liver

Hepatobiliary and pancreatic disorders

ANATOMY This is the external surface of a normal liver. The color is brown and the surface is smooth. A normal liver is about 1200 to 1600 grams.

HISTOLOGY

• Hexagonal plates

• Portal Triads
• Bile duct branch
• Arteriole
• Venuole
• Blood flows from periphery to Central vein
• Sinusoids


The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.

Patterns of hepatic injury

Following hepatic injury, the liver has a limited set of responses:
Necrosis
Inflammation
Regeneration
Fibrosis.

LABORATORY EVALUATION OF LIVER DISEASE Hepatocyte integrity, enzymes -(AST, ALT)

Hepatocyte function -(serum albumin, prothrombin time)
Biliary excretory function -substances secreted in bile .(serum bilirubin)
-plasma membrane enzymes (from damage to bile canaliculi) .(serum alkaline phosphatase)

FUNCTIONS

The liver performs multifold functions:
• Synthesis of several major plasma proteins.
• Metabolism of proteins, carbohydrates and lipids.
• Storage of vitamins (A, D and B12) and iron.
• Detoxification of toxic substances such as alcohol and drugs.
• Manufacture and excretion of bile


BILIRUBIN METABOLISM AND BILEFORMATION
Bilirubin Production:

Source of Bilirubin

Major (85%) is derived from the catabolism of hemoglobin during the breakdown of senescent red cells.
Minor (15–20%) is derived from the degradation of heme produced from other sources ( premature destruction of hemoglobin in developing red cell precursors in the bone marrow).

Bile Formation

Hemoglobin breakdown

Conversion in liver to water soluble form Bilirubin

Excretion in bile

Some is reabsorbed

Jaundice and Cholestasis
Definition: yellowish pigmentation of skin, mucous membranes and sclera due to increased levels of bilirubin in the blood. .
Normal serum bilirubin level: 0.3 to 1.2 mg/dL.
Jaundice: > 2.0 to 2.5 mg/dL.
Indirect hyperbilirubinemia is called when unconjugated bilirubin is 85% or more of the total bilirubin.
insoluble in water complexed to serum albumin, it can not be secreted in urine.

Direct hyperbilirubinemia corresponds to conjugated bilirubin more than 15% of total.

Conjugated bilirubin is water soluble & loosely bound to albumin. It's excess can be excreted in urine.

• Classification of Jaundice

1. Based on the type of bilibobin:
Predominantly unconjugated
Predominantly conjugated.

2. Based on the underlying cause:

Hemolytic jaundice
Hepatocellular jaundice
Obstructive jaundice.

Predominantly Unconjugated Hyperbilirubinemia

1- Excess Production of Bilirubin
Hemolytic anemias
Ineffective erythropoiesis
Internal hemorrhage (e.g.hematomas)
2- Reduced Hepatic Uptake
Drugs
Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)
3- Impaired Bilirubin Conjugation
Physiologic jaundice of the newborn


Predominantly Conjugated Hyperbilirubinemia
4- Decreased Hepatocellular Excretion
Drug-induced canalicular membrane dysfunction (e.g., oral contraceptives)
Hepatocellular damage or toxicity (e.g., viral or drug-induced hepatitis)
5- Impaired Intra- or Extrahepatic Bile Flow
Inflammatory destruction of intrahepatic bile ducts (e.g., primary biliary cirrhosis, primary sclerosing cholangitis ) gall stones, carcinoma of the pancreas
• Causes of Jaundice

CHOLESTASIS

Definition : is the impairment of bile flow resulting in the retention of bilirubin, bile acids, and cholesterol.
Clinical features : jaundice, pruritis, skin xanthomas, malabsorption syndrome.
Results from: - Primary hepatocellular dysfunction (e.g. neonatal cholestasis, drug cholestasis, sepsis) .

- Bile duct injuries, mechanical (e.g., obstruction of large ducts by stones or tumor) or inflammatory (such as autoimmune diseases).
Characteristic laboratory finding: elevated serum alkaline phosphatase

Morphology :

1.Accumulation of bile pigment within hepatic parenchyma :
2.Distention of bile ducts
3. bile lakes with cellular debris &pigment .
4. Portal tract edema.
5. Portal fibrosis on long standing obstruction leading to biliary cirrhosis

Liver, intracellular cholestasis

Cholestasis: Prominent bile plugs are present in dilated canaliculi .

CIRRHOSIS

Definition : It is the end stage of chronic liver disease defined by three characteristics:
1. Disruption of the architecture of the entire liver
2. Bridging fibrous septae : bands of fibrosis that link portal tracts with one another and portal tracts with centrilobular veins.
3. Parenchymal nodules containing regenerating hepatocytes encircled by fibrosis
Types :
micronodular ( if nodule is <3mm)
macronodular (>3 mm)
mixed.

Causes of cirrhosis

• Alcoholic liver disease
• Viral hepatitis
• Non-alcoholic steatohepatitis (NASH)
• Autoimmune liver disease (autoimmune hepatitis and primary biliary cirrhosis)
•primary Hemochromatosis
• Wilson disease
• a-1-antitrypsin deficiency
•Cryptogenic/idiopathic

Pathogenesis

Four important processes are involved:
Death of liver cells with loss of architecture.
Regenerating nodules: The surviving hepatocytes regenerate and proliferate to form regenerating nodules.
Fibrosis : It is mainly due to the activation of hepatic stellate cells, which are transformed into highly fibrogenic cells called myofibroblasts.
Vascular reorganization: The parenchymal damage and fibrosis disrupt the vascular architecture of the liver.

Clinical features

-asymptomatic
-non-specific (anorexia, weight loss , weakness)
-hepatic failure

Complications of cirrhosis

Death is due to :
1. Progressive liver failure
2. Portal hypertension related complications
3. The development of hepatocellular carcinoma.

• Histopathological Features of cirrhosis:

Grossly
• The liver may be normal in size, enlarged, or shrunken.
• The cut surface has a firm texture and shows diffuse nodularity.

Microscopically

The regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts

CIRRHOSIS, TRICHROME STAIN

INFLAMMATORY & INFECTIOUS DISORDERS

INFLAMMATORY & INFECTIOUS DISORDERS
Very common condition , include:
• Infection
• Viruses
• Hepatic specific
• EBV
• CMV
• Bacteria
• Cholangitis
• Abscesses
• Parasites
• Autoimmune
• Toxins and drugs


Viral Hepatitis
Definition: viral infection of hepatocytes that produces necrosis and inflammation of the liver.
It is a common cause of hepatitis.
Generally taken to mean hepatic specific viruses.

Hepatitis A

RNA picovirus
Transmission—faecal-oral route
Time course— incubation period of 2-6 weeks .
virus is shed in stool for 2-3 wks before & 1 wk after onset of jaundice can also be detected in serum & saliva.
Prognosis— self-limited disease
Full recovery with restoration of normal liver function tests.
No chronic hepatitis
No carrier state

The fatality rate associated with HAV is only about 0.1-0.3%.

A vaccine is available for long-term immunity.

Hepatitis B

DNA virus of the Hepadna group. It can integrate into host DNA.
Incubation period 4-26 wks.
Transmission :
• • blood-borne—blood transfusions, IV drug abusers,
• tattooing, acupuncture
• • sexual—sexual intercourse
• • vertical—transmission from mother to child; either
• perinatally (transplacental) or postnatally (breast
• milk).

The viral genome encodes:

Surface glycoprotein (HBs Ag).
Anucleocapsid core protein (HBc Ag ) .
A DNA polymerase which exhibit reverse transcriptase activity .
A protein (HBX) act as transcriptional transactivator ,is necessary for viral replication ,play a role in hepatocellular carcinoma.

Potential outcomes of hepatitis B infection in adults

Potential outcomes of hepatitis B infection in adults -acute hepatitis with recovery -nonprogressive chronic hepatitis -progressive chronic disease>cirrhosis -fulminant hepatitis -asymptomatic carrier state (presence of HBs Ag in serum for 6 months or longer) -hepatocellular carcinoma

Hepatitis C Virus

This RNA flavivirus

• Incubation period 2-26 weeks

• Transmission
—predominantly blood-borne spread among intravenous drug, although sexual and vertical transmissions do occur.

The potential outcomes of hepatitis C infection in adults

The potential outcomes of hepatitis C infection in adults -acute hepatitis. -chronic hepatitis. characteristic clinical feature is episodic elevations in serum aminotransferases -cirrhosis. in 20%-30% of patients with chronic infection after 5-20y of acute infection

Pathological features of viral hepatitis

1- Acute viral hepatitis

2- Chronic viral hepatitis

Acute viral hepatitis

1. Inflammation:
– Lobular inflammation: Inflammation involving liver parenchyma throughout the lobule mainly consists of lymphocytes and macrophages.
– Interface hepatitis .

2. Hepatocyte injury:

– Ballooning degeneration: swelling of hepatocytes, empty and pale stained cytoplasm .

– Hepatocyte necrosis:

i. Dropout necrosis: aggregates of macrophage around necrotic hepatocyte.
ii. Councilman body: Apoptotic hepatocytes shrink become intensely eosinophilic and have with a densely staining pyknotic or fragmented nuclei .
iii. Bridging necrosis : band/zone of necrosis may extend from portal tract to portal tract, central vein to central vein, or portal-to-central regions of adjacent lobules.


3. Lobular disarray: disruption of the normal orderly architecture of the liver
cell plates.

Chronic viral hepatitis

1- Inflammation:
i. Portal inflammation: In mid hepatitis, inflammation is limited to portal tracts and predominantly consists of lymphocytes, macrophages, and occasional plasma cells.
ii. Interface hepatitis (periportal necrosis): It is spillover of inflammatory cells from portal tract into the adjacent periportal hepatocytes.
iii. Parenchymal inflammation and necrosis: It is variable in severity but usually spotty. Mononuclear inflammatory cells surround the damaged hepatocytes. Bridging necrosis between portal tracts and portal tracts-to-terminal hepatic veins may be seen.

2. Fibrosis: It is the hallmark of chronic liver damage due to continued inflammation and associated necrosis.
a. portal tracts.
• Periportal fibrosis
• bridging fibrosis between adjacent fibrotic portal tracts (i.e. portal to portal) or portal-central.








Acute viral hepatitis, Lobular inflammation

Ballooning degeneration

Chronic viral hepatitis, Portal Inflammation

Chronic viral hepatitis








Chronic HBV hepatitis, ground-glass hepatocytes

ALCOHOLIC LIVER DISEASE

ALCOHOLIC LIVER DISEASE
Excessive ethanol consumption is a common cause of chronic liver disease in Western countries and accounts for up to 50% of deaths due to cirrhosis.

Chronic heavy drinkers are predisposed to 3 distinctive forms of alcoholic liver disease; these may overlap.
1. Hepatic steatosis (almost all heavy drinkers)
2. Alcoholic steato hepatitis (30%)
3. Cirrhosis (15%)

Steatosis

Steatohepatitis
Cirrhosis
ALCOHOLIC LIVER DISEASE


ALCOHOLIC LIVER DISEASE
Alcoholic cirrhosis
Alcoholic hepatitis
Hepatic steatosis
• Irreversible form of
alcoholic liver disease

• Initially, liver is

enlarged and later
there is presence of
micronodules .

• Later, the whole liver

has tough, pale scar
tissue (Laennec
Cirrhosis).
• Grossly : liver is mottled red & yellow-green (bile stained) may increase in size.

•hepatocyte swelling

and necrosis (ballooning
degeneration)


• Neutrophilic infilitration in lobule

• Perivenular and periportal

fibrosis

• Some hepatocytes show eosinophilic, cytokeratin filaments called

‘Mallory Hyaline bodies’.
• Grossly : liver is large (up to 4 or even 6 kg), soft, yellow, and greasy

• small (microvesicular) or

large (macrovesicular)
lipid droplets inside the
hepatocytes

• Initial centrilobular

involvement followed by
entire lobule involved

• Reversible if there is

abstinence from alcohol.


Hepatic Steatosis (Fatty Liver)

Alcoholic Hepatitis

Liver cell ballooning
degeneration

Neutrophils

Mallory bodies

Alcoholic Cirrhosis

About 15-20% of alcoholics
Micronodular pattern.

METABOLIC LIVER DISEASE

METABOLIC LIVER DISEASE

1. Nonalcoholic fatty liver disease

2. Hemochromatosis
3. Wilson disease
4. α1-antitrypsin deficiency.

Nonalcoholic Fatty Liver Disease (NAFLD)

May present as :
Steatosis (fatty liver)
Nonalcoholic steatohepatitis (NASH) similar to alcoholic hepatitis.
Cirrhosis.

Pathogenesis: genetics & environment factors
“two-hit” model .hepatic fat accumulation .hepatic oxidative stress
1. Insulin resistance including Type 2 diabetes, is the most common associated condition . Insulin resistance results in the accumulation of triglycerides in hepatocytes.
2. Obesity
3. Dyslipidemia (hypertriglyceridemia, low HDLP cholesterol, high LDLP cholesterol).
The presence of type 2 diabetes and obesity are the best predictors of severe fibrosis and disease progression.


Clinical features :
Most persons with steatosis are asymptomatic; NASH may also be asymptomatic, or present with symptoms of chronic liver disease.

Steatosis (fatty liver)

Non-alcoholic steatohepatitis. Moderate macrovesicular fatty change is seen with a moderate predominantly neutrophilic infiltrate.



Non-alcoholic fatty liver disease, cirrhotic stage. regenerative nodules are small and rather well-circumscribed (“micronodular”). Moderate fatty change is present.



HEMOCHROMATOSISExcessive accumulation of body iron, mostly in liver & pancreas Types -primary -secondary (hemosiderosis)


primary (hereditary) hemochromatosis
• Autosomal recessive, due to excessive intestinal absorption of iron
• Mainly at 5th decade of life
• Males predominate by 5:1 to 7:1
• Fully developed cases show trade of :
1. Cirrhosis (all patients)
2. Diabetes mellitus (75%)
3. Skin pigmentation (75%).

• Pathogenesis: Excessive iron is toxic to tissues through: -lipid peroxidation via free radicals. -stimulation of collagen via activation of stellate cells -interaction of reactive oxygen species & iron with DNA lethal cell injury or hepatocellular carcinoma

Microscopic features

The golden-yellow hemosiderin granules accumulate in the cytoplasm of periportal hepatocytes; these stain blue with the Prussian blue stain.
Iron is a direct hepatotoxic, and inflammation is characteristically absent.

Hemochromatosis, golden-yellow hemosiderin granules accumulate in the cytoplasm of hepatocytes






Hemochromatosis, Prussian blue stain

WILSON DISEASE

Autosomal-recessive disease due to deficiency of ATP7B enzyme, results in deposition of cupper in various tissues: - liver, (steatohepatitis, necrosis, cirrhosis) - brain, (damage to basal ganglia) - eye, (Kayser-Fleischer ring)

Copper physiology:

-Absorption from GIT (2-5mg/day) to the liver.
-In hepatocytes some cupper molecules bind to ceruloplasmin (copper- binding protein) by enzyme ATP7B ,while the excess of cupper excreted to the bile.
-Resecretion of ceruloplasmin in plasma.

.In wilson dis.

Copper absorption & transport to liver is normal
Failure of ceruloplasmin formation & biliary excretion of Copper is ⇓ ↠ Copper accumulation in liver ↠ toxic free radicals injury.
With time ,Copper is deposited in other organs (brain & cornea) with ↑ urinary excretion of copper.

Morphology:

acute hepatitis
chronic hepatitis
cirrhosis
massive liver necrosis
copper can be demonstrated on liver biopsy by special stain (Rhodanin stain ).

Kayser-Fleischer Rings

Rhodanin stain

α1-Antitrypsin Deficiency

Autosomal recessive disease.
α1- antitrypsin enzyme is synthesized in hepatocytes, it is a major protease inhibitor to neutrophil elastase secreted at inflammatory sites.

Pathogenesis

-Mutation cause misfolded protein which accumulate in the endoplasmic reticulum.
- Accumulation of α1AT in endoplasmic reticulum leads to: .mitochondrial dysfunction .inflammation & hepatocyte damage

Morphology :

The hepatic involvement ranges from neonatal hepatitis with fibrosis to childhood cirrhosis to chronic hepatitis & cirrhosis appear later in life.
Liver cells contain round to oval cytoplasmic globular inclusions which are acidophilic.

α1-antitrypsin deficiency, PAS stain

α1-antitrypsin deficiency, EM showing dilatation of endoplasmic reticulum