologic liver injury and associated cellular responses.

Explain (3) patterns of injury that cause liver failure.

Explain pathogenesis of liver cirrhosis.

Explain four (4) clinical consequences of portal hypertension.

List five (5) pathological changes seen in acute hepatitis.

References

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 604-614.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 596-613, 618-632.

Xiu P.;(2012): Crash Course Pathology (4th Ed.) Elsevier Saunders, USA. Pg. 124-133.

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Session 28 Liver Pathology

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Lecture Notes