Case Nº4 - FJM

A 68-year-old woman was admitted to our hospital with
general fatigue, palpitation, shortness of breath and leg
edema. She was diagnosed as having rheumatoid arthritis
(RA) at age 59 years at another hospital. She had since been
treated with nonsteroidal anti-inflammatory drugs, gold sodium
thiomalate and steroids. When she consulted our hospital,
clinical classification was stage IV and class II, due to
the bilateral erosive arthritis in her hands, wrists, knees and
feet.

In 1996 (at age 62 years), pancytopenia, which might
have been induced by gold sodium thiomalate, gradually developed.
This medication was discontinued, but the pancytopenia
persisted. Over the subsequent year, findings on gastrointestinal
endoscopy and abdominal computed tomography
revealed contracted liver, splenomegaly and esophageal
varices. Laboratory data showed no antigens or
antibodies for hepatitis virus, or antibodies for mitochondria
or smooth muscle, with the exception of antinuclear antibody
(ANA). Esophageal variceal banding ligature was thus performed.
Physical examination demonstrated deformities of the bilateral
joint of the hands, wrists, and feet. Swan-neck, boutonniere
deformity and radial deviation at the wrists with
ulnar deviation of the digits were noted in both hands.
Respiratory and heart sounds were normal. The spleen was
palpable about 5 cm below the left costal margin. Slight pitting
edema was observed in the bilateral lower extremities.

Laboratory findings are shown in Table 1. Urinalysis was
within the normal range. Neutropenia and hypoproteinemia
worsened, and hypoalbuminemia at 2.0 g/dl was detected.
Elevated levels of total bilirubin and aspartate aminotransferase
were observed, and the Child-Pugh classification was C (10 points).
ANA was positive at a titer of 640 (homogenous
and speckled), but other antibodies were negative.
Abdominal computed tomography revealed contracted liver,
splenomegaly, ascites and enlarged serpiginous
splenic vein.






























During admission, oral prednisolone was discontinued
due to various infections, including bacterial pneumonia and
methicillin resistant Staphylococcus aureus (MRSA) colitis.
Subcutaneous administration of granulocyte colony stimulating
factor (three times a week) was thus performed, while
ascites was simultaneously treated with diuretics. Laparoscopic
liver biopsy was not performed due to marked ascites
and neutropenia. Liver dysfunction worsened gradually and
ascites became prominent. She developed
hepatic encephalopathy and died from hepatic failure
and emaciation on March 31, 2003. Autopsy was not permitted.

¿What is the diagnosis?

Needle autopsy of the liver confirmed chronic hepatitis, the lobular architectures were maintained, while part of the portal field exhibited fibrosis including piecemeal necrosis, and was invaded by inflammatory cells and numerous lymphocytes with plasma cells (Fig. 3A, 3B). Pathological findings were consistent with a diagnosis of chronic hepatitis, which appeared to be AIH, although inflammatory cell invasion was not severe. According to the criteria of the International Autoimmune Hepatitis Group (Table 3A, 3B), the patient scored 19 points based on laboratory findings, pathophysiological consequences and clinical course, and her condition was diagnosed as AIH.

Discussion
In 1924, Felty first called attention to five cases with a
triad of RA, splenomegaly and neutropenia (5). This combination
of disorders was designated Felty’s syndrome in a
subsequent report by Hanrahan and Miller (6). This syndrome
frequently induces extra-articular features including
liver involvement, while common hepatic abnormalities are
nodular regenerative hyperplasia, abnormal lobular architecture,
portal fibrosis and cirrhosis (7–11). Thorne et al reported
a tendency for patients with abnormal liver findings to
have a higher incidence of vasculopathy and Felty’s syndrome
patients should be screened for portal hypertension as
they have an increased likelihood of bleeding from esophageal
varices (9). Indeed, in this patient, esophageal varices
were observed. The most common liver involvement in patients
with Felty’s syndrome is nodular regenerative
hyperplasia (12, 13). Goritsas et al recommended that signs
of portal hypertension and/or intrahepatic cholestasis in RA
patients should alert the physician to the possibility of nodular
regenerative hyperplasia, even in the absence of Felty’s
syndrome (14). However, the cause of hepatic nodular regenerative
hyperplasia in patients with Felty’s syndrome remains
unresolved.
In the present case, contracted liver was thought to be
clinically liver cirrhosis based on blood test, abdominal computed
tomography and ultrasonography findings. However,
liver autopsy findings revealed chronic hepatitis. Histological
findings showed a basically normal architecture and
338 Internal
a partly piecemeal necrosis in the portal triad field, in addition
to infiltration of lymphocytes with plasma cells, which
suggested AIH.
AIH was first reported by Mackay et al in 1965. The characteristic
pathologic features were chronic active hepatitis
with piecemeal necrosis, lobular involvement, and bridging
necrosis with lymphocytes and plasma cells (15). The clinical
features were similar to chronic viral hepatitis. For diagnosis
of AIH, it was recently recommended to use the
scoring system of the International Autoimmune Hepatitis
Group (16). According this scoring system, the present patient
was diagnosed as having autoimmune hepatitis with a
score 19 points. Kaise et al reported that one in 49 patients
with Felty’s syndrome exhibits concomitant AIH (11). Based
on that report, it is certain that AIH in Felty’s syndrome is
extremely rare.

Minimum Required Parameter



















Aditional Parameters



















Splenomegaly in patients with Felty’s syndrome might be
due to expansion of the sinusoidal pulp, as indicated by
wider separation of the periarterial lymphoid sheaths and
hyperplastic germinal center (17). In the present case, we are
convinced that increasing blood flow to the spleen due to
splenomegaly caused portal hypertension, congestion of
blood within the liver, and chronic hepatitis gradually worsened
to liver failure.
The present patient had contracted liver disease of unknown etiology. Chronic hepatitis compatible with AIH was
diagnosed based on an international scoring system and the
pathological findings of needle autopsy respectively. In patients
with Felty’s syndrome, severe hepatitis is rarely observed
and correlations with the liver are difficult to confirm.
When treating Felty’s syndrome patients with severe liver
dysfunction, AIH should be considered. Inaba et al reported
a case in which the patient had been treated by prednisolone
for AIH and was diagnosed as having Felty’s syndrome (18).
This report raises the possibility that our patient had AIH when she was diagnosed with RA and prednisolone therapy suppressed the clinical features of AIH. Retracing the clinical course, liver dysfunction may have developed after steroid therapy was discontinued. If this was the case scenario, the response to therapy in this patient should, in fact, be considered as a relapse with a score of 21 points. In the present
patient, the most difficult point was that steroid therapy had
to be discontinued due to life threatening infections (MRSA
colitis, recurrent pneumonia) which might have been due to
neutropenia and steroid therapy. Interruption of steroid therapy
in this patient may have been a crucial event in the ultimate
clinical course.

Reference

- Felty’s Syndrome with Chronic Hepatitis and
Compatible Autoimmune Hepatitis: A Case Presentation

Case N3 - FJM

A previously healthy 65-year-old woman went to her primary care physician in late
August, seeking evaluation of a “spot” that had appeared on her right leg 3 weeks
earlier. She felt completely well and recalled no trauma or tick bites. Her physical
examination was notable only for a low-grade temperature elevation (37.7°C) and a
7-to-8-mm erythematous macule on her right leg. She had no lymphadenopathy or
articular abnormalities and was told that the lesion was most likely the result of an
insect bite; still, she was advised to follow up if its appearance changed.
One week later, the skin lesion had resolved, but the patient returned, reporting
malaise and diffuse arthralgias that had progressively worsened, with intense, disabling
pain and stiffness in her neck, shoulders, wrists, hands, knees, and ankles.
She also reported a transient occipital headache and scalp tenderness when brushing
her hair. In addition, she noted pain in the left anterior part of her chest that had
awakened her from sleep, was exacerbated by respiration, and was partially relieved
by sitting up.

The white-cell count was 4600 per cubic millimeter
(72% neutrophils, 20% lymphocytes, 4%
monocytes, 3% eosinophils, and 1% basophils).
The hematocrit was 38.2%, and the platelet count
227,000 per cubic millimeter. The creatinine level
was 0.9 mg per deciliter (79.6 μmol per liter). The
levels of sodium, potassium, and glucose were
normal. The aspartate aminotransferase level was
25 units per liter, and the alanine aminotransferase
level 33 units per liter. The thyrotropin level
was 1.9 μU per milliliter. Tests for Lyme disease
— enzyme-linked immunosorbent assay (both
IgM and IgG antibodies) and Western blotting —
were negative. The erythrocyte sedimentation rate was
40 mm per hour



The patient had persistent arthralgias and sought
care from another internist. She reported no fever,
rash, visual changes, jaw claudication, sore
throat, cough, dyspnea, nausea, vomiting, diarrhea,
or dysuria. Her chest pain had resolved. Her
medical history was notable for osteoporosis, for
which she was taking raloxifene. She was taking
no other medications. There was no personal or
family history of psoriasis or other rheumatologic
illness. She reported extensive international travel,
including travel to Africa, but her most recent trip
had been several years ago. She noted no recent
contact with anyone who was sick and had last
seen her grandchildren 6 weeks earlier. She also
reported no risk factors for hepatitis B or C infection
or for sexually transmitted diseases.

On physical examination, the patient appeared
pale. Her temperature was 36.5°C, pulse 88 beats
per minute and regular, and blood pressure
125/80 mm Hg. She had no mucocutaneous or
nail abnormalities, lymphadenopathy, or ocular
inflammation. Temporal-artery pulses were present
and symmetrical, and there was no overlying
tenderness. The results of cardiac and pulmonary
examinations were normal, with no pleural or
pericardial rubs, and an abdominal examination
revealed no abnormalities. Examination of her
joints revealed notable swelling, tenderness, and
palpable warmth in several proximal interphalangeal
joints and the second and third metacarpophalangeal
joints of her hands. The range of
motion of her neck, shoulders, and wrists was
limited by mild-to-moderate pain, but there was
no appreciable synovitis in these joints.

¿What is the Diagnosis?

No imaging studies were performed. Consultation with a
rheumatologist confirmed the presence of synovitis in
the small joints of the patient's hands. A repeat white-cell
count was 4130 per cubic millimeter, with the differential
count revealing 70% neutrophils, 20% lymphocytes, 6%
monocytes, 2% eosinophils, and 2% basophils. The
hematocrit was 39.2%, and the platelet count 242,000
per cubic millimeter. The urinary sediment was unremarkable.
The erythrocyte sedimentation rate was 40 mm per hour.
Antinuclear antibodies were not detected, nor was rheumatoid
factor. An electrocardiogram was normal.

The IgG index for parvovirus B19 was 1.9 units, and the IgM index 10.4 units (normal value, <0.9).

The elevated parvovirus IgM titer is diagnostic of acute parvovirus infection. Parvovirus B19 infection can have a polyarticular presentation that affects both large and small joints in a symmetrical fashion, resembling rheumatoid arthritis. In contrast to rheumatoid arthritis, however, parvovirus-associated arthritis is generally self-limited.

The patient's inflammatory articular symptoms resolved over a period of several months. On routine evaluation 1 year later, she had no residual synovitis.

Commentary

Human parvovirus B19 is a single-stranded DNA virus that was identified in 1975. The cell-surface receptor — P antigen, or globoside (Gb4) — mediates tropism for the primary target of the virus, erythroid precursor cells. Gb4 is also expressed on granulocytes; platelets; heart, lung, liver, and kidney cells; vascular endothelial cells; smooth-muscle cells; and, notably, synovial cells.

Outbreaks of parvovirus B19 infection typically occur from late winter to early summer. Careful questioning may elicit a report of contact with a sick child, but as this case illustrates, the absence of known contact with someone who is sick does not rule out infection with this virus. Transmission commonly occurs through aerosolized droplets, but other means of transmission are possible, including transfusion of contaminated blood products.

The incubation period is 6 to 18 days, and clinical manifestations vary with the host. Infection in children is often asymptomatic or mild. The most common clinical presentation in childhood is erythema infectiosum, or fifth disease, which presents with a characteristic facial rash (“slapped cheek” appearance) and a reticular rash on the torso and limbs. In contrast, adults with parvovirus B19 infection often present with a more debilitating, influenza-like illness. The facial rash is rare in adults, and the reticular rash, which is common in children, is present in only a minority of adults. Whereas joint symptoms develop infrequently in children with parvovirus, as many as 60% of adults present with clinically significant arthralgias or arthritis. Joint symptoms are twice as likely to develop in women as in men. Articular involvement is symmetrical and most commonly affects the wrists, hands, knees, and ankles, a pattern mirroring that seen in rheumatoid arthritis, certain forms of psoriatic arthritis, and systemic lupus erythematosus. The diagnostic process may be further complicated by the occasional presence of autoantibodies, including rheumatoid factor and antinuclear antibodies, which may be found in the presence of viral infections, albeit at a low titer.

Parvovirus-associated arthritis is usually self-limited, resolving in 1 to 3 weeks. However, in as many as 20% of infected women, articular symptoms persist for months to years. It has been suggested that parvovirus B19 infection may precipitate the development of rheumatoid arthritis, systemic lupus erythematosus, or juvenile rheumatoid arthritis. However, this view remains controversial. Elevated levels of interleukin-6, tumor necrosis factor α, and granulocyte–macrophage colony-stimulating factor have been found to be negatively associated with the development of acute parvovirus-associated arthritis.7 Expression of antibodies to the 77-kD nonstructural parvovirus B19 protein, NS1, found in 15 to 30% of those infected, is associated with the development of chronic arthritis but not acute arthritis.

Although acute arthritis is the usual clinical manifestation of parvovirus B19 infection in healthy adults, other manifestations may occur, including anemia and leukopenia. Intrauterine infection is a major cause of hydrops fetalis. The estimated risk of fetal infection when a woman is infected with parvovirus during pregnancy is 30%, with a 5 to 9% risk of fetal loss. Infection during the second trimester appears to pose the greatest risk of hydrops fetalis.

In patients who have chronic hemolysis, such as sickle cell anemia, infection may be manifested as a transient aplastic crisis.In other patients with immunosuppression, such as organ-transplant recipients, chronic anemia may develop as a result of persistent viral suppression of erythrocyte production.

The presence of the IgM antibody to parvovirus B19, as in the patient described, indicates acute infection. This antibody appears 10 to 12 days after infection and persists for 1 to 3 months. IgG-antibody expression, found in 40 to 80% of adults, follows and confers lifelong immunity. Although infection commonly occurs early in life, a substantial number of middle-aged and older adults remain susceptible.

This case illustrates the importance of considering parvovirus B19 infection in the differential diagnosis of acute-onset arthritis, regardless of the patient's age. This is particularly important in cases of symmetrical polyarthritis that may otherwise suggest other rheumatic diseases, especially rheumatoid arthritis and systemic lupus erythematosus. As many as 15% of new cases of inflammatory arthritis may be caused by parvovirus infection.Including parvovirus B19 infection in the differential diagnosis of new-onset polyarthritis and ordering appropriate serologic testing to confirm the diagnosis can eliminate the need for expensive additional testing and consultation, avoid inappropriate treatment, and enable the physician to reassure the patient that the arthritis is likely to be self-limited.

Source

1. No respect for age - NEJM

FJM - Related Articles

Parvovirus B19

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

Case Nº1 - FJM

A 60-year-old man presented to the emergency department for evaluation of rectal

bleeding, syncope, and pain in the right leg. Five days earlier, diffuse abdominal pain

that worsened with movement had developed in association with nausea, anorexia,

and malaise. He had not traveled recently or ingested any unusual foods, and he had

no history of fever, weight loss, or change in bowel habits. Approximately six hours

before admission, he had a single episode of gross hematochezia and hematuria followed by syncope. Soon after, he began to have intense pain in his right leg, and he

sought medical care.

The patient had a two-year history of chronic diarrhea, without bleeding. One year

before his presentation he had undergone a colonoscopy, which showed diverticulosis

and two polyps. The polyps were excised and proved to be benign. The results of

an upper gastrointestinal series with small-bowel follow-through and endoscopy

performed at that time were normal. Empirical treatment with metronidazole for

possible giardiasis and hyoscyamine for possible irritable bowel syndrome were minimally effective in controlling the symptoms.

The patient also had a history of hypertension, hyperlipidemia, and gout. His medications included atenolol (50 mg daily), atorvastatin (20 mg daily), allopurinol (300 mg daily), and aspirin (81 mg daily). His father had died of colon cancer at an advanced age. The patient had a remote history of alcohol abuse, but he reported no alcohol intake for the past 20 years. He had a 100 pack-year smoking history but had recently quit.

On physical examination, the patient appeared alert but in moderate distress. He appeared obese; he weighed 108.4 kg, was 175 cm tall, and had a body-mass index (the weight in kilograms divided by the square of the height in meters) of 35.4. He was afebrile; the blood pressure was 74/40 mm Hg, and the heart rate 72 beats per minute. The oxygen saturation level was 98 percent while the patient was breathing ambient air. He was edentulous, wore dentures, and had dry mucosa. Cardiac examination revealed a regular rate and rhythm, without murmur or gallop. There was no jugular venous distention, and no bruits were present. The abdomen was diffusely tender, but there was no guarding, pulsatile mass, or rebound tenderness. The bowel sounds were normal. The rectal examination revealed normal sphincter tone and gross blood, but no tenderness or mass. The legs were nontender; both legs were considered to be warm, but the right leg had diminished pulses as compared with the left. The neurologic examination revealed no focal deficits.

The white-cell count was 16,100 per cubic millimeter, with 87 percent neutrophils and 7 percent band forms. The hemoglobin level was 12.7 g per deciliter, with a normal mean corpuscular volume. The platelet count was 85,000 per cubic millimeter. The serum creatinine level was 1.4 mg per deciliter (123.8 μmol per liter), and the level of urea nitrogen was 34 mg per deciliter (12.1 mmol per liter). The electrolyte levels were normal, and the bicarbonate level was 27 mmol per liter. The prothrombin time was prolonged, at 16.2 seconds (international normalized ratio, 1.8), and the partial- thromboplastin time was normal (31 seconds). The erythrocyte sedimentation rate was 57 mm per hour. Amylase and lipase levels were normal, and the results of liver-function studies were normal, except for an albumin level of 2.6 g per deciliter. No blood smear was obtained. Urinalysis demonstrated the presence of blood (3+), with 2 to 4 red cells, 2 to 4 white cells, and 1+ granular casts per high-power field.

A radiograph of the chest showed no acute disease, and abdominal radiographs demonstrated no obstruction, free air, or stones. The electrocardiogram was normal. Computed tomography (CT) of the abdomen and pelvis revealed an area of sigmoid diverticulosis, thickening of the wall of the sigmoid colon, and a peripherally calcified right iliac artery with infiltration of the surrounding fat.

Blood cultures were obtained, and empirical antibiotic therapy with levofloxacin, metronidazole, and gentamicin was begun, as was vigorous intravenous administration of fluids. Initially, there was transient hemodynamic improvement, but the patient then had another episode of hematochezia followed by syncope, with a fall in blood pressure

to 69/41 mm Hg. A second complete blood count obtained within several hours after the initial assessment revealed that the hemoglobin level had fallen to 7.6 g per deciliter and the platelet count had declined to 55,000 per cubic millimeter. The pain in the patient’s right leg worsened, and his right foot was cooler than the left. Specialists from both general and vascular surgery were consulted.

Packed red cells, fresh-frozen plasma, and platelets were administered. The blood pressure increased to 134/80 mm Hg, but the prothrombin time remained elevated. Duplex ultrasonography revealed no flow in the right common femoral artery and absent systolic pressures in the right ankle. Technetium-99m scintigraphy demonstrated active bleeding in the rectosigmoid colon.

¿What diagnostic test is the most appropiate?¿What is the diagnosis?

The patient was taken to the operating room. Laparotomy revealed diverticulosis and extensive calcification of the aorta and iliac vessels. Further exploration revealed a thin, solid foreign body perforating the rectosigmoid junction into the right

external iliac artery, producing extensive hemorrhage and thrombus in the colon and vessel. Arteriotomy and thromboembolectomy were performed, but stool contamination of the field prevented graft placement during the arterial repair. The iliac laceration was closed; intraoperative Doppler study showed a slight signal distal to the repair, suggesting only minimal improvement in vascular flow. Sigmoid colectomy with colostomy formation was performed without complications. Blood cultures grew Clostridium ramosum and C. cadaveris. Pathological examination revealed

colonic inflammatory changes, diverticulosis with a perforated diverticulum, and a wooden toothpick, 5.8 by 0.3 cm. The postoperative course was complicated by persistent pain and ischemia in the right leg. Additional revascularization procedures were avoided because of the possibility of infection and irreversible ischemic damage. The development of gangrene resulted in a below-theknee amputation on the sixth postoperative day, which required revision to an above-the-knee amputation 20 days later because of poor wound healing. The patient returned home one week after this surgery, without further complications. The patient did not recall ever chewing or ingesting a toothpick

Perforations of the gastrointestinal tract by ingested toothpicks are rare, with an annual rate of 0.2 per 100,000 persons.1 Of foreign-body ingestions, however, toothpicks have been reported to have the highest rate of impaction and perforation

(9 percent).2 These small, thin, and indigestible foreign bodies have at least one sharply pointed end, and their length makes it difficult for them to traverse the tortuous intestinal lumen.3 Perforations have occurred throughout the gastrointestinal

tract, including the duodenum, jejunum, cecum, sigmoid colon, appendix, and a Meckel’s diverticulum,4 with complications including abscess formation, sepsis, hemorrhage, and perforations of major vessels resulting in death.5-9 This patient had a major arterial perforation complicated by sepsis and limb gangrene that eventually necessitated amputation. The timely

identification and treatment of toothpick perforations are warranted; however, the diagnosis remains challenging, since patients may be unable to recall ingesting a toothpick, the symptoms of the condition may mimic those of other disorders,

and a toothpick is difficult to identify radiographically. This patient had no recollection of chewing or swallowing a toothpick, and such a response is not uncommon. Among a series of patients found to have toothpick ingestion, only 12 percent

were aware that it had occurred.10 Many affected patients have altered oral sensation or awareness owing to dentures, the use of alcohol, or underlying psychiatric illness.1 Accidental ingestion has also been reported in competent adults, especially

in those who habitually chew toothpicks, although this patient denied this practice.9 His use of dentures was his only risk factor. The symptoms and signs associated with toothpick perforation are similar to those of several intraabdominal diseases, including diverticulitis, appendicitis, renal colic, and inflammatory bowel disease.10-12 Because of this patient’s history of

diverticular disease and symptoms of anorexia, malaise, and nausea, his physicians initially suspected diverticulitis. The addition of ischemia of the right leg and rectal bleeding to the abdomi-nal pain was key in diagnosing the arterioenteric

fistula, since this provided a single unifying explanation for this patient’s unusual presentation. Although the operative note did not clearly identify the cause of hematuria, it may have been related to associated ureteral inflammation.

Because of their radiolucency, toothpicks are difficult to image. In a series of 57 patients who ingested toothpicks, these foreign bodies were visualized by ultrasonography, CT, and radiography in only 14 percent.10 The definitive diagnosis

of toothpick perforation was most commonly made by laparotomy (53 percent) or by endoscopy (19 percent).10

In the case under discussion, the brisk bleeding and other factors contraindicated colonoscopy. Although the sensitivity and specificity of nuclear scintigraphy are generally suboptimal (85 percent and 70 percent, respectively),13 the technique

in this case successfully identified the bleeding site, allowing for prompt and definitive surgical intervention. Laparotomy confirmed the perforation of the sigmoid colon by the toothpick, with penetration of the right external iliac artery.

Diverticulosis has been noted to be a predisposing factor for perforation.14 Given the evidence of diverticular perforation on pathological examination, it is likely that this patient’s toothpick lodged in a sigmoid diverticulum and was forced by peristalsis to make a sharp right turn, resulting in penetration of the mucosa and the right external iliac artery and, ultimately, an arterial

fistula. The unfortunate combination of preexisting peripheral vascular disease with trauma, hemorrhage, and subsequent infection resulted in unsalvageable ischemic changes that eventuated in gangrene and amputation.