Zachary D. Goodman, M.D., Ph.D.
Division of Hepatic Pathology
Armed Forces Institute of Pathology
Microvesicular steatosis can be defined as the accumulation of numerous small lipid droplets in hepatocyte
cytoplasm, leaving the nucleus centrally placed and giving the affected cell a foamy appearance.
Microvesicular steatosis is usually contrasted with macrovesicular steatosis, in which a single large fat
droplet is present, distending the hepatocyte and displacing the nucleus to the edge of the cell, often out
of the plane of section. The size of the fat droplets in microvesicular steatosis is seldom mentioned as a
criterion for recognition of the lesion. Sizes of up to 4 m or less that 1 m have been suggested,1,2 but
in fact, lesions recognizable as microvesicular steatosis may have fat vacuoles as large as 30 m or so small
as to be less than the resolving power of the light microscope.
Causes of Microvesicular Steatosis (adapted from reference 3, with some additions)
Acute fatty liver of pregnancy
Jamaican vomiting sickness
Multiple hornet stings
Alcoholic foamy degeneration
Inherited urea cycle disorders
Inherited disorders of fatty acid metabolism
Cholesterol ester storage disease
Hepatitis D in Amazonian Indians (Labrea fever)
Bacillus cereus toxin
Acute iron toxicity
Nonspecific or Physiologic Microvesicular Steatosis
Some degree of microvesicular fat is a normal finding in human hepatocytes, although it may only be
visualized with fat stains or by electron microscopy. In times of injury, illness or other forms of
metabolic stress, there may be increased amounts of cytoplasmic lipid droplets as the body mobilizes energy
reserves, probably accounting for some of the items (such as hornet stings, heat stroke, and ecstasy
intoxication) on the list of causes. Fat stains performed on frozen sections of livers from autopsies of
hospitalized adults2 and children dying of trauma4 have shown that some degree of microvesicular
steatosis is nearly always present, even though it is often not appreciated with routine paraffin-embedded
sections. Consequently, microvesicular steatosis alone should never be used to establish a diagnosis
without supportive clinical and biochemical findings.
Microvesicular fat droplets are also frequently seen in livers with macrovesicular steatosis of any cause.
In such cases, it may be presumed that the small droplet fat is a stage in the development of large droplet
Genetic Disorders of Mitochondria
Over the past fifty years a number of disorders were recognized in which microvesicular steatosis was
associated with severe metabolic abnormalities, often leading to liver failure and metabolic encephalopathy.
The major advance in understanding of this group of diseases is the recognition that most if not all are due
to interference with mitochondrial function which may result in overproduction of toxic metabolites that
interfere with cellular metabolism and/or inadequate production of energy and energy-producing substrates.
The tissues that are most severely affected by these disorders are those that rely most heavily on
mitochondrial energy production - the liver, skeletal muscle, heart and brain. The clinical syndromes that
have been recognized over the years relate to the degree of involvement of each of these tissues.
Fatty acid transport and oxidation disorders - There are currently 22 recognized autosomal recessive
diseases (mostly rare) in this group, each representing an abnormality in one of the membrane-bound
transport proteins (3 plasma membrane proteins, 9 mitochondrial membrane proteins) or one of 10 enzymes of
the mitochondrial matrix involved in the metabolism of fatty acids to produce energy.5,6,7 Most diseases
in this category present in early childhood with an acute illness that often becomes manifest after a period
of fasting or a viral illness. Patients may have a "Reye's-like" syndrome with hyperamonemia, hypoglycemia,
encephalopathy and microvesicular steatosis on liver biopsy; or the clinical picture may be dominated by
skeletal or cardiomyopathy; or there may be sudden unexplained death. Medium-chain acyl-CoA dehydrogenase
deficiency with an estimated incidence of 1 in 10,000 live births is the most common of these.
Mitochondrial oxidation chain disorders - These are also sometimes called "mitochondrial cytopathies."
Defective enzyme complexes in the mitochondrial oxidative phosphorylation chain can manifest as neonatal
liver failure associated with lactic acidosis and hypotonia; or they may present as or it may present as
progressive liver failure leading to cirrhosis, and usually associated with hypotonia, refractory epilepsy
and neurologic deterioration with death by age four. Such cases have been called Alpers' syndrome.
Steatosis, often microvesicular, is a frequent finding in the liver. Some cases (Pearson's syndrome) have
been associated with bone marrow and pancreatic disease rather than neurologic disease.5,8,9
Mitochondrial DNA depletion - This presents with neonatal or early childhood liver failure which no
qualitative defect in mitochondrial genes but with an overall depletion of mitochondrial DNA, thought to be
due to a defective nuclear regulatory factor.5,8,9 It has also been suggested that a mitochondrial DNA
depletion syndrome is the cause of Navajo neuropathy (or neurohepatopathy), in Navajo Indian children,
characterized by severe neurologic deterioration associate with a Reye's-like syndrome or chronic liver
disease and cirrhosis.5,9,10
Acquired Disorders of Mitochondria
Drug induced and toxic mitochondrial injury with microvesicular steatosis - Some genetic disorders of
mitochondrial function that lead to severe metabolic derangement with microvesicular steatosis can be
mimicked by certain drugs and toxins.11,12 Fialuridine (FIAU) is a nucleoside analog that was tried as a
treatment for chronic hepatitis B. The drug was highly successful in suppressing hepatitis B replication,
but unfortunately it also suppressed mitochondrial DNA synthesis, producing a syndrome of mitochondrial DNA
depletion with hepatic failure, lactic acidosis and pancreatitis in a few patients before the trial was
terminated. Microvesicular steatosis and swollen mitochondria were seen in explanted livers.12
Nuceloside analogs such as zidovudine (AZT) and didanosine (ddI) used to treat HIV infection are less toxic,
but with prolonged therapy they may produce a similar toxic injury.
Several drugs can produce liver injury with microvesicular steatosis by interfering with fatty acid
beta-oxidation, producing a Reye's-like syndrome. Valproic acid is transported by carnitine and metabolized
to valproyl-CoA, thus depleting the substrates of short, medium and long-chain acyl-CoA dehydrogenases.
Aspirin is metabolized to salicylyl-CoA and can also interfere with fatty acid metabolism in high doses,
causing microvesicular steatosis. Several other drugs, inclding ketoprofen, and amineptine are thought to
cause injury on occasion by similar mechanisms, as does hypoglycin A, a toxin in unripe ackee fruit, which
causes Jamican vomiting sickness. The exotoxin produced by Bacillus cereus has also been shown to inhibit
beta-oxidation, producing liver failure.13 Tetracyclines may cause liver injury with microvesicular
steatosis and liver failure, especially when given in large intravenous doses as occurred in the
mid-twentieth century. These drugs not only inhibit beta-oxidation of fatty acids but also inhibit protein
synthesis and thus block the secretion of lipoproteins by hepatocytes.
Microvesicular steatosis probably due to mitochondrial injury
Alcoholic foamy degeneration - It has been recognized that some patients who engage in alcoholic binge
drinking present with a clinical picture that mimics decompensated alcoholic hepatitis, while their liver
biopsies show only microvesicular steatosis.14 Mitochondrial toxicity is well-recognized in all forms of
alcoholic liver disease, so it seems likely that the lesion of alcoholic foamy degeneration is related to
Acute fatty liver of pregnancy - This was the first recognized disorder of microvesicular steatosis, but its
pathogenesis is still incompletely understood. The typical patient is a woman in the third trimester of
pregnancy who presents with liver failure, hypoglycemia and jaundice. Liver biopsy typically shows
microvesicular steatosis, and the patient improves markedly with termination of the pregnancy. A major
advance in understanding of the pathogenesis was the discovery that women pregnant with an infant that is
homozygous for the fatty acid oxidation disorder long-chain 3-hydroxyacyl-coA dehydrogenase deficiency
(LCHAD) have a very high incidence of acute fatty liver of pregnancy, approximately 80% of such pregnancies.15
The mothers are obligate heterozygotes for the disorder, and it may be that fetal-placental demand
for fatty acid metabolites overwhelms the liver's ability to oxidize fatty acids normally. Acute fatty
liver of pregnancy has also been reported in a patient carrying a fetus with short-chain acyl-coA
dehydrogenace deficiency, so it may be that other fatty acid oxidation disorders may play a role.16
However, the majority of cases of acute fatty liver of pregnancy have not been associated with fatty acid
oxidation disorders,7 so other genetic or acquired metabolic defects leading to mitochondrial dysfunction
Idiopathic Reye's syndrome - Classic Reye's syndrome has virtually disappeared since its association with
aspirin use was recognized, and parents stopped giving aspirin to children with viral illnesses.5,17 The
clinical syndrome of microvesicular steatosis with acute liver failure and encephalopathy suggests
mitochondrial injury, and ultrastructurally, Reye's syndrome shows more severe ultrastructural
abnormalities, including swollen and misshapen mitochondria, than any of the well-characterized genetic
mitochondrial disorders. Sine aspirin overdose can cause microvesicular steatosis, it seems plausible that
the combination of non-toxic doses of aspirin in a patient with some degree of genetic susceptibility (?
perhaps heterozygous for one of the fatty acid oxidation disorders) might have been the trigger for the
development of Reye's syndrome. However, it is unlikely that this will ever be elucidated in the absence of
Microvesicular steatosis probably unrelated to mitochondrial injury
Cholesterol ester storage disease and Wolman's disease are adult and infantile forms (respectively) of
lysosomal acid lipase deficiency. Lipid stored in liver cells often has a foamy or microvesicular
Urea cycle disorders do not directly affect lipid metabolism, but microvesicular fat is often the most
impressive histologic finding in the liver, especially on ultrastructural examination.18 The
pathogenesis is not known, but is seems likely that it is secondary to the other metabolic derangements of
these disorders, and it may be another cause of nonspecific/physiologic adaptation to stress.
Acute hepatitis D superimposed on hepatitis B has been known to occur in epidemics, particularly in rural
areas of South America. Labrea fever in the Brazilian Amazon basin, Santa Marta hepatitis in Columbia, and
the hepatitis of Yucpa Indians of Venezuela had been known for decades and characterized a severe acute
hepatitis with prominent Reye's syndrome-like microvesicular steatosis.19 In other parts of the world,
this histologic appearance is quite unusual. The pathogenesis of the lesion and the reason for its
geographic distribution is unknown.
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