- Email: [email protected]
Sickle Cell Hepatopathy
Review Article
SICKLE CELL HEPATOPATHY Sandhya Chandrakar* and Devendra Singh** *Senior Resident, **Senior Consultant, Department of Gastroenterology, Apollo Hospitals, Bilaspur, Chhattisgarh Correspondence: Dr. Devendra Singh, Senior Consultant, Department of Gastroenterology, Apollo Hospitals, Bilaspur, Chhattisgarh, India. e-mail:[email protected] 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, Exchange transfusion, Multitransfusion hepatopathy.
EPIDEMIOLOGY 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. Apollo Medicine, Vol. 7, No. 4, December 2010
282
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
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, Table 1. Hepatobiliary complications of sickle cell disease
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
Budd-Chiari syndrome
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.
Hepatic infarction
Sickle cell intrahepatic cholestasis (SCIC)
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
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)
Sickle cell intrahepatic cholestasis is a rare but potentially fatal complication of SCD. Its characteristic features include hepatomegaly, extreme total hyperbilirubinemia, coagulopathy, 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
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.
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].
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.
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.
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 Apollo Medicine, Vol. 7, No. 4, December 2010
MULTITRANSFUSION HEPATOPATHY 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
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
284
On analyzing the clinical and laboratory data of 16
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.
4. Mills LR, Mwakyusa D, Milner PF. Histopathologic features of liver biopsy specimens in sickle cell disease. Arch Pathol Lab Med. 1988;112(3): 290-294.
CONCLUSION
8. Shao SH, Orringer EP; Sickle cell intrahepatic cholestasis: approach to a difficult problem. American journal of Gastroentrology, 1995; 90(11): 2048-2050.
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. REFERENCES 1. Subhas Banerjee, Sanjiv Chopra, Stanley L Schrier, Peter A L Bonis; Hepatic manifestations of sickle cell disease; Uptodate 2010.
5. Berry PA, Cross TJ,Thein SL,Portmann BC,Wendon JA, Karani JB, Heneghan MA, Bomford A. Heptic dysfunction in sicklecell disease: a new system of classification based on clinical assessment. Clinical Gastroenterology Hepatology. 2007; 5 (12):1469-1476. 6. Abdul-Wahed Nasir Meshikhes. Gastroenterological manifestations of sickle cell disease;The Saudi Journal of Gastroenterology. 1997; 3(1): 29-33. 7. Lacaille, Florence; Lesage, Fabrice, de Montalembert, Mariane. Acute hepatic crisis in children with sickle cell disease. Journal of Pediatric Gastroenterology & Nutrition: 2004; 39 (2): 200-202.
9. Ahmad M Al-Suleiman, Jawad Bu-sobaih. Acute fulminant cholestatic jaundice in sickle cell disease. Annals of Saudi Medicine. 2006; 26 (2): 138-140. 10. Khurshid I, Anderson L, Downie GH, Pape GS. Sickle cell disease, extreme hyperbilirubinemia, and pericardial tamponade: case report and review of the literature. Critical care medicine. 2002; 30(10): 2363-2367. 11. Nada Zakaria, Alex Knisely, Bernard Portmann, Giorgina Mieli-Vergani, Julia Wendon, Roopen Arya, John Devlin. Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy. Blood. 2003; 101 (1): 101-103.
2. Subhas Banerjee, Charls Owen, Sanjeev Chopra. Sickle cell hepatopathy. Hepatology. 2001; 33 (5).
12. Mekeel KL, Langham MR Jr, Gonzalez-Peralta R, Fujita S, Hemming AW. Liver transplantation in children with sickle-cell disease. Liver Transplantation. 2007; 13(4): 505-508.
3. Bauer TW, Moore GW. Hutchins GM. The liver in sickle cell disease: A clinicopathologicstudy of 70 patients. Am J Med. 1980;69(6):833-837.
13. Maha M Mahera, C Amany H. Mansourb. Study of chronic hepatopathy in patients with sickle cell disease. Gastroenterology Research. 2009; 2(6): 338-343.
285
Apollo Medicine, Vol. 7, No. 4, December 2010
SICKLE CELL HEPATOPATHY Sandhya Chandrakar* and Devendra Singh** *Senior Resident, **Senior Consultant, Department of Gastroenterology, Apollo Hospitals, Bilaspur, Chhattisgarh Correspondence: Dr. Devendra Singh, Senior Consultant, Department of Gastroenterology, Apollo Hospitals, Bilaspur, Chhattisgarh, India. e-mail:[email protected] 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, Exchange transfusion, Multitransfusion hepatopathy.
EPIDEMIOLOGY 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. Apollo Medicine, Vol. 7, No. 4, December 2010
282
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
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, Table 1. Hepatobiliary complications of sickle cell disease
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
Budd-Chiari syndrome
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.
Hepatic infarction
Sickle cell intrahepatic cholestasis (SCIC)
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
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)
Sickle cell intrahepatic cholestasis is a rare but potentially fatal complication of SCD. Its characteristic features include hepatomegaly, extreme total hyperbilirubinemia, coagulopathy, 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
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.
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].
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.
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.
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 Apollo Medicine, Vol. 7, No. 4, December 2010
MULTITRANSFUSION HEPATOPATHY 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
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
284
On analyzing the clinical and laboratory data of 16
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.
4. Mills LR, Mwakyusa D, Milner PF. Histopathologic features of liver biopsy specimens in sickle cell disease. Arch Pathol Lab Med. 1988;112(3): 290-294.
CONCLUSION
8. Shao SH, Orringer EP; Sickle cell intrahepatic cholestasis: approach to a difficult problem. American journal of Gastroentrology, 1995; 90(11): 2048-2050.
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. REFERENCES 1. Subhas Banerjee, Sanjiv Chopra, Stanley L Schrier, Peter A L Bonis; Hepatic manifestations of sickle cell disease; Uptodate 2010.
5. Berry PA, Cross TJ,Thein SL,Portmann BC,Wendon JA, Karani JB, Heneghan MA, Bomford A. Heptic dysfunction in sicklecell disease: a new system of classification based on clinical assessment. Clinical Gastroenterology Hepatology. 2007; 5 (12):1469-1476. 6. Abdul-Wahed Nasir Meshikhes. Gastroenterological manifestations of sickle cell disease;The Saudi Journal of Gastroenterology. 1997; 3(1): 29-33. 7. Lacaille, Florence; Lesage, Fabrice, de Montalembert, Mariane. Acute hepatic crisis in children with sickle cell disease. Journal of Pediatric Gastroenterology & Nutrition: 2004; 39 (2): 200-202.
9. Ahmad M Al-Suleiman, Jawad Bu-sobaih. Acute fulminant cholestatic jaundice in sickle cell disease. Annals of Saudi Medicine. 2006; 26 (2): 138-140. 10. Khurshid I, Anderson L, Downie GH, Pape GS. Sickle cell disease, extreme hyperbilirubinemia, and pericardial tamponade: case report and review of the literature. Critical care medicine. 2002; 30(10): 2363-2367. 11. Nada Zakaria, Alex Knisely, Bernard Portmann, Giorgina Mieli-Vergani, Julia Wendon, Roopen Arya, John Devlin. Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy. Blood. 2003; 101 (1): 101-103.
2. Subhas Banerjee, Charls Owen, Sanjeev Chopra. Sickle cell hepatopathy. Hepatology. 2001; 33 (5).
12. Mekeel KL, Langham MR Jr, Gonzalez-Peralta R, Fujita S, Hemming AW. Liver transplantation in children with sickle-cell disease. Liver Transplantation. 2007; 13(4): 505-508.
3. Bauer TW, Moore GW. Hutchins GM. The liver in sickle cell disease: A clinicopathologicstudy of 70 patients. Am J Med. 1980;69(6):833-837.
13. Maha M Mahera, C Amany H. Mansourb. Study of chronic hepatopathy in patients with sickle cell disease. Gastroenterology Research. 2009; 2(6): 338-343.
285
Apollo Medicine, Vol. 7, No. 4, December 2010