50 year old male who had been a heavy drinker for 20 years.

He had been in and out

of the hospital for the past year because of recurrent bouts of ascites associated with
jaundice and emaciation. Ultrasound of the liver shows hepatomegaly. Based on the
above history of sonographic findings, the patient was diagnosed as a case of fatty
steatosis (fatty change of liver).

Risk factors: Age – 50 yr. old; Gender – Male; Lifestyle – Heavy drinker for 20 yrs
Symptoms: Recurrent bouts of ascites associated with jaundice and emaciation
Labs: UTZ of liver – hepatomegaly
Differentials: Alcoholic hepatitis, Alcoholism, Malabsorption
Diagnosis: Fatty steatosis (?)

Questions and guide to discussion :

1. Review the anatomy and histology of the organ involved.

 Liver - largest organ of the body,

 Weight - 1–1.5 kg
 Size and shape - Vary and generally match the general body shape—long
and lean or squat and square.
 Location - RUQ of the abdomen under the right lower rib cage
 Blood supply - dual; ~20% of the blood flow = oxygen-rich blood from the
hepatic artery, 80% = nutrient-rich blood from the portal vein
 Cell types found in the liver: hepatocytes, Kupffer cells, stellate cells,
endothelial cells and blood vessels, bile ductular cells, and supporting
structures.
 Light microscopy: organized in lobules, with portal areas at the periphery
and central veins in the center of each lobule.
 Hepatocytes - distinct polarity. Basolateral = lines the space of Disse and
is richly lined with microvilli; it demonstrates endocytotic and
pinocytotic activity. Apical = forms the cannicular membranes through
which bile components are secreted. The canniculi of hepatocytes form a
fine network, which fuses into the bile ductular elements near the portal
areas.
 Kupffer cells - lie within the sinusoidal vascular space and represent the
largest group of fixed macrophages in the body.
 Stellate cells - located in the space of Disse but are not usually prominent
unless activated, when they produce collagen and matrix.
 Red blood cells - stay in the sinusoidal space as blood flows through the
lobules
 White blood cells - migrate through or around endothelial cells into the
space of Disse and from there to portal areas, where they can return to
the circulation through lymphatics.
 Functions of hepatocytes:
- synthesis of most essential serum proteins,
 - production of bile and its carriers,
- the regulation of nutrients, and metabolism and conjugation of lipophilic
compounds for excretion in the bile or urine.
 Most commonly used liver "function" tests:
- serum bilirubin,
- albumin,
- prothrombin time.
 Serum bilirubin level - measure of hepatic conjugation and excretion,
 Serum albumin level and prothrombin time - measures of protein
synthesis.
 Abnormalities of bilirubin, albumin, and prothrombin time are typical of
hepatic dysfunction.
 Frank liver failure is incompatible with life, and the functions of the liver
are too complex and diverse to be subserved by a mechanical pump;
dialysis membrane; or concoction of infused hormones, proteins, and
growth factors.

2. Understand how these cells respond to injury

3. Identify type of cell injury in this case. Is this reversible or irreversible?

 The fatty change is completely reversible if there is abstention from

further intake of alcohol.

4. Discuss the mechanism of cell injury with emphasis to this particular

case.

Hepatocyte Steatosis characteristic histologic features:

 Ballooning - due to accumulation of fat
 Apoptosis
 Lobular inflammatory infiltrate

 Ethanol – causes changes of mitochondrial and microsomal dysfunction

- causes oxidative stress
- Bax (anti- or pro-apoptosis regulator) tanslocation to
mitochondria
- Mitochondrial permeability (cytochrome c release and caspase
activation)
- Induces cytochrome P450 2E1 in hepatocytes leading to
formation of reactive oxygen species (ROS).
- Activation of Kupffer cells (secretes multiple inflammatory
cytokines that further promote liver inflammation

o Cytokines secreted by Kupffer cells:

 1. TNF-a – mediates both hepatocyte apoptosis and hepatic
inflammation
2. TNFR – enhanced in chronic alcohol ingestion

 Mode of cell death of hepatocytes – apoptosis

 Acetaldehyde – an ethanol metabolite, induces ER stress in cell culture

systems leads to mitochondrial dysfunction

5. Discuss the causes of cell injury with emphasis to this particular case.

 Oxygen Deprivation
- Lipid peroxidation in membranes
 Acetaldehyde (major intermediate metabolite of alcohol)
 Reactive oxygen species produced by Cytochrome P-450
- Oxidative modification of proteins
 Methionine
 Drugs
- Induction of CYP2E1 and other Cytochrome P-450 enzymes
 Infectious Agents
- Release of bacterial endotoxin from the GUT into the portal circulation
 Nutritional Imbalance
- Displacing other nutrients
- Leading to Malnutrition
- Deficiency of Vitamins (such as Thiamine)
 Others
- Stimulates the release of Endothelins from sinusoidal endothelial cells

6. Describe the morphologic alterations in cell injury.

 Hepatocyte swelling and necrosis

- Single or scattered foci of cells undergo swelling and necrosis
- Results from the accumulation of fats and water, as well as protein
 Mallory Bodies
- Scattered hepatocytes accumulate tangled skeins of cytokeratin
intermediate filaments such as Cytokeratin 8 and 18
- Visible as Eosinophilic Cytoplasmic Clumps in hepatocytes
 Neutrophilic Reaction
- Neutrophils permeate the hepatic lobule and accumulate around
degenerating hepatocytes
 Fibrosis
- Prominent activation of sinusoidal stellate cells and portal tract
fibroblasts

7. Identify type of intracellular accumulation in this case and discuss its

etiopathogenesis that leads to accumulation of abnormal amounts of
this substance intracellularly.

 Liver is involved in fat metabolism.

 Fatty change in the liver is caused by accumulation of endogenous products,
which are formed by abnormal synthesis or metabolism.
 In this case, cause of steatosis is due to toxins from alcoholic beverages.
(Alcohol is a hepatotoxin that alters mitochondrial and microsomal functions,
and membrane permeability, leading to increased and reduced breakdown of
lipids)
 Patho – excess accumulation of trigylcerides within the liver parenchymal
cells (hepatocytes) caused by reduced synthesis of apoproteins. (Apoprotein
is a lipid-binding protein that is a constituent of the plasma lipoprotein.)

Mechanisms for triglyceride accumulations in the liver:

Free fatty acids from adipose tissue or ingested food are normally
transported into hepatocytes. In the liver they are esterified to triglycerides,
converted into cholesterol or
phospholipids, or oxidized to ketone bodies. Release of triglycerides from the
hepatocytes requires association with apoproteins to form lipoproteins,
which may be transported from the blood into the tissues. Excess
accumulation of triglycerides within the liver may result from excessive
entry. Several such defects are induced by alcohol.

 Intracellular accumulations – triglycerides

o Moderate intake of alcohol – microvesicular lipid droplets in
hepatocytes
o Chronic intake – large, clear macrovesicular globules that compress
and displace the hepatocyte nucleus to the periphery of the cell
 8. Discuss the clinic-pathologic correlation of cell injury in this particular
case.

GROSS APPEARANCE
 Soft
 Yellow
 Greasy
 Large ( 4 to 6 kg)

Highlights:
↑ Free Fatty Acids (chronic alcoholism)
↓ Oxidation of Free Fatty Acids
↑ Esterification of Free Fatty Acids into Triglycerides (which is caused or secondary
to changes to the first two changes mentioned)
↓ Export of Triglycerides due to deficiency of lipid binding apoprotein

Supporting facts:
↑ Hepatic levels of glycerol 3-phosphate after ethanol ingestion is related to...
↑ Ratio of the reduced form of nicotinamide adenine dinucleotide (NAD) to the
reduced form (NADH) in the liver...
↑ Concentration of 3-GP results in enhanced esterification of fatty acids (factor 3,
which would stimulate the following cascading effects leading to Fatty Steatosis).

 Large amounts of alcohol enhance lipolysis through direct stimulation of the

adrenal-pituitary axis.
 Chronic ethanol ingestion (alcoholism) inhibits oxidation of fatty acids in the
liver (factor 2) and release VLDL into the blood.
-These mechanisms lead to/ or favour steatosis.
 SCHEMATIC DIAGRAM OF HEPATIC STEATOSIS

Predisposing factors: Precipitating factors:

- Heredity - Alcoholic (long term
- Metabolic disorder (Iron ingestion of at least
overload, Glycogen storage dse, 80g/day of ethanol)
Wilson’s dse) - *female: 20g/day
- Females are more prone than - *male : 40g/day
males but reports have higher - Poor diet
cases in males - Diet high in fat/low in
- Highly civilized countries protein
- obesity

Increased Liver synthesis of triglycerides and

fatty acid reduction in oxidation of Fatty acid and
decreased release of lipoprotein

Fat accumulation in the parenchymal cells of

liver and distention of cytoplasm with fats

LIVER STEATOSIS / FATTY

LIVER

Differential diagnosis:
 LIVER STEATOSIS HEPATITIS CIRRHOSIS

Weak Fever Portal hypertension

Poor appetite Abdominal pain Ascites
Nausea Ascites Bleeding tendencies
Malaise Loss of muscle mass Splenomegaly
Weight loss Jaundice Jaundice
Jaundice Palmar erythema
Itchiness of the skin Bone marrow changes
Liver enlargement Ankle edema
Fever
Abdominal pain
Ascites
Splenomegaly
Loss of muscle mass

Jaundice and Ascites in Fatty Liver:

 Jaundice :
o Bile formation requires healthy hepatocytes. If hepatocytes are not
fully functional, a yellow discoloration becomes evident in the skin
and sclera due to retention of pigmented bilirubin.
o Diminished heaptic uptake of bilirubin
o Defective hepatic conjugation of bilirubin

 Ascites
o Due to inability of the liver to produce enough protein to retain fluid
in the bloodstream. Normally, water is held in the bloodstream by
oncotic pressure. The pull of proteins keep water molecules from
leaking out of the capillary blood vessels into the surrounding tissue.

Treatment:
 alcohol withdrawal and provision of an adequate diet