Caso N2 - FJM (CPC)

A 46-year-old Mexican immigrant presented to the
hospital because of epigastric pain and the vomiting of
coffee-grounds material. He had had fatigue, malaise,
jaundice, and a 20-lb (9.1 kg) weight loss during the
previous two months. He had also had dark stools,
light-headedness, and mild shortness of breath, but
no fever, chills, or night sweats

The patient worked on livestock farms in Mexico
before moving to the United States 15 years earlier.
His medical history was unremarkable, and he said
he did not use alcohol or illicit drugs. He was not taking
any medications or herbs. His most recent travel had
been to Mexico three years previously. He was married
with four children, worked as a gardener, and had no pets.

On physical examination, the patient had a temperature
of 37.7°C, a pulse of 106 beats per minute,
a blood pressure of 127/54 mm Hg, and 18 respirations
per minute. His oxygen saturation was
100 percent while he was breathing ambient air. He
had obvious jaundice, without palpable lymphadenopathy.
His cardiac examination was normal,
except for tachycardia. His lungs were clear to auscultation
and percussion. There was mild epigastric
tenderness without hepatosplenomegaly or
masses. He had no signs or symptoms of chronic
liver disease. The neurologic examination was normal.
The rectal examination revealed melena.

Laboratory evaluation revealed a white-cell count
of 3300 per cubic millimeter; a hemoglobin level
of 4.5 g per deciliter, with a mean corpuscular volume
of 87.4 μm3; and a platelet count of 361,000
per cubic millimeter. Analysis of a peripheralblood
smear showed 13 percent band forms, 27
percent monocytes, and 25 percent nucleated red
cells, with evidence of basophilic stippling but no
schistocytes. Levels of electrolytes were normal,
except the blood urea nitrogen level was 36 mg per
deciliter (12.9 mmol per liter). Serum chemical
analysis revealed the following values: albumin,
2.7 g per deciliter; alkaline phosphatase, 170 U per
liter (normal range, 53 to 128); alanine aminotransferase,
25 U per liter (normal range, 10 to 35);
aspartate aminotransferase, 36 U per liter (normal
range, 14 to 50); and total bilirubin, 12.7 mg per
deciliter (217 μmol per liter; normal range, 0.3 to
1.2 [5.13 to 20.52]), with a direct bilirubin level of
7.7 mg per deciliter (131.67 μmol per liter; normal,
less than 0.2 [3.42]). The level of lactate dehydrogenase
was 210 U per liter (normal range, 100 to
190), and the haptoglobin level was 33 mg per deciliter
(normal range, 33 to 255). The international
normalized ratio was 3.4 before the administration
of vitamin K and subsequently returned to
normal. A radiograph of the chest showed no abnormalities.
Computed tomography (CT) of the
abdomen showed a nodule at the base of the right
lung and lymphadenopathy in the upper portion
of the abdomen and retroperitoneum. Endoscopy
revealed a duodenal ulcer; a urease enzyme test of
a biopsy specimen was positive for H. pylori


Panel A shows a lymph node that is 2.5 cm in diameter
and superior to the right main bronchus (arrow). Panel B
shows a lymph node that is 2.4 cm in diameter and
adjacent to the aorta and inferior vena cava (arrow).














The patient was a Jehovah’s Witness; therefore, his
treatment was limited to iron dextran, folic acid,
and erythropoietin. A fever (temperature of up to
38.8°C) developed on the third hospital day, which
subsequently resolved without treatment. A test
for human immunodeficiency virus and a tuberculin
test (without controls) were negative. A biopsy
specimen of the bone marrow was negative
for a malignant tumor or granulomas and showed
adequate iron stores. Diagnostic laparoscopy revealed
a grossly congested liver with bilious ascites
and diffuse lymphadenopathy of the lesser
omentum. A lymph node obtained from the lesser
curvature of the stomach contained caseating granulomas;
a simultaneously obtained liver specimen
was characterized by marked hepatocellular and
canalicular cholestasis with mild ductopenia, but
no fibrosis or cirrhosis. Staining of all tissues for
acid-fast bacilli was negative. On the basis of the
insidious nature of this patient’s illness, the fever
and lymphadenopathy, and the history of exposure
to livestock, he was treated empirically for brucellosis
with doxycycline and gentamicin; in addition,
he was treated for H. pylori with amoxicillin,
clarithromycin, and omeprazole. Despite the lack
of a clear diagnosis, the patient was discharged to
his home with a plan for close follow-up

At a follow-up visit one week later, the patient had
no improvement in his symptoms. The white-cell
count was 1100 per cubic millimeter, with an absolute
neutrophil count of 200. The hemoglobin
level was 11.5 g per deciliter; the platelet count was
normal. Serologic tests for brucella and viral hepatitis
were negative, as were tests for antinuclear,
antineutrophil cytoplasmic, anti–smooth-muscle,
and antimitochondrial antibodies. He was readmitted
to the hospital. The fall in the white-cell
count was attributed to the antibiotics, and it resolved
after treatment with granulocyte colonystimulating
factor (G-CSF) and the discontinuation
of his medications. He remained afebrile.
Mag netic resonance cholangiopancreatography
showed no dilatation of pancreatic or intrahepatic
biliary ducts. Empirical, four-drug therapy for tuberculosis
was begun, and the patient was discharged.

The patient was readmitted two weeks later because
of a white-cell count of 1700 per cubic millimeter
and an absolute neutrophil count of 750.
The level of alanine aminotransferase was 31 U
per liter; that of aspartate aminotransferase, 41 U
per liter; that of alkaline phosphatase, 350 U per
liter; and that of total bilirubin, 11.9 mg per deciliter
(203 μmol per liter). Repeated bone-marrow
aspiration revealed no abnormalities. CT of the
chest and abdomen showed enlarging retroperitoneal
lymph nodes with new lymph nodes above
the right main bronchus and in the left inguinal
region (Fig. 1). Surgical biopsy specimens of the
hilar and inguinal lymph nodes revealed reactive
lymphoid tissue and no granulomas; staining for
acid-fast bacilli was negative. The neutropenia resolved
after discontinuation of the antituberculosis
treatment. The patient was discharged while
taking empirical prednisone (60 mg daily orally)
for presumed granulomatous hepatitis.

After vacationing in Mexico for a month, during
which he continued corticosteroid therapy, the patient
returned to the clinic with persistent weight
loss and abdominal pain, but without fever. He was
readmitted to the hospital and was found to have
an alanine aminotransferase level of 818 U per liter,
an aspartate aminotransferase level of 379 U per
liter, an alkaline phosphatase level of 2132 U per
liter, and a total bilirubin level of 36 mg per deciliter
(616 μmol per liter). Endoscopic retrograde
cholangiopancreatography showed relatively thin
intrahepatic ducts, with a decreased number of
ducts in the left hepatic lobe. He was transferred to
a liver-transplantation center, where examination
of a specimen from the second liver biopsy showed
marked hepatocellular and canalicular cholestasis
and no intact interlobular bile ducts. After a progressive
downhill course complicated by diffuse pulmonary
infiltrates, clinical sepsis, and two cardiopulmonary
arrests, the patient died.

¿What was the diagnosis at autopsy?

After a progressive downhill course complicated
by diffuse pulmonary infiltrates, clinical sepsis, and
two cardiopulmonary arrests, the patient died. At
autopsy, he was found to have had Hodgkin’s disease
in the mediastinal and mesenteric lymph
nodes (Fig. 2) and marked cholestasis and ductopenia
in the liver (Fig. 3). A suppurative, necrotizing
fungal pneumonia was present throughout the
lungs. There was no identifiable pulmonary malignant
tumor or evidence of hepatic fungal infection.
A diagnosis of vanishing bile-duct syndrome
due to Hodgkin’s disease was made. A retrospective
review of all previous biopsy specimens showed
no evidence of Hodgkin’s disease.






Specimen of an Abdominal Lymph Node
Obtained at Autopsy, Showing Infiltrates of Lymphocytes,
Plasma Cells, Eosinophils, and Reed–Sternberg
Cells (Arrow).












Bile ducts are absent in the portal tract shown in
Panel A, whereas a bile duct is present in the portal
tract shown in Panel B (arrow).
















Liver involvement is uncommon in Hodgkin’s
disease at diagnosis. Cervantes et al8 found 7.4% of
liver involvement in Hodgkin’s disease in 421 cases
studied. Infiltration is defined by the presence of Reed
Sternberg cells usually accompanied by lymphocytes,
histiocytes, eosinophils and plasma cells in the portal
tracts. This infiltration of the liver can lead to
cholestasis and jaundice. Other causes of jaundice
in Hodgkin’s disease include extra-hepatic biliary obstruction
by enlarged portal lymph nodes, hemolysis,
viral hepatitis and drug toxicity.4 Recently, the
vanishing bile duct syndrome has been described as
a rare and severe cause of intra-hepatic cholestasis
in Hodgkin’s disease.2,3
This syndrome consists of the destruction of
the biliary apparatus with the disappearance of the
small and medium-sized intra-hepatic bile ducts.2,3,5
It has been observed in different congenital or acquired
diseases such as chronic rejection of liver
transplantation, resulting in graft failure in 5% to 20%
of allograft recipients; graft-versus-host-disease after
bone marrow transplantation; primary biliary cirrhosis;
primary sclerosing cholangitis; chronic druginduced
cholestasis (clindamycin; carbamazepine;
trimethoprim-sulphamethoxazole) and histiocytosis
X in children.4-6,9-11
Hubscher, et al.2 described three cases of
Hodgkin’s disease that presented reduction of biliary
ducts. The three cases died with intractable liver
damage. The first case, a 26-year-old man (Hodgkin’s
disease of the nodular sclerosing type), presented
a two-week history of jaundice, fatigue and weight
loss. Laboratory studies showed severe cholestasis,
although abdominal ultrasound examination
showed no evidence of biliary obstruction. He was
treated with chemotherapy. He died 24 weeks later
with hepatic encephalopathy, renal failure, severe
diarrhea and neutropenia. The cause of the death
was disseminated fungal infection. No residual lymphoma
was detected in any of the organs examined
at autopsy. The second case, a 44-year-old man, presented
a 2-week history of jaundice. The liver biopsy
showed intrahepatic cholestasis of unknown
pathogenesis. The diagnosis of Hodgkin’s disease
(lymphocyte predominant type) was made 7 months
later. At this time the jaundice got worse and the
liver biopsy showed involvement by Hodgkin’s disease.
He began treatment with radiotherapy and
chemotherapy and died three days later. The third
case, a 37-year-old woman presented pruritus,
weight loss, persistent cough and night sweats. The
diagnosis of Hodgkin’s disease of the nodular sclerosing
type was made by thoracotomy. Ten days after
chemotherapy she developed jaundice. The ultrasound
examination was normal. Liver function
deteriorated and the patient developed renal and
respiratory failure and died. At autopsy no residual
lymphoma was detected. In the three cases
cholestasis and paucity of bile ducts were noted in
the liver biopsies. Only case 2 showed evidence of
lymphomatous infiltration. Gottrand et al described
a 3.5-year-old child with a three-week history of submaxillary
lymphadenopathy. The lymph node biopsy
showed a mixed cellularity Hodgkin’s disease. On
admission she had jaundice without hepatosplenomegaly.
The biochemical values were consistent
with cholestasis. No infiltration by Hodgkin’s disease
was found at the liver biopsy. There was a paucity
of interlobular bile ducts. Cholestasis progressively
increased without any signs of hepatic failure.
Chemotherapy and radiotherapy were given.
Five months later, the lymphadenopathy had regressed,
but cholestasis continued to increase. Liver
transplantation was considered, but the patient died
with signs of hepatic failure.

In all these four cases described in the literature,
as well as in the present one, vanishing bile
duct syndrome was detected at diagnosis or at least
when Hodgkin’s disease showed tumor activity.
However, even after a good response to chemotherapy,
and complete remission of Hodgkin’s disease,
vanishing bile duct syndrome progressed. All
patients died from irreversible hepatic failure. At
autopsy, no evidence of Hodgkin’s disease was
found.
The pathophysiology of vanishing bile duct
syndrome is not well understood. Immunological
mechanisms seem to be involved. Hubscher, et al.2
suggested that there is a release of toxic cytokines
from lymphoma cells in Hodgkin’s disease. The destruction
of bile ducts in primary biliary cirrhosis,
primary sclerosing cholangitis and liver allograft
rejection seems to be related to cell-mediated immunological
attack by cytotoxic T lymphocytes of
either CD4 or CD8 phenotype. Other investigations
have indicated the presence of immunoglobulins in
interlobular bile ducts, suggesting the involvement
of humoral immune reactions. Hodgkin’s disease
may be associated with autoimmune manifestations
but, even with complete remission of Hodgkin’s disease
after chemotherapy, vanishing bile duct syndrome
is irreversible, probably due to the fact that
the affected bile ducts have a low regeneration capacity.
Patients with liver disease as the initial manifestation
of Hodgkin’s disease have a poor prognosis.
In particular, vanishing bile duct syndrome is a
progressive and always fatal complication in this
setting, although some reversible cases have been
described in association with other liver transplantations.
12 Liver transplantation for vanishing bile
duct syndrome in Hodgkin’s disease should be considered.
Our patient died before any procedure
could be done.

Case Analysis

When a patient’s condition worsens despite the
use of empirical therapy, clinicians must decide
whether to continue the empirical therapy, change
the empirical therapy, or repeat diagnostic testing.
Such decisions, which must often be made in
practice, ultimately require clinical judgment to
determine whether the presumed diagnosis is correct
and to evaluate the risks of treating or not
treating the patient. In this case, the discussant
was concerned about the empirical use of corticosteroids.
The use of that therapy, together with
certain other factors (including the patient’s unrecognized
underlying lymphoma, the frequent
hospitalizations, and the use of intravenous catheters
and antibiotics), probably contributed to the
ultimate development of fungal pneumonia.
Because a mathematical decision-tree analysis
is too complex for physicians’ daily use in establishing
the best course of action, they tend to
make decisions in an incremental or consecutive
fashion.7 This approach allows them to use whatever
limited data are available, including personal
experience and the patient’s response to therapy,
to decide the next treatment. In this way, each
course of failed empirical therapy serves as a new
piece of diagnostic information and may help exclude
another disorder from the differential diagnosis.
However, when using a consecutive approach
to problem solving, clinicians may fail to reanalyze
the data on which previous decisions were
made. In this case, the lack of an identifiable malignant
tumor in numerous biopsy specimens gave
the clinicians the false sense that cancer had definitively
been ruled out. Thus, infectious and
inflammatory conditions became the two most
likely categories of disease, leading to a series of
empirical treatments aimed at the most probable
cause. Ideally, clinicians should retrospectively
evaluate the clinical data on which they have
based their previous decisions and consider repeating
diagnostic studies if the trial-and-error
approach seems to be failing.
In this case, the histologic identification of
vanishing bile-duct syndrome and the recognition
of the potentially latent appearance of Hodgkin’s
disease in association with this syndrome might
have led to earlier diagnosis and potentially lifesaving
treatment. This case reminds us of the link
between the vanishing bile-duct syndrome and
Hodgkin’s disease and the frustration and consequences
that result from being empirically incorrect.

References

1. Empirically Incorrect
2. Vanishing Bile Duct Syndrome in Hodgkin’s Disease