Experimental and Molecular Pathology 88 (2010) 324–325

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Experimental and Molecular Pathology

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Hypervitaminosis A Inducing Intra-hepatic Cholestasis—A Rare Case Report

Vivek S. Ramanathan a,⁎, Gary Hensley a, Samuel French c, Victor Eysselein b,
David Chung b, Sonya Reicher b, Binh Pham b
a
Department of Internal Medicine, St Mary Medical Center, Long Beach, CA, USA
b
Division of Gastroenterology, Harbor UCLA Medical Center, Torrance, CA, USA
c
Division of Pathology, Harbor UCLA Medical Center, Torrance, CA, USA

a r t i c l e i n f o a b s t r a c t

Article history: The use of over-the-counter supplements is commonplace in today's health conscious society. We present an
Received 16 November 2009 unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one
Available online 24 November 2009 HerbalifeTM shake with two multivitamin tablets of the same brand for 12 years. When calculated this
equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function
Keywords:
tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features
Vitamin A
Toxicity
pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his
Cholestasis jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care
Herbalife providers documenting non-prescribed dietary supplements and considering them in the etiology of
cholestatic liver disease.
© 2009 Elsevier Inc. All rights reserved.

We present an unusual case of a 46-year-old Caucasian male with
increasing jaundice and pruritus. He had a reported common bile duct
stricture and recent stent removal at an outside hospital 15 days prior.
He also had a history of B cell lymphoma, status post-chemotherapy
3 years ago, now in remission. Examination revealed hepatomegaly,
jaundice and excoriations. His alkaline phosphatase was 193 U/L
(normal 38–126 U/L), aspartate transaminase (AST) 44 U/L (normal
15–41 U/L), alanine transaminase (ALT) 68U/L (normal 7–35 U/L)
and total bilirubin (TB) 11.2 mg/dl (normal 0.3–1.2 mg/dl). Viral
(HBsAg, anti-HAV, anti-HCV, CMV, EBV) autoimmune (ANA, anti
smooth muscle antibody, anti-liver kidney microsomal antibody),
common toxic (salicylates, acetaminophen), and metabolic (ferritin,
iron studies, ceruloplasmin) serologies were also negative. Ultrasound
with doppler showed normal common bile duct size, no gallbladder
wall thickening, and no hepatic artery or portal vein thrombosis.
Three days after admission he underwent ERCP, which showed an
8-mm distal common bile duct stricture with evidence of prior
sphinterotomy. Although bile was seen to be flowing, a biliary stent
was placed (10 Fr, 7 cm). Despite this intervention his TB of 20.3 mg/dl
and alkaline phosphatase of 288 U/L continued to rise. A repeat ERCP
was performed that showed good flow of bile and no intrahepatic duct
dilatation. Thirteen days after the admission a liver biopsy was
performed secondary to persistently elevated total bilirubin despite
adequate drainage via a biliary stent.
⁎ Corresponding author. 1048, Palo Verde Ave., Long Beach, CA 90815, USA.
E-mail address: drvivekram@gmail.com (V.S. Ramanathan).
Pathology revealed prominent centrilobular cholestasis caused by
stellate cells with multiple fat vacuoles (see Figs. 1 and 2). Focal
intracellular cytoplasmic necrosis with apoptotic bodies in Kupffer cells
and thrombi in dilated intrahepatic bile ducts was also demonstrated.
These features were all consistent with vitamin A toxicity. There was no
evidence of fibrosis or cirrhosis.
Based on this result a focused history was gathered, in particular
the use of dietary supplements. He admitted to drinking a Herbalife™
shake once per day with two multivitamin tablets of the same brand
for the past 12 years. When calculated this amounted to 5082 IU (see
Table 1) which exceeds the recommended daily allowance (RDA) for
vitamin A (5000 IU). Additional vitamin A from unaccounted food
intake would have further exceeded the recommended daily allow-
ance. He was eventually discharged home with strict instructions to
discontinue the afore mentioned products. He was followed up
2 months later with complete resolution of his jaundice and liver
function tests. When the biliary stent was removed 3 months later, no
stricture was seen and the cholangiogram confirmed patent ducts
without dilatation. His laboratory values were repeated 8 months after
the stent removal and were completely normal. He continues to
abstain from nutritional supplementation.
The exact mechanism of vitamin A toxicity remains unknown,
although various theories have been proposed. The first involves
vitamin A binding to the cell membranes of fat-storing cells (FSCs/
stellate cells/Ito cells) when levels exceed that of retinol binding
proteins. These FSCs then produce extracellular matrix components
including laminin and type III collagen causing fibrosis (Kent et al.,
1976; Ballardini et al., 1989). The second hypothesis involves an

0014-4800/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.yexmp.2009.11.007
 V.S. Ramanathan et al. / Experimental and Molecular Pathology 88 (2010) 324–325
Fig. 1. Showing thick section light microscopy slide (1500 magnification) of changes
consistent with vitamin A toxicity: Prominent centrilobular cholestasis caused by
multiple fat vacuoles in the stellate cells. Absence of perisinusoidal fibrosis.
observation seen in the histology of alcohol fed rat livers. Toxic levels
of vitamin A leads to increased metabolism of retinol with the ethanol
induced cytochrome p450 mediated system. This in turn leads to the
production of direct hepatotoxins (Leo et al., 1982; Kim et al., 1988).
Thirdly, vitamin A activates Kupffer cells, through interferon gamma
production by activated T-lymphocytes (Abril et al., 1989; Sim et al.,
1989). Activated Kupffer cells potentiate liver toxicity even at low
levels of hepatotoxins, including ethanol, other environmental agents
and medications (Mobley et al., 1989).
Symptoms of hypervitaminosis A include anemia, anorexia,
alopecia, arthralgias, and eventually signs of chronic liver disease
from cirrhosis including jaundice and ascites. The biochemical pattern
of injury is hepatocellular with significant rises in transaminases. The
Fig. 2. Electron microscopy slide showing increased fat vacuoles in stellate cells (similar
to Fig. 1).
325
Table 1
Showing calculations for vitamin a daily ingestion.
Vitamin A (IU) Quantity per day Total ingested (IU)
Shake with 8 fl oz. 1750 1 1750
non-fat milk
Multivitamins 1666 2 3332
Cumulative Total 5082
characteristic features on liver biopsy are well described; hyperplasia
and hypertrophy of lipid laden stellate cells, with associated fibrosis
and atrophy of adjacent hepatocytes. Resultant sinusoidal congestion
and dilatation accounts for the obliteration of the space of Disse
(Geubel et al., 1991; Le Marchand et al., 1984; Jacques et al., 1979).
Interestingly, our patient had an absence of fibrosis or cirrhosis.
Intrahepatic cholestasis was secondary to the stellate cells packed
with lipid vacuoles only. To date only one other case of vitamin A-
induced cholestatic hepatitis has been reported in the literature
(Becker et al., 2007).
Our presumption that the hypervitaminosis A caused the chole-
stasis is supported by the following: (a) The patient did have a history
of distal common bile duct stricture. However, we believe this to be a
“red herring” as repeated ERCPs demonstrated good bile flow. All
other causes of bile duct and liver parenchymal injury were ruled out.
(b) Cessation of the vitamin A supplements resulted in complete
resolution of his liver function tests. (c) Histology was pathognomonic
of vitamin A being the culprit in causing cholestatic hepatitis.
Our health conscious society is becoming increasingly better
educated on the benefits of a healthy diet, which includes vitamins.
The billions of dollars being spent in the health foods industry is a
reflection of the prevalence of non prescribed supplements. Firstly,
the case highlights the importance of health care providers doc-
umenting a thorough medication history including dietary supple-
ments. Secondly, consideration should be given to dietary
supplements causing cholestatic liver disease, even when taking as
directed on the packaging. Failure to do either, may lead to chronic
liver disease and ensuing failure, which could have easily been
avoided by simply stopping the agent (Cheruvattath et al., 2006).
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