Reversal of liver function without exchange transfusion
in sickle cell intrahepatic cholestasis
Nattamol Hosiriluck, MD, Supannee Rassameehiran, MD, Erwin Argueta, MD, and Lukman Tijani, MD
Sickle cell intrahepatic cholestasis (SCIC) is a rare but fatal complication
of sickle cell disease. It is found mainly in homozygous sickle cell disease.
To date, there are no standard diagnostic criteria or well-established
therapeutic approaches to this condition. Herein, we report this case of a
48-year-old man with sickle cell anemia and a total bilirubin of 78.5 mg/dL
without evidence of extrahepatic biliary obstruction or viral hepatitis.
The patient had a hemoglobin S level of 87.9%, acute renal failure, and
mild coagulopathy. Despite the disease severity, he refused exchange
transfusion (ET) with packed red blood cells. He was transfused with
2 units of blood and treated mainly with supportive measures. His total
bilirubin levels trended down to normal days after discharge. Multiple
studies have shown a significant decrease in the mortality rate in SCIC
after ET. To date, only two reported adult cases have survived SCIC without aggressive treatment. Our case is the third case that demonstrates
recovery of severe SCIC without ET.
S
ickle cell intrahepatic cholestasis (SCIC), one of the
syndromes secondary to sickle cell hepatopathy, is a
rare but potentially fatal complication of sickle cell
disease. The pathophysiology results from hepatic
ischemia due to intrahepatic obstruction from sickling in
the sinusoids (1, 2). It is characterized by abdominal pain,
hepatomegaly, and extreme hyperbilirubinemia with variable
transaminase levels (3, 4). Its clinical course ranges from benign hyperbilirubinemia to fulminant hepatic failure (3, 5).
Benign hyperbilirubinemia is considered self-limited and is
characterized by serum bilirubin levels between 10 and 30 mg/
dL. In severe cases, bilirubin levels are usually >30 mg/dL and
in some cases >80 mg/dL (3). In fatal cases, renal failure and
coagulopathy can develop (5). The only effective management
for severe SCIC is early exchange transfusion (ET) to reverse
liver function (6–8). We report the case of a patient with
severe SCIC, acute kidney injury, and spontaneous return of
bilirubin and hemoglobin S levels to baseline despite refusing
red blood cell ET.
CASE REPORT
A 48-year-old man with sickle cell anemia presented with
jaundice and mild abdominal pain that had lasted for 1 week.
He denied fever, shortness of breath, chest pain, and any change
Proc (Bayl Univ Med Cent) 2014;27(4):361–363
in urine or stool color. His physical exam was unremarkable
except for icteric sclerae. Blood analysis was significant for a total
bilirubin level of 48.9 mg/dL. His hemoglobin at baseline was
7 g/dL, and hepatitis serology was nonreactive. An ultrasound
revealed cholelithiasis without evidence of cholecystitis and
choledocholithiasis. Because the patient had taken doxycycline
as malaria prophylaxis for a trip to China 2 months earlier, he
was initially diagnosed with doxycycline-induced hyperbilirubinemia. His bilirubin level prior to hospital discharge was
50 mg/dL; follow-up in the clinic showed a stable bilirubin
level of 50.3 mg/dL.
He was seen 1 week later with increased abdominal pain,
fatigue, and fever. Physical examination now revealed mild
epigastric and right upper quadrant tenderness and a palpable
liver. Blood analysis was significant for a total bilirubin level
of 77.5 mg/dL; aspartate aminotransferase, 91 IU/dL; alanine
aminotransferase, 31 IU/dL; creatinine, 1.4 mg/dL (an increase
from a baseline of 0.8 mg/dL); hemoglobin, 6.5 g/dL; white
blood cell count, 13.6 K/uL, with predominant neutrophils;
platelets, 400 K/uL; a normal albumin and coagulation panel;
alkaline phosphatase, 179 IU/L; and lactate dehydrogenase,
702 U/L. Hemoglobin electrophoresis showed a hemoglobin
S of 88.6%. A computed tomography scan of the abdomen
confirmed the findings from the previous ultrasound. Magnetic
resonance cholangiopancreatography ruled out an obstruction.
The patient was diagnosed with intrahepatic cholestasis.
The patient refused ET and liver biopsy but accepted intermittent transfusions. He received 2 units of packed red blood
cells. His bilirubin level then rose to a maximum level of 78.9
on day 6 of readmission, and his serum creatinine increased to
3.3 mg/dL. The next day, the patient developed a myoclonic jerk
with normal mental status, which was relieved with clonazepam.
His ammonia level and results of magnetic resonance imaging
of his brain were normal. Electroencephalography completed
while the patient was sleeping showed a slow wave form pattern. His kidney function improved with fluids and returned to
From the Department of Internal Medicine, Texas Tech University Health Sciences
Center, Lubbock, Texas.
Corresponding author: Nattamol Hosiriluck, MD, Department of Internal
Medicine, Texas Tech University Health Sciences Center, 3601 4th Street,
Lubbock, TX 79430 (e-mail: [email protected]).
361
Table 1. Laboratory findings in relation to hospital course
First
Second
Day 2
Baseline admission admission Transfusion
Day 4
Day 7
Day 16
Day 48
Discharge Day 20 Transfusion Day 103
White blood cell count (K/uL)
9.6
7.47
13.16
13.28
8.79
18.54
18.48
16.90
8.33
7.23
Hemoglobin (g/dL)
6.6
7.0
6.5
5.7
6.6
7.9
6.1
6.7
6.9
7.3
Reticulocyte (%)
–
11.5
8.46
–
–
7.92
–
–
–
–
Hemoglobin S (%)
–
–
–
87.9
–
–
–
56.3
60.7
41.9
Prothrombin time (seconds)
–
12.7
19
–
21.9
20.6
–
–
–
–
International normalized ratio
–
1.15
1.74
–
2.04
1.89
–
–
–
–
Creatinine (mg/dL)
0.8
0.7
1.4
1.7
3.3
1.5
1.2
1.3
0.7
0.8
Bilirubin (mg/dL)
4.8
48.9
77.5
76.1
70.6
78.5
56.5
36.4
7.8
4.2
Direct bilirubin (mg/dL)
–
>10
>10
–
–
>10
–
–
–
0.8
Aspartate aminotransferase (IU/dL)
64
45
91
88
83
115
157
130
62
71
Alanine aminotransferase (IU/dL)
15
24
31
28
37
51
70
85
32
41
(defined as >13 mg/dL) (3), a careful physical examination and
appropriate laboratory and radiologic studies should be conducted (7, 9). Liver biopsy was not strongly indicated to establish the
diagnosis, since histological findings do not differ from findings
of other sickle cell disease liver involvement (3). In our patient,
viral hepatitis and cholelithiasis with cholecystitis were ruled out
by negative serology and lack of evidence to suggest extrahepatic
obstruction in imaging studies. Hepatic crisis is another common
complication of sickle cell disease, characterized by short disease
duration (2–3 weeks) with a serum bilirubin level that seldom
exceeds 15 mg/dL (1). The development of myoclonic jerks was
DISCUSSION
related to an abnormally high bilirubin level. Normal ammonia
Sheehy first categorized sickle cell hepatopathy in 1977 into
levels and lack of altered mentation in this clinical setting made
five clinical syndromes: viral hepatitis, hepatitis crisis, cirrhohepatic encephalopathy unlikely.
sis, cholelithiasis with cholecystitis, and intrahepatic cholestasis
Q fever may have also contributed to hyperbilirubine(SCIC). The clinical manifestations of each entity are similar,
mia through two mechanisms. First, infection can trigger the
including fever, right upper quadrant pain, and jaundice. There
development of SCIC (1). Second, the disease itself can cause
was no suggested guideline for diagnosis and treatment of SCIC.
an increase in bilirubin levels. However, studies have shown
When a patient presents with extreme hyperbilirubinemia
that only one-third of Q fever patients develop hyperbilirubinemia, and the highest serum bilirubin
level reported was 18.7 mg/dL (10).
Therefore, Q fever itself was not the
major cause of extreme hyperbilirubinemia in this case.
SCIC has an overall mortality rate
of over 50% (3, 11). The only known
effective management is ET to lower
hemoglobin S levels to <30% (8). Ahn
et al (3) conducted a literature review
that compared two groups of 44 patients from 1953 to 2002 according
to the degree of hepatic dysfunction.
There were 16 adult cases in the study
(those >18 years), 15 of whom were in
the severe group, with a mean maximum bilirubin level of 76.8 mg/dL
(opposed to 36.2 mg/dL in the mild
Figure 1. Hemoglobin, bilirubin, and hemoglobin S level in relation to hospital course.
baseline. Broad-spectrum intravenous antibiotics were initiated
early in the hospital stay and were subsequently deescalated to
oral moxifloxacin. Cultures came back as negative, as did HIV,
syphilis, and leptospirosis serology results, but IgG results for
Q fever were positive in both phase I and II. Bilirubin trended
down to a range of 50 to 60 mg/dL before discharge from
the current hospital admission (Table 1). Outpatient follow-up
showed a normal bilirubin level in a 2-month period (Figure 1).
After being discharged from the hospital, the patient remained
asymptomatic and now continues with his regular clinic visits.
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Baylor University Medical Center Proceedings
Volume 27, Number 4
Table 2. Patients over 18 years of age with sickle cell intrahepatic cholestasis, 2003 to 2014
Year of
publication First author Age (years) Gender Type of sickle cell
2003
Tiftik
2004
2005
HbSS
Clinical feature
A, H, J
Max. total
Hemoglobin
bilirubin (mg/dL)
S (%)
48
79
Treatment
Outcome
21
F
Long-term ET Survived
Tsimpoukas
40
M
HbS–beta
C, F, H, J, U
54.6
–
ET
Survived
Baichi
27
F
HbSS
AHF
80
–
ET, transplant
Died
2005
Baichi
26
F
HbSS
AHF
58.5
15.1
ST, transplant Died
2006
Costa
48
M
HbS–beta
A, C, H, J, ARF
59.7
58
ET
Died
2010
Brunetta
41
M
HbSS
A, H, J
58.9
88.4
ET
Survived
ET, dialysis
Survived
2011
Khan
21
F
HbSS
A, C, H, J, ARF, AHF
14.1
–
2014
Vlachaki
37
M
HbS–beta
H, J
46.8
74.5
Long-term ET Survived
A, abdominal pain; AHF, acute hepatic failure; ARF, acute renal failure; C, coagulopathy; ET, exchange transfusion; F, female; F, fever; H, hepatomegaly; HbSS, hemoglobin SS disease;
HbS–beta, hemoglobin S–beta thalassemia; J, jaundice; M, male; ST, simple transfusion; U, dark urine.
group). The mortality rate in the two groups was 4% and 64%,
respectively. One death was reported among five patients who received ET, while 9 deaths were reported among 10 patients who
underwent supportive treatment. This finding supports the evidence that ET can significantly reduce the mortality rate of SCIC.
Recent case reports have confirmed the successful outcome
with ET. Eight adult cases (5, 11–16) have been reported since
Ahn et al published their review in 2002 (Table 2). Seven out of
the eight patients received ET, and two of them progressed to
hepatic failure and death (5, 13). Two of the patients continued
to receive regular ET to maintain their hemoglobin S level (14,
16). Overall, there are 24 case reports in the adult population. The
mortality rate among those who received ET was 25% (3 deaths
among 12 patients), compared with 83% in the supportive group
(10 deaths among 12 patients). Only two reported cases (17, 18)
survived SCIC without ET. One case presented as mild, selflimited hyperbilirubinemia (17). The other presented with severe
anemia, with a hemoglobin of 2.8 g/dL and hepatic and renal
failure (18). The patient was treated with packed red blood cells
and plasma transfusions to correct anemia and coagulopathy. He
then had reversal of organ failure within 48 hours of admission.
Our case represents a third known case report of SCIC in an
adult who had a favorable outcome with supportive treatment.
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