The term ‘Sickle Cell Hepatopathy’ encompasses a range of hepatic dysfunction arising from a wide variety of insults to the liver in patients with sickle cell disease(SCD). It occurs predominantly in patients with homozygous sickle cell anemia, and to a lesser extent in patients with sickle cell trait, HbSC disease and HbSb Thalassemia. The liver can be affected by a number of complications due to the disease itself and its treatment. The direct affection of liver in sickle cell disease is predominantly due to vascular occlusion by sickled RBCs with acute ischemia, sequestration, and cholestasis. The risk of viral hepatitis B and C and iron overload due to multiple blood transfusions and chronic hemolysis leading to the development of pigment stones, with consequent cholecystitis and choledocholithiasis contribute to the development of liver disease. Reversible hepatic toxicity may be seen with androgenic steroids used in the past as a therapy for SCD with severe anaemia. In some cases cardiac failure may lead to hepatocellular damage in SCD.

1. SICKLE CELL HEPATOPATHY

2. Review Article
*Senior Resident, **Senior Consultant, Department of Gastroenterology, Apollo Hospitals, Bilaspur, Chhattisgarh
Correspondence: Dr. Devendra Singh, Senior Consultant, Department of Gastroenterology,
The term ‘Sickle Cell Hepatopathy’ encompasses a range of hepatic dysfunction arising from a wide variety
of insults to the liver in patients with sickle cell disease(SCD). It occurs predominantly in patients with
homozygous sickle cell anemia, and to a lesser extent in patients with sickle cell trait, HbSC disease and
HbSb Thalassemia.
The liver can be affected by a number of complications due to the disease itself and its treatment. The direct
affection of liver in sickle cell disease is predominantly due to vascular occlusion by sickled RBCs with acute
ischemia, sequestration, and cholestasis. The risk of viral hepatitis B and C and iron overload due to
multiple blood transfusions and chronic hemolysis leading to the development of pigment stones, with
consequent cholecystitis and choledocholithiasis contribute to the development of liver disease. Reversible
hepatic toxicity may be seen with androgenic steroids used in the past as a therapy for SCD with severe
anaemia. In some cases cardiac failure may lead to hepatocellular damage in SCD.
Key words: Sickle cell disease, Abnormal liver function Tests, Ineffective erythropoiesis, Acute hepatic crisis,
EPIDEMIOLOGY
SICKLE CELL HEPATOPATHY
Sandhya Chandrakar* and Devendra Singh**
Apollo Hospitals, Bilaspur, Chhattisgarh, India.
e-mail:devsvirdi@yahoo.com
Exchange transfusion, Multitransfusion hepatopathy.
The overall incidence of liver disease in patients with sickle
cell anaemia has not been well established. In one American
study 32 of 100 patients had abnormal liver biochemical tests
during a five-year follow-up period [1]. In an autopsy series,
hepatomegaly was noted in 91% of 70 patients with sickle
cell anemia, sickle cell disease, and HbSß-thalassemia,
suggesting that some form of liver involvement is relatively
common [2]. In another autopsy series, 16 to 29% of
patients had cirrhosis. However, it is unclear whether
cirrhosis was due to the sickle cell anemia itself or to
concurrent liver disease acquired as a consequence of
multiple transfusions, leading to iron overload and chronic
hepatitis B or C infection. Although predominantly affecting
blacks, SCD is also present in the white population
(particularly in Mediterranean countries) in which the liver
disease appears to be milder [1].
While in west SCD predominantly affects blacks, in India
it is clustered in several parts of MP, Chhattisgarh,
Maharashtra, Orissa, Jharkhand and parts of Andhra
Pradesh. The various ethnic groups involved Agharias,
Sahus. Telis and some backwards classes. The status of
SCD is alarming in the states of Madhya Pradesh and
Chhattisgarh as more than 5000 newborns with SCD are
being added to the population every year.
Variations of liver function tests in the absence
of liver disease in sickle cell disease patients
Even in the absence of liver disease abnormal liver
function tests are common in patients with sickle cell
anemia. Hyperbilirubinemia usually less than 6 mg/dL,
predominantly unconjugated, is universal in sickle cell
patients due to chronic hemolysis. In a study by Johnson,
et al, 72 out of 100 patients with sickle cell anemia had an
isolated elevation of bilirubin, with no other clinical or
laboratory evidence of liver disease. Serum bilirubin levels
correlate with lactic dehydrogenase levels, suggesting that
variable levels found in patients are related to the degree of
hemolysis and/or ineffective erythropoiesis rather than to
disorders of bilirubin transport or processing.
Hemolysis also raises plasma aspartate transaminase
(AST) levels, which therefore also correlate with lactic
dehydrogenase levels. Plasma alanine transaminase (ALT)
levels therefore more accurately reflect hepatocyte injury in
sickle cell patients. Serum alkaline phosphatase is also
elevated in patients with sickle cell anemia, particularly
during pain crises and bone alkaline phosphatase is the major
enzyme fraction [2].
Clinical syndromes of sickle cell hepatopathy
Patients with sickle cell disease may present with an
Apollo Medicine, Vol. 7, No. 4, December 2010 282

3. Review Article
acute syndrome characterized by right upper quadrant
abdominal pain and jaundice or may present with chronic
liver dysfunction (Table 1)..
Histopathological findings of liver biopsy specimen in
sickle cell disease patients show hepatomegaly, distended
Kupffer cells with erythro-phagocytosis (in 91% markedly
distended sinusoids having sickled red cells), 27% focal
parenchymal necrosis, 34% reparative changes, portal
fibrosis, regenerative nodules suggestive of cirrhosis [3],
lobular cholestasis, acute or chronic hepatitis and rarely
changes of Budd-Chiari Syndrome have been seen [4].
Another study by Berry PA, et al in 2007 has shown massive
hepatocellular necrosis (5%), acute severe sequestration,
cholestasis (18%), cirrhosis (18%), chronic, fluctuating
sequestration without cholestasis (21%), mechanical biliary
obstruction (8%), siderosis without cirrhosis (8%),
generalized cholangiopathy (8%), venous outflow
obstruction (3%), and miscellaneous (11%) [5]. An
association between focal nodular hyperplasia (FNH) and
SCD has been questioned [6].
Acute sickle hepatic crisis
This syndrome occurs in approximately 10% of patients
with sickle cell anemia. Patients commonly present with
acute right upper quadrant pain, nausea, low grade fever,
tender hepatomegaly, and jaundice. Plasma AST and ALT
levels seldom exceed 300 IU/L, although levels of 1,000 IU/L
or greater have been occasionally reported, presumably
because of more severe hepatic hypoxic injury. Serum
bilirubin levels are usually less than 15 mg/dL. Liver biopsy
shows sinusoidal obstruction by sickle cell thrombi, Kupffer
cell hypertrophy, and engorgement with red blood cells. Mild
centrilobular necrosis and occasional bile stasis was also
noted. Sometimes liver biopsy shows sickle cell changes
only. The syndrome is self limiting, usually resolving within 3
to 14 days with intravenous hyperhydration and analgesia.
Acute hepatic crisis is less commonly seen in children
but is similar to that reported in adults, except that the
children experience higher bilirubin levels (usually less than
200 μM in adults). Liver and multiorgan failure can develop
rapidly [7]. In this situation, the prognosis is poor. Acute
hepatic crisis is very similar to acute viral hepatitis, except
that transaminases are not so elevated; there is a more rapid
decrease in transaminase levels with treatment whilst viral
serology is negative [6,7].
Cocaine use by sickle cell anemia patients can precipitate
a severe crisis due to synergistic hypoxic injury from
cocaine-induced vasospasm and from sickling and can
subsequently lead to hepatic failure [2].
Hepatic sequestration crisis/reverse
sequestration
Hepatic sequestration of red blood cells, although
unusual, presents with right upper quadrant pain, rapidly
increasing hepatomegaly, and a falling hematocrit and mild to
moderate elevation in transaminase levels. On resolution of
the crisis and relief of sinusoidal obstruction undestroyed red
blood cells may return to the circulation and may lead to rapid
rise in the hemoglobin. Even death has been reported as a
consequence of the resultant hypervolemia, hypertension,
heart failure, and intracerebral hemorrhage. Exchange
transfusion is probably preferable to partial exchange or
additive transfusions in patients experiencing a sequestration
crisis.
Sickle cell intrahepatic cholestasis (SCIC)
Sickle cell intrahepatic cholestasis is a rare but potentially
fatal complication of SCD. Its characteristic features include
hepatomegaly, extreme total hyperbilirubinemia, coagulo-pathy,
and acute liver failure [8]. It occurs as a consequence
of widespread sickling within sinusoids with vascular stasis
and hepatic ischemia. Damage caused by local hypoxia may
result in ballooning of the hepatocytes and Kupffer Cell
hypertrophy with resultant intracanalicular cholestasis [2,9].
The presentation is similar to sickle hepatic crisis, with
right upper quadrant pain, nausea, vomiting, fever, tender
283 Apollo Medicine, Vol. 7, No. 4, December 2010
Table 1. Hepatobiliary complications of sickle cell
disease
A. Clinical syndromes
Acute sickle hepatic crisis
Hepatic sequestration/reverse sequestration
Sickle cell intrahepatic cholestasis
Acute sickle cell intrahepatic cholestasis
Benign hyperbilirubinemia
Chronic intrahepatic cholestasis
Miscellaneous
Budd-Chiari syndrome
Hepatic infarction
Hepatic abscess
Hepatic biloma
Zinc deficiency with hyperammonemia
Autoimmune hepatitis (15)
B. Complications of chronic hemolysis and multiple
transfusions
Cholelithiasis and choledocholithiasis (pigment
stones)
Hepatic iron overload
Viral hepatitis B and C (rare in current practice)

4. Review Article
hepatomegaly and leukocytosis. However, striking jaundice
develops subsequently accompanied frequently by renal
impairment, a bleeding diathesis, and increasing
encephalopathy [2].One case reported by Khurshid, et al
developed pericardial temponade along with the above
features in addition to respiratory failure and cardiac
dysrrythmias, a rare complication [10]. On laboratory
investigations, the characteristic finding is that of strikingly
high plasma bilirubin concentrations, with a level of 273
mg/dL documented in 1 patient. In most cases the
conjugated fraction exceeds 50% of the total bilirubin. The
extremely high bilirubin levels are caused by a combination
of on-going hemolysis, intrahepatic cholestasis, and renal
impairment.
Plasma ALT levels range from 34 to 3,070 IU/L, plasma
AST levels from 100 to 6,680 IU/L, and alkaline
phosphatase levels from normal to 860 IU/L. Lactic
dehydrogenase levels are usually elevated (660-7760 IU/L),
and, prolongation of the prothrombin time and partial
thromboplastin time is common. Elevations in blood urea,
creatinine, and ammonia are also seen.
Hypofibrinogenemia, thrombocytopenia, and lactic
acidosis may accompany the liver failure.
The renal impairment in sickle intrahepatic cholestasis is
postulated to be multifactorial (hyperbilirubinemia, perhaps
combined with volume depletion, and hemoglobinuria
leading to acute tubular necrosis, antibiotics and multiple
renal infarcts), but appears reversible and improves
concurrently with hepatic improvement. A Tc-99m
sulphur colloid liver spleen scan done in a single patient
showed hepatomegaly with patchy uptake of colloid.
Postmortem liver biopsies in 4 patients with sickle
intrahepatic cholestasis showed dilated canaliculi with bile
plugs, micro infarcts, widespread anoxic necrosis with
areas of acute and chronic inflammation in addition to the
usual findings noted in sickle cell patients. Ahn H, et al
found in this study that both children and adults can
present with SCIC, however, adults have a more severe
form. Older age and underlying hepatic disease are poor
prognostic factors for adult SCIC patients [11].
Exchange transfusion and supportive care aimed at
correction of coagulopathy, stabilization of the acute liver
disease, and perhaps most important, avoidance of surgical
intervention are the keys to a successful outcome [8].
Acute hepatic disease complicating sickle cell anemia
represents a newly identified contraindication to
percutaneous liver biopsy because of bleeding
complications. Renal impairment is usually reversible but
may need hemodialysis and/or peritoneal dialysis [12].
Mekeel KL, et al found that children with SCD and acute
and chronic liver failure can be successfully transplanted
with good outcomes. Overall patient and graft survival
was found to be 66%. Careful attention must be paid to
HbS fraction (<30%) and hemoglobin level to prevent
sickling and vascular thrombosis. Unfortunately, liver
transplant cannot alter the natural course of the disease
[13].
MULTITRANSFUSION HEPATOPATHY
Apollo Medicine, Vol. 7, No. 4, December 2010 284
Autopsy series indicate a 16% to 29% prevalence of
cirrhosis in sickle cell anemia patients. Cirrhosis in sickle
cell anemia patients is usually secondary to chronic
hepatitis B or C infection or because of iron overload.
Hepatic iron overload in sickle cell patients
In patients with sickle cell anemia, serum ferritin levels
correlate with the number of units of blood transfused. A
painful vaso-occlusive sickle crisis also increases serum
ferritin level. In multitransfused patients, increased
deposition of iron occurs within reticuloendothelial cells,
including Kupffer cells. Plasma steady-state ferritin levels
correlate with hepatic iron stores and with ALT levels.
Hepatic parenchymal iron accumulation may be severe
enough to lead to cirrhosis. Exchange transfusions, Iron
chelation therapy with intravenous or subcutaneous
deferoxamine and erythrocytapheresis have been shown to
retard iron accumulation and histologic progression to
fibrosis in sickle cell patients.
Viral hepatitis in sickle cell anemia patients
Viral hepatitis due to hepatitis B and C viruses was
previously common in SCD patients because of need of
multiple transfusions. In one study the SCD patients
suffering from acute hepatitis B did not differ in the clinical
course, and, liver function tests from control patients
without sickle cell disease. In contrast, Johnson, et al
found higher mean peak bilirubin level in acute hepatitis B,
which was attributed to the underlying chronic hemolytic
state. In parts of the world where hepatitis B is more
prevalent, much higher rates of chronic hepatitis B exist in
sickle cell patients as also in the general population. In
several studies, hepatitis C serologies showed a relationship
with the mean number of units transfused, while hepatitis
B did not. HCV can cause mild (1.5-4 fold) elevation in
plasma AST /ALT level or lead to cirrhosis.
The occurrence of autoimmune hepatitis type -1 in SCD
patients has been reported in 4 patients. Whether a
pathological link exists between SCD and autoimmune
hepatitis remains to be determined.
OUR EXPERIENCE
On analyzing the clinical and laboratory data of 16

5. Review Article
patients of sickle cell hepatopathy admitted in Apollo Hospital
Bilaspur, the results were alarming. There was clinical
evidence of jaundice in 100% patients, elevated SGOT &
SGPT in 80%, elevated alkaline phosphatase in 71% and
prolonged Prothrombin time in 100% patients. The mean
age, serum bilirubin level, SGOT, SGPT, Alkaline
phosphatase and prothrombin time were 32±16 yrs, 31±23
mg/dL, 407.6±732 IU/dL, 306.3±428.67 IU/L, 362.6±
200.7 and 22.66±11 seconds respectively, and these were
significantly higher when compared to available studies done
in other parts of world. Out of 16 patients, 10 patients
survived. Only one patient underwent exchange transfusion
from among the remaining six who succumbed, but, could
not be saved.
CONCLUSION
The clinical spectrum of sickle cell hepatopathy ranges
from mild liver function test abnormalities in asymptomatic
patients, to fulminant hepatic failure. Multiple factors may
contribute to the development of the liver disease, including
vaso-occlusion, transfusion related viral hepatitis, iron
overload, and gallstones. Dominant etiology can be clarified
by proper history, a comprehensive workup, including
serologic testing and abdominal imaging. Patients with
fulminant hepatic failure even can be saved with exchange
transfusion, hyperhydration and supportive care.
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