Fmge MCQ

An 84-year-old woman complained of dark brown urine.
Her medical history was

significant for hypertension, congestive heart failure, and supraventricular tachycardia.
The arrhythmia had been treated with amiodarone. She was also on diuretics, nifedipine
and aspirin. She had no history of alcohol abuse. Her bilirubin, alanine aminotransferase
level and alkaline phosphatase levels were markedly elevated. Her serum levels of
amiodarone was within the normal reference range. Prothrombin time and activated partial
thromboplastin time were normal. Urinalysis was positive for bilirubin and urobilinogen.
Viral hepatitis A, B, C markers and antimitochondrial and antinuclear antibodies were all
negative.
She was suspected to have obstruction of the biliary tree but endoscopic retrograde
cholangiography revealed cholelithiasis, and an ultrasound of the liver showed evidence of
non-alcoholic steatosis.
Her bilirubin increased further and it wa decided to perform a liver biopsy. The liver
biopsy revealed portal fibrosis but no evidence of cirrhosis. The hepatocytes showed
intense ballooning degeneration and abundant Mallory bodies.
Hepatocytes from the liver biopsy core were then examined by an electron microscope.
What most relevant finding would you expect in the cytoplasm of these hepatocytes?
a) Polar bodies
b) Dohle's bodies
c) Hematoxylin bodies
d) Lamellar bodies
e) Negri bodies
The correct answer is D
Explanation
The answer should be Lamellar bodies
The history and histology should have pointed you towards amiodarone-induced
hepatotoxicity. You should then be aware that a characteristic feature of
amiodarone-induced hepatotoxicity on electron microscopy is the finding of lamellar
bodies. If you were unaware of this fact, you could also have come to the correct
answer by elimination of the other choices.
The histomorphologic findings of the liver biopsy were consistent with amiodarone-
induced cholestatic hepatotoxicity. Therefore you should expect the electron microscopic
examination to confirm this diagnosis.The single feature that is virtually diagnostic of
amiodarone-induced hepatotoxicity on electron microscopic examination are cytoplasmic
lysosomal lameller inclusions .
Although we cannot completely exclude the possibility of liver damage secondary to

medications other than amiodarone in this patient, the histologic findings and clinical
course are against this possibility. The patient was taking multiple cardiac and
hypertensive medications prior to and after the onset of her liver injury, including calcium
channel blockers, diuretics, and aspirin. Calcium channel blockers as a class have been
associated with hepatocellular and cholestatic injury, presumably through a
hypersensitivity mechanism. However, in the reported cases with nifedipine-induced liver
injury, only 1 of 10 cases had Mallory bodies present in the liver biopsy specimen.
Lysosomal lamellar bodies occur almost uniformly in any patient taking amiodarone, even
in the absence of overt liver damage, and therefore are not confirmatory of amiodarone
toxicity. In our case, however, the histologic changes of cholestatic hepatitis with alcohol-
like hepatocellular injury in the presence of lysosomal lamellar inclusions is consistent
with amiodarone toxicity as the major cause of this patient’s jaundice. Other causes of
cholestasis, such as viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis, and
extrahepatic biliary obstruction, were ruled out by the serologic and imaging studies. The
presence of bile ducts excluded the possibility of idiopathic adult ductopenia. There was
also no history of alcohol abuse, which may cause a similar histologic picture. In the
presence of cholelithiasis, the possibility of transient gallstones in the common bile duct
causing obstruction cannot be entirely excluded, but endoscopic retrograde
cholangiography did not demonstrate obstruction, and the imaging studies (abdominal
ultrasound and dimethyl iminodiacetic acid scan) performed at the peak of the jaundice
were again negative.
What are the histological features of amiodarone-induced hepatotoxicity ?

Histology is likely to show lobular architecture distorted by moderate portal fibrosis and
moderate pericellular sinusoidal fibrosis in zone 1 of the Rappaport acinus and focally
irregular lobular sinusoidal fibrosis. No bridging fibrosis or cirrhosis is evident. The
expanded portal tracts show moderate to severe ductular proliferation and a mild
lymphocytic infiltrate with rare polymorphonuclear leukocytes. There is no cholangitis.
The hepatocytes show intense ballooning degeneration and abundant Mallory bodies.
Hepatocellular necrosis with neutrophil satellitosis are also present. Anisonucleosis,
prominent binucleation, and glycogenated nuclei are present. Bile stasis has no zonal
distribution and is canalicular and cytoplasmic often in areas of ballooned, degenerated
liver Periodic acid–Schiff stain after diastase digestion shows abundant sinusoidal lining
cells and macrophages with periodic acid–Schiff–positive ceroid-lipofuscin cytoplasmic
pigment
electron microscopic examination

The diagnosis of amiodarone-induced hepatotoxicity is further supported by transmission
electron microscopic examination, which revealed a variable number of cytoplasmic
lysosomal lameller inclusions , compatible with secondary amiodarone-induced
phospholipidosis. Such inclusions may be noted in hepatocytes, bile duct epithelium,
Kupffer cells, and macrophages. Additionally, the hepatocytes contain aggregates of
paranuclear haphazardly arranged intermediate cytoplasmic filaments consistent with
Mallory bodies. Small lipid droplets are noted in some hepatocytes. Abundant
pericanalicular autophagic vacuoles and secondary lysosomes with a granular matrix
reflecting bile stasis were present. Few canaliculi show dilatation with condensed
pericanalicular filaments, distorted, focally flattened microvilli, and electron-dense
granular luminal contents presumed to be bile. Degenerated hepatocytes, portal fibrosis,
and portal neutrophils and lymphocytes are also noted.
History
Cholestasis has been reported as a rare presentation among patients with amiodarone
hepatotoxicity. There are reports of patients who presented with jaundice as the major
clinical manifestation of amiodarone hepatotoxicity. Cholestasis appears to occur in older
patients . The presence of increased serum bilirubin level indicated a poor prognosis even
with the relatively unremarkable serum alanine aminotransferase and aspartate
aminotransferase levels. Histopathologic findings of hepatic fibrosis and necrosis
correlates highly with poor prognosis. Besides prognostic significance, histopathologic
examination of a liver biopsy specimen is of value in rendering the diagnosis of
amiodarone-induced cholestatic liver injury. Steatosis, both macrovesicular and
microvesicular, was the most frequent histopathologic change. Ballooning of hepatocytes,
Mallory bodies, and fibrosis were also common. Characteristic lamellar lysosomal
inclusion bodies representing phospholipidosis are usually found ultrastructurally.
Lamellar bodies
Lamellar bodies are ctoplasmic inclusion bodies that contain lipids to be secreted. In
alveolar epithelial cells lamellar bodies are specialized for the storage of surfactant
phospholipids. Secretion of lung surfactant occurs via exocytosis of lamellar bodies in
alveolar epithelial cells and is one of the most important aspects in lung surfactant
homeostasis.
Other types of intracytoplasmic bodies

Döhle's bodies, Döhle's inclusion bodies, round to oval blue-staining inclusions seen in
the periphery of the cytoplasm of neutrophils, consisting mainly of RNA derived from
rough endoplasmic reticulum; they are found in association with many infections, burns,
aplastic anemia, uncomplicated pregnancy, and after administration of toxic agents.
Similar structures, usually larger and more prominent, are present in granulocytes other
than neutrophils in the May-Hegglin anomaly. Called also Amato b's and leukocyte
inclusions.
Hematoxylin body, a dense, homogeneous, cyanophilous particle consisting of the

denatured nuclear material of an injured cell together with a small amount of cytoplasm,
occurring in systemic lupus erythematosus; lymphocytes that ingest such particles are
known as LE cells. Called also LE b.
Negri bodies, oval or round inclusion bodies, seen in the cytoplasm and sometimes in the
processes of nerve cells of rabid animals or patients with rabies after death; their presence
is considered conclusive proof of rabies.
Polar bodies, 1. the small nonfunctional cells with a haploid chromosome complement,
consisting of a small amount of cytoplasm and a nucleus, resulting from unequal division
of the primary oocyte (first polar b.) and, if fertilization occurs, of the secondary oocyte
(second polar b.); the polar body appears as a speck at the animal pole of the egg. 2.
metachromatic granules located at one or both ends of a bacterial cell.

Fmge MCQ

Uploaded by

Copyright:

Available Formats

Fmge MCQ

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Fmge MCQ

Uploaded by

Copyright:

Available Formats

An 84-year-old woman complained of dark brown urine.

Her medical history was

The correct answer is D

The answer should be Lamellar bodies

Although we cannot completely exclude the possibility of liver damage secondary to

What are the histological features of amiodarone-induced hepatotoxicity ?

electron microscopic examination

Other types of intracytoplasmic bodies

Hematoxylin body, a dense, homogeneous, cyanophilous particle consisting of the

You might also like