Clinico- Pathologic Presentation

CASE 2 A 55-year old woman presents to the

emergency department with profuse bright red bleeding with emesis diagnosed as bleeding esophageal varices. She also is icteric and is suspected of having a cirrhosis. She has been followed for several years for Sjogren syndrome and Raynaud syndrome. Investigation into the cause of her cirrhosis reveals negative hepatitis antibodies but elevated antimitochondrial antibodies.

CLINICAL SENARIO:

Emesis w/ Bleeding Bleeding from Esophageal varices Icterus Sjogren syndrome Raynauld’s syndrome Positive for Anti-Mitochondrial Antibody Suspect for Cirrhosis

Microscopic Features that are Characteristic of Cirrhosis:

Fibrosis Bridging septa in the form of delicate

band or broad scars Nodules

Created by regeneration of hepatocytes encircled by fibrosis

Disruption of hepatic parenchymal architecture

Major etiologic agent of cirrhosis: Alcoholic liver disease

60 to 70% Higher incidence in men than in womenFifth leading cause of death (automobile

accident) Viral Hepatitis

10%Infection of the liver caused by group of

viruses having a particular affinity of the liver

Major etiologic agent of cirrhosis:Biliary Disease

5 to 10%Inflammation or obstruction of the bile ducts

resulting in the accumulation of bile in and functional impairment of the liver

Primary Hemochromatosis5%Excessive accumulation of body iron, most

of which is deposited in parenchymal organs such as the liver and pancreas

Major etiologic agent of cirrhosis:Wilson Disease

RareAutosomal-recessive disorderMarked by accumulation of toxic levels of

copper in many tissues and organs (liver, brain, eye)

α1-antitrypsin Deficiency

RareAutosomal-recessive disorderMarked by abnormally low serum level of

important protease inhibitor

Major etiologic agent of cirrhosis: Cryptogenic Cirrhosis

10 to 15%Wastebasket categorySpeaks eloquently to the difficulties in

discerning the many origins of cirrhosis

Two Variants of Cirrhosis Micronodular cirrhosis

Nodules were small (>3 mm) Cause by metabolic disturbances or

chemicals that uniformly affect the liver

Macronodular cirrhosis When normal parenchyma was replaced by

larger nodules Cause by viruses that invades the liver in

an unpredictable manner

Hepatic Encephalopathy

sometimes hepatoencephalopathy or portosystemic encephalopathy.

is a potentially-reversible neuropsychiatric abnormality in the setting of liver failure, whether chronic (as in cirrhosis) or acute. It can be diagnosed only after exclusion of other neurological, psychiatric, infectious, and metabolic etiologies.

• With severe liver impairment, toxic substances normally removed by the liver accumulate in the blood and impair the function of brain cells.

• If there is also portal hypertension, and subsequent bypassing of the liver filtration system of blood flowing in from the intestines, these toxic substances can travel directly to the brain, without being modified or purified.

• Signs can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness including coma (hepatic coma or coma hepaticum), cerebral edema, and, ultimately, death.

Hepatorenal syndrome

• Hepatorenal syndrome occurs when there is a decrease in kidney function in a person with a liver disorder. The most common symptom is decreased urine production. As a result of reduced elimination of urine, nitrogen-containing waste products accumulate in the blood stream (azotemia).

The exact cause of hepatorenal syndrome is unknown. For some reason, there is drastic reduction in blood flow to the kidneys. The kidney structure remains essentially normal and the kidneys often will instantly function well if the liver disease is corrected (for example, by liver transplantation).

The disorder occurs in up to 10% of patients hospitalized with liver failure. It may be a sign of impending death caused by the accumulated effects of liver damage and kidney failure in people with acute liver failure, cirrhosis or alcoholic hepatitis. It is diagnosed when other causes of kidney failure are ruled out.

ALCOHOL LIVER DISEASE

1. FATTY LIVER

2. HEPATITIS

3. CIRRHOSIS

Morphology:● Hepatic Steatosis ( Fatty Liver)

– Following even moderate intake of alcohol, small (microvesicular) lipid droplets accumulate in the hepatocytes.

– Which chronic intake: lipid accumulates – large macrovesicular globules compress and displace the nucleus to the periphery of the hepatocyte.

– Macroscopic: large soft organ that is yellow and greasy

Morphology● Alcoholic Hepatitis:

– Hepatocyte swelling and necrosis● Swelling result from accumulation of fat and water.● Mild deposition of hemosiderin in hepatocytes and

kupffer cells.– Mallory bodies

● Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins seen as eosinophilic cytoplasmic inclusions in degenerating hepatocytes.

● Neutrophillic reaction– Neutrophils permeate the lobule and accumulate around

degenerating hepatocytes.

– Lymphocytes and macrophages also enter portal tracts and spill into the parynchema.

● Fibrosis– Activation of sinusoidal stellate cells and portal tract

fibroblasts.

● Mx: although steatotic hepatocytes are present they are intersped with the inflammatory cells and activated stellate cells.

● Macro: motted red with bile stained areas. Maybe normal or increased size, often contains visible nodules and fibrosis indicative of evolution to cirrhosis

Morphology● Alcoholic Cirrhosis

– Final and irreversible form of liver disease

– At first the cirrhotic liver is yellow – tan, fatty, and enlarged usually weighing over 2 kg.

– Cirrhosis develop more rapidly in the setting of alcoholic hepatitis within 1 – 2 years.

– Formation of micronodules then it becomes prominent then it scatters and creates “hobnail” appearance

– Liver becomes more fibrotic, loses fat and shrinks

– Both macroscopic and microscopic appearance resembles viral hepatitis

PATHOGENESIS● Steatosis results from shunting of substrates

toward lipid biosynthesis, impaired lipoprotein assemby and secretion, and increasing peripheral catabolism of fat.

● Cellular injury results from:– Induction of cytochrome P – 450 augmenting

catabolism of other drugs to potentially toxic metabolites'

– free radical generated by the microsomal ethanol oxidizing system that react which proteins and membranes.

● -Acetaldehyde generated from alcohol to induce lipid peroxidation and acetladehyde – protein adduct formation

● Alcohol induces an immunologic attack on hepatic neoantigens, possibly due to alterations in native proteins.

● Alcohol is a caloric food source, displacing nutrients.

● Fibrosis is the result of collagen deposition by perisinusoidal stellate cells, eventuating in cirrhosis. Stimuli include:

● Fibrosis is the result of collagen deposition by perisinusoidal stellate cells, eventuating in cirrhosis. Stimuli include:

● 1. Kupffer cell activation which proinflammatory cytokine release

● 2. Amplification of cytokine stimuli by platelet – activating factor, a lipid release by endothelial and kuppfer cells

● 3. Influx of neutrophils into the parenchyma, which release of free radicals, proteases, and other inflammatory mediators.

1.

● Deranged hepatic blood flow is the result of progressive fibrosis and alcohol – inducive release of vasoconstriction in endothelins from sinusoidal endothelial cells.

Alcoholic Liver Disease• Alcohol consumption is high in most Western

countries. In the US, > 10% of people abuse or are dependent on alcohol. The male:female ratio is about 2:1. Disorders that occur in alcohol abusers, often in sequence, include

• Fatty liver (in > 90%)• Alcoholic hepatitis (in 10 to 35%)• Cirrhosis (in 10 to 20%)• Hepatocellular carcinoma may also develop,

especially in association with iron accumulation.

Risk Factors

The main causative factors in alcoholic liver disease are

Quantity and duration of alcohol use (usually > 8 yr)

Sex Genetic and metabolic traits Nutritional status

Quantity of alcohol• Among susceptible people, a linear correlation

generally exists between the amount and duration of alcohol use and the development of liver disease.

• Risk increases markedly for men who drink > 40 g, particularly > 80 g, of alcohol/day for > 10 yr (eg, 3 to 6 cans of beer, 3 to 6 shots of hard liquor, 4 to 8 glasses of wine).

• For cirrhosis to develop, consumption must usually be > 80 g/day for > 10 yr. If consumption exceeds 230 g/day for 20 yr, risk of cirrhosis is about 50%. But only some chronic alcohol abusers develop liver disease. Thus, variations in alcohol intake do not fully explain variations in susceptibility, indicating that other factors are involved.

Sex Women are more susceptible to

alcoholic liver disease, even after adjustment for body size.

Women require only 20 to 40 g of alcohol to be at risk—½ of that for men.

Risk in women may be increased because they have less alcohol dehydrogenase in their gastric mucosa; thus, first-pass oxidation of alcohol is decreased.

Genetic factors

Alcoholic liver disease often runs in families, suggesting genetic factors

(eg, deficiency of cytoplasmic enzymes that eliminate alcohol).

Nutritional status

Undernutrition, particularly protein-energy undernutrition, increases susceptibility, as does a diet high in unsaturated fat and obesity.

Other factors

Other risk factors include iron accumulation in the liver (not necessarily related to iron intake) and concomitant hepatitis C.

Prognosis

Prognosis is determined by the degree of hepatic fibrosis and inflammation. Fatty liver and alcoholic hepatitis without fibrosis are reversible if alcohol is avoided. With abstinence, fatty liver completely resolves within 6 wk. Fibrosis and cirrhosis are irreversible.

Once cirrhosis and its complications (eg, ascites, bleeding) develop, the 5-yr survival rate is about 50%; survival is higher in patients who abstain and lower in patients who continue drinking.

Coexisting iron accumulation or chronic hepatitis C increases risk of hepatocellular carcinoma.

Identify the most complication of hepatic involvement in hemachromatosis

•ComplicationsIf the disease is not detected early and treated, iron will accumulate in body tissues and may eventually lead to serious problems such as the following.

 - Arthritis

-  Liver disease, including enlarged liver, hepatitis, cirrhosis, cancer, and liver failure

  - Heart abnormalities, such as irregular heart rhythms or congestive heart failure

  

-Impotence

 -  Early menopause

  - Abnormal pigmentation of the skin, making it look gray or bronze

  - Damage to the pancreas, possibly causing diabetes

   -Thyroid deficiency

   -Damage to the adrenal gland

CLINICAL MANIFESTATIONS  Emesis ( Vomiting)

- Stimulation of Area Postrema

- Caused by: Hepatitis, Increased Intracranial Pressure

Esophageal varices

- Dilated submucosal veins in the lower esophagus

- tendency to Bleed

CLINICAL MANIFESTATIONS  Icterus

-Due to hyperbilirubinemia

-causes:

Pre-Hepatic: inc. Hemolysis

Hepatic: Hepatitis, Hepatotoxicity, Alcohol Liver cirrhosis, Primary Biliary cirrhosis

Post-Hepatic: Obstruction

CLINICAL MANIFESTATIONS  Sjogren syndrome - AKA : Sicca syndrome- Autoimmune disorder directed to exocrine

glands ( Tears & Saliva)- Affected patients: 9/10 are Women- Average age of onset: 40- Affects Kidney, Blood vessels, Lungs,

pancreas, Brain

CLINICAL MANIFESTATIONS  Raynauld’s syndrome- Vasospastic disorder causing discoloration

of the finger, toes & extremities- Assoc. w/ other disorders like Sjogren

syndrome- Due to prolonged stimulation by the

Sympathetic Nervous system.

CLINICAL MANIFESTATIONS  Antimitochondrial antibodies- Antibodies against the Mitochondria of

the liver cells;- Pyruvate dehydrogenase- 2-oxoglutarate dehydrogenase- Branched- Chain 2-oxo acid

dehydrogenase

Etiology of Hepatic disease Infectious disorders Autoimmune Hepatitis Drug and Toxin induced liver disease Metabolic Liver diseases Intrahepatic Biliary tract diasease Circulatory disorders Nodules and Tumors

The Causes of Cirrhosis Alcoholic liver disease – 60% to 70% Viral Hepatitis – 10% Biliary diseases – 5% to 10% Primary Hemochromatosis- 5% Wilson’s diasease – Rare Alpha 1 Antitrypsy defficiency –Rare Cryptogenic cirrhosis – 10 to 15 %

Laboratory Studies Elevation of :

- alanine aminotransferase (ALT)

- aspartate aminotransferase (AST)

- alkaline phosphatase (ALP)

- g -glutamyl transpeptidase (GGTP)

- immunoglobulin levels (mainly IgM)

significant

Lipid levels and cholesterol levels may be increased

increased high-density lipoprotein (HDL) fraction

increased erythrocyte sedimentation rate(ESR)

As the disease progresses to cirrhosis:elevated bilirubin level (ominous sign of

disease progression)prolonged prothrombin timedecreased albumin level

Thrombocytopenia is indicative of portal hypertension

Antimitochondrial antibodies (AMAs)-hallmark

• 90-95% of patients with primary biliary cirrhosis• specificity of 98%• anti-M2, anti-M4, anti-M8, and anti-M9

associated with the severity of primary biliary cirrhosis.

• Enzyme-linked immunosorbent assay [ELISA])

○ profile A only anti-M9 – positive by ELISA

○ profile B anti-M9 and/or anti-M2–positive by ELISA

○ profile C anti-M2, anti-M4, and/or anti-M8–positive by

ELISA

○ profile D anti-M2, anti-M4, and/or anti-M8–positive by

ELISA and complement-fixation test

Antinuclear antibodies (ANAs)20-50% of patients with primary biliary cirrhosis

Some patients have clinical, biochemical, and histological features of primary biliary cirrhosis, but their sera are negative for AMA

The diagnosis of autoimmune cholangitisbut whether these patients represent the AMA-

negative primary biliary cirrhosis group is a matter of debate

Imaging Studies

Abdominal ultrasonography CT scan MRI

important to exclude biliary obstruction

MORPHOLOGY

Primary biliary cirrhosis

-is a chronic disease that causes the bile ducts in the liver to become inflamed and damaged and, ultimately, disappear. Bile is a liquid produced in the liver that travels through the bile ducts to the gallbladder and then the small intestine, where it helps digest fats and fat-soluble vitamins A, D, E, and K. When the bile ducts become damaged from chronic inflammation, bile builds up in the liver, injuring liver tissue.

-*normal liver and biliary system

Injured liver tissue from chronic inflammation and the buildup of bile leads to cirrhosis, a condition in which the liver slowly deteriorates and malfunctions. Scar tissue replaces healthy liver tissue, partially blocking the flow of blood through the liver.

Primary biliary cirrhosis

GROSS

Primary Biliary Cirrhosis:formation of nodules                                  

T cell mediated destruction of the bile ducts of the liver. This results in the bile ducts becoming clogged or destroyed, resulting in fibrosis and degeneration of the hepatocytes.

Note the lymphocyte infiltration and the absence of bile ducts 

A liver with macronodular cirrhosis

Primary biliary cirrhosis

Due to the autoimmune nature of the disease, there is infiltration of the liver with macrophages and other lymphocytes which results in an intense inflammatory response.

•Bile duct intraepithelial lymphocytes - key feature.

•Bile duct epithelial cells with eosinophilic cytoplasm.

•Granulomata - close to the bile duct.

•Portal inflammation with mixed cell population, i.e. lymphocytes, plasma cells, eosinophils.

Primary biliary cirrhosis with fibrosis

Primary biliary cirrhosis with portal granuloma

Primary biliary cirrhosis with bile duct inflammation and damage

Drug therapy Immunosuppressive drugs- corticosteroids are not

as useful as expected though marked relief of fatigue and pruritis is seen. However, risk of osteoporosis limits its use.

Colchicines- it is safe and free of toxic effects but despite improvement in hepato-cellular function it has no effect on survival.

Ursodeoxycholic acid (UDCA) – it is a non-hepatotoxic bile acid which has a potential of reversing hepatotoxicity of endogenous bile acids. It is a promising drug with modest reduction in death rates.

Liver transplantLiver transplantation is the only option for patients

with PBC with.

life-threatening end-stage liver disease and its complications.

severe intractable symptoms (severe pruritus, profound fatigue, and severe bone disease).

patients with PBC are good candidates for transplantation and have a better long-term prognosis compared to those with other common.

Survival is excellent 85% at 5 years