SI

      

ICKLE CELLL HEPATO

  

OPATHY 

Review Article

EPIDEMIOLOGY

The overall incidence of liver disease in patients with sicklecell anaemia has not been well established. In one Americanstudy 32 of 100 patients had abnormal liver biochemical testsduring a five-year follow-up period [1]. In an autopsy series,hepatomegaly was noted in 91% of 70 patients with sicklecell anemia, sickle cell disease, and HbSß-thalassemia,suggesting that some form of liver involvement is relativelycommon [2]. In another autopsy series, 16 to 29% ofpatients had cirrhosis. However, it is unclear whethercirrhosis was due to the sickle cell anemia itself or toconcurrent liver disease acquired as a consequence ofmultiple transfusions, leading to iron overload and chronichepatitis B or C infection. Although predominantly affectingblacks, SCD is also present in the white population(particularly in Mediterranean countries) in which the liverdisease appears to be milder [1].

While in west SCD predominantly affects blacks, in Indiait is clustered in several parts of MP, Chhattisgarh,Maharashtra, Orissa, Jharkhand and parts of AndhraPradesh. The various ethnic groups involved Agharias,Sahus. Telis and some backwards classes. The status ofSCD is alarming in the states of Madhya Pradesh andChhattisgarh as more than 5000 newborns with SCD arebeing added to the population every year.

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:devsvirdi@yahoo.com

The term ‘Sickle Cell Hepatopathy’ encompasses a range of hepatic dysfunction arising from a wide varietyof insults to the liver in patients with sickle cell disease(SCD). It occurs predominantly in patients withhomozygous sickle cell anemia, and to a lesser extent in patients with sickle cell trait, HbSC disease andHbSb Thalassemia.

The liver can be affected by a number of complications due to the disease itself and its treatment. The directaffection of liver in sickle cell disease is predominantly due to vascular occlusion by sickled RBCs with acuteischemia, sequestration, and cholestasis. The risk of viral hepatitis B and C and iron overload due tomultiple blood transfusions and chronic hemolysis leading to the development of pigment stones, withconsequent cholecystitis and choledocholithiasis contribute to the development of liver disease. Reversiblehepatic toxicity may be seen with androgenic steroids used in the past as a therapy for SCD with severeanaemia. 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.

Variations of liver function tests in the absenceof liver disease in sickle cell disease patients

Even in the absence of liver disease abnormal liverfunction tests are common in patients with sickle cellanemia. Hyperbilirubinemia usually less than 6 mg/dL,predominantly unconjugated, is universal in sickle cellpatients due to chronic hemolysis. In a study by Johnson,et al, 72 out of 100 patients with sickle cell anemia had anisolated elevation of bilirubin, with no other clinical orlaboratory evidence of liver disease. Serum bilirubin levelscorrelate with lactic dehydrogenase levels, suggesting thatvariable levels found in patients are related to the degree ofhemolysis and/or ineffective erythropoiesis rather than todisorders of bilirubin transport or processing.

Hemolysis also raises plasma aspartate transaminase(AST) levels, which therefore also correlate with lacticdehydrogenase levels. Plasma alanine transaminase (ALT)levels therefore more accurately reflect hepatocyte injury insickle cell patients. Serum alkaline phosphatase is alsoelevated in patients with sickle cell anemia, particularlyduring pain crises and bone alkaline phosphatase is the majorenzyme fraction [2].

Clinical syndromes of sickle cell hepatopathy

Patients with sickle cell disease may present with an

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acute syndrome characterized by right upper quadrantabdominal pain and jaundice or may present with chronicliver dysfunction (Table 1)..

Histopathological findings of liver biopsy specimen insickle cell disease patients show hepatomegaly, distendedKupffer cells with erythro-phagocytosis (in 91% markedlydistended sinusoids having sickled red cells), 27% focalparenchymal necrosis, 34% reparative changes, portalfibrosis, regenerative nodules suggestive of cirrhosis [3],lobular cholestasis, acute or chronic hepatitis and rarelychanges of Budd-Chiari Syndrome have been seen [4].Another study by Berry PA, et al in 2007 has shown massivehepatocellular necrosis (5%), acute severe sequestration,cholestasis (18%), cirrhosis (18%), chronic, fluctuatingsequestration without cholestasis (21%), mechanical biliaryobstruction (8%), siderosis without cirrhosis (8%),generalized cholangiopathy (8%), venous outflowobstruction (3%), and miscellaneous (11%) [5]. Anassociation between focal nodular hyperplasia (FNH) andSCD has been questioned [6].

Acute sickle hepatic crisis

This syndrome occurs in approximately 10% of patientswith sickle cell anemia. Patients commonly present withacute right upper quadrant pain, nausea, low grade fever,

tender hepatomegaly, and jaundice. Plasma AST and ALTlevels seldom exceed 300 IU/L, although levels of 1,000 IU/Lor greater have been occasionally reported, presumablybecause of more severe hepatic hypoxic injury. Serumbilirubin levels are usually less than 15 mg/dL. Liver biopsyshows sinusoidal obstruction by sickle cell thrombi, Kupffercell hypertrophy, and engorgement with red blood cells. Mildcentrilobular necrosis and occasional bile stasis was alsonoted. Sometimes liver biopsy shows sickle cell changesonly. The syndrome is self limiting, usually resolving within 3to 14 days with intravenous hyperhydration and analgesia.

Acute hepatic crisis is less commonly seen in childrenbut is similar to that reported in adults, except that thechildren experience higher bilirubin levels (usually less than200μM in adults). Liver and multiorgan failure can developrapidly [7]. In this situation, the prognosis is poor. Acutehepatic crisis is very similar to acute viral hepatitis, exceptthat transaminases are not so elevated; there is a more rapiddecrease in transaminase levels with treatment whilst viralserology is negative [6,7].

Cocaine use by sickle cell anemia patients can precipitatea severe crisis due to synergistic hypoxic injury fromcocaine-induced vasospasm and from sickling and cansubsequently lead to hepatic failure [2].

Hepatic sequestration crisis/reversesequestration

Hepatic sequestration of red blood cells, althoughunusual, presents with right upper quadrant pain, rapidlyincreasing hepatomegaly, and a falling hematocrit and mild tomoderate elevation in transaminase levels. On resolution ofthe crisis and relief of sinusoidal obstruction undestroyed redblood cells may return to the circulation and may lead to rapidrise in the hemoglobin. Even death has been reported as aconsequence of the resultant hypervolemia, hypertension,heart failure, and intracerebral hemorrhage. Exchangetransfusion is probably preferable to partial exchange oradditive transfusions in patients experiencing a sequestrationcrisis.

Sickle cell intrahepatic cholestasis (SCIC)

Sickle cell intrahepatic cholestasis is a rare but potentiallyfatal complication of SCD. Its characteristic features includehepatomegaly, extreme total hyperbilirubinemia, coagulo-pathy, and acute liver failure [8]. It occurs as a consequenceof widespread sickling within sinusoids with vascular stasisand hepatic ischemia. Damage caused by local hypoxia mayresult in ballooning of the hepatocytes and Kupffer Cellhypertrophy with resultant intracanalicular cholestasis [2,9].

The presentation is similar to sickle hepatic crisis, withright upper quadrant pain, nausea, vomiting, fever, tender

Table 1. Hepatobiliary complications of sickle celldisease

A. Clinical syndromesAcute sickle hepatic crisisHepatic sequestration/reverse sequestrationSickle cell intrahepatic cholestasisAcute sickle cell intrahepatic cholestasisBenign hyperbilirubinemiaChronic intrahepatic cholestasis

MiscellaneousBudd-Chiari syndromeHepatic infarctionHepatic abscessHepatic bilomaZinc deficiency with hyperammonemiaAutoimmune hepatitis (15)B. Complications of chronic hemolysis and multiple

transfusionsCholelithiasis and choledocholithiasis (pigmentstones)Hepatic iron overloadViral hepatitis B and C (rare in current practice)

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hepatomegaly and leukocytosis. However, striking jaundicedevelops subsequently accompanied frequently by renalimpairment, a bleeding diathesis, and increasingencephalopathy [2].One case reported by Khurshid, et aldeveloped pericardial temponade along with the abovefeatures in addition to respiratory failure and cardiacdysrrythmias, a rare complication [10]. On laboratoryinvestigations, the characteristic finding is that of strikinglyhigh plasma bilirubin concentrations, with a level of 273mg/dL documented in 1 patient. In most cases theconjugated fraction exceeds 50% of the total bilirubin. Theextremely high bilirubin levels are caused by a combinationof on-going hemolysis, intrahepatic cholestasis, and renalimpairment.

Plasma ALT levels range from 34 to 3,070 IU/L, plasmaAST levels from 100 to 6,680 IU/L, and alkalinephosphatase levels from normal to 860 IU/L. Lacticdehydrogenase levels are usually elevated (660-7760 IU/L),and, prolongation of the prothrombin time and partialthromboplastin time is common. Elevations in blood urea,creatinine, and ammonia are also seen.Hypofibrinogenemia, thrombocytopenia, and lacticacidosis may accompany the liver failure.

The renal impairment in sickle intrahepatic cholestasis ispostulated to be multifactorial (hyperbilirubinemia, perhapscombined with volume depletion, and hemoglobinurialeading to acute tubular necrosis, antibiotics and multiplerenal infarcts), but appears reversible and improvesconcurrently with hepatic improvement. A Tc-99msulphur colloid liver spleen scan done in a single patientshowed hepatomegaly with patchy uptake of colloid.Postmortem liver biopsies in 4 patients with sickleintrahepatic cholestasis showed dilated canaliculi with bileplugs, micro infarcts, widespread anoxic necrosis withareas of acute and chronic inflammation in addition to theusual findings noted in sickle cell patients. Ahn H, et alfound in this study that both children and adults canpresent with SCIC, however, adults have a more severeform. Older age and underlying hepatic disease are poorprognostic factors for adult SCIC patients [11].

Exchange transfusion and supportive care aimed atcorrection of coagulopathy, stabilization of the acute liverdisease, and perhaps most important, avoidance of surgicalintervention are the keys to a successful outcome [8].Acute hepatic disease complicating sickle cell anemiarepresents a newly identified contraindication topercutaneous liver biopsy because of bleedingcomplications. Renal impairment is usually reversible butmay need hemodialysis and/or peritoneal dialysis [12].Mekeel KL, et al found that children with SCD and acuteand chronic liver failure can be successfully transplanted

with good outcomes. Overall patient and graft survivalwas found to be 66%. Careful attention must be paid toHbS fraction (<30%) and hemoglobin level to preventsickling and vascular thrombosis. Unfortunately, livertransplant cannot alter the natural course of the disease[13].

MULTITRANSFUSION HEPATOPATHY

Autopsy series indicate a 16% to 29% prevalence ofcirrhosis in sickle cell anemia patients. Cirrhosis in sicklecell anemia patients is usually secondary to chronichepatitis B or C infection or because of iron overload.

Hepatic iron overload in sickle cell patients

In patients with sickle cell anemia, serum ferritin levelscorrelate with the number of units of blood transfused. Apainful vaso-occlusive sickle crisis also increases serumferritin level. In multitransfused patients, increaseddeposition of iron occurs within reticuloendothelial cells,including Kupffer cells. Plasma steady-state ferritin levelscorrelate with hepatic iron stores and with ALT levels.Hepatic parenchymal iron accumulation may be severeenough to lead to cirrhosis. Exchange transfusions, Ironchelation therapy with intravenous or subcutaneousdeferoxamine and erythrocytapheresis have been shown toretard iron accumulation and histologic progression tofibrosis in sickle cell patients.

Viral hepatitis in sickle cell anemia patients

Viral hepatitis due to hepatitis B and C viruses waspreviously common in SCD patients because of need ofmultiple transfusions. In one study the SCD patientssuffering from acute hepatitis B did not differ in the clinicalcourse, and, liver function tests from control patientswithout sickle cell disease. In contrast, Johnson, et alfound higher mean peak bilirubin level in acute hepatitis B,which was attributed to the underlying chronic hemolyticstate. In parts of the world where hepatitis B is moreprevalent, much higher rates of chronic hepatitis B exist insickle cell patients as also in the general population. Inseveral studies, hepatitis C serologies showed a relationshipwith the mean number of units transfused, while hepatitisB did not. HCV can cause mild (1.5-4 fold) elevation inplasma AST /ALT level or lead to cirrhosis.

The occurrence of autoimmune hepatitis type -1 in SCDpatients has been reported in 4 patients. Whether apathological link exists between SCD and autoimmunehepatitis remains to be determined.

OUR EXPERIENCE

On analyzing the clinical and laboratory data of 16

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patients of sickle cell hepatopathy admitted in Apollo HospitalBilaspur, the results were alarming. There was clinicalevidence of jaundice in 100% patients, elevated SGOT &SGPT in 80%, elevated alkaline phosphatase in 71% andprolonged Prothrombin time in 100% patients. The meanage, serum bilirubin level, SGOT, SGPT, Alkalinephosphatase and prothrombin time were 32±16 yrs, 31±23mg/dL, 407.6±732 IU/dL, 306.3±428.67 IU/L, 362.6±200.7 and 22.66±11 seconds respectively, and these weresignificantly higher when compared to available studies donein other parts of world. Out of 16 patients, 10 patientssurvived. Only one patient underwent exchange transfusionfrom among the remaining six who succumbed, but, couldnot be saved.

CONCLUSION

The clinical spectrum of sickle cell hepatopathy rangesfrom mild liver function test abnormalities in asymptomaticpatients, to fulminant hepatic failure. Multiple factors maycontribute to the development of the liver disease, includingvaso-occlusion, transfusion related viral hepatitis, ironoverload, and gallstones. Dominant etiology can be clarifiedby proper history, a comprehensive workup, includingserologic testing and abdominal imaging. Patients withfulminant hepatic failure even can be saved with exchangetransfusion, hyperhydration and supportive care.

REFERENCES

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2. Subhas Banerjee, Charls Owen, Sanjeev Chopra. Sicklecell hepatopathy. Hepatology. 2001; 33 (5).

3. Bauer TW, Moore GW. Hutchins GM. The liver in sickle celldisease: A clinicopathologicstudy of 70 patients. Am JMed. 1980;69(6):833-837.

4. Mills LR, Mwakyusa D, Milner PF. Histopathologicfeatures of liver biopsy specimens in sickle cell disease.Arch Pathol Lab Med. 1988;112(3): 290-294.

5. Berry PA, Cross TJ,Thein SL,Portmann BC,Wendon JA,Karani JB, Heneghan MA, Bomford A. Heptic dysfunctionin sicklecell disease: a new system of classificationbased on clinical assessment. Clinical Gastro-enterology Hepatology. 2007; 5 (12):1469-1476.

6. Abdul-Wahed Nasir Meshikhes. Gastroenterologicalmanifestations of sickle cell disease;The Saudi Journalof Gastroenterology. 1997; 3(1): 29-33.

7. Lacaille, Florence; Lesage, Fabrice, de Montalembert,Mariane. Acute hepatic crisis in children with sickle celldisease. Journal of Pediatric Gastroenterology &Nutrition: 2004; 39 (2): 200-202.

8. Shao SH, Orringer EP; Sickle cell intrahepaticcholestasis: approach to a difficult problem. Americanjournal of Gastroentrology, 1995; 90(11): 2048-2050.

9. Ahmad M Al-Suleiman, Jawad Bu-sobaih. Acutefulminant 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 celldisease, extreme hyperbilirubinemia, and pericardialtamponade: case report and review of the literature.Critical care medicine. 2002; 30(10): 2363-2367.

11. Nada Zakaria, Alex Knisely, Bernard Portmann, GiorginaMieli-Vergani, Julia Wendon, Roopen Arya, John Devlin.Acute sickle cell hepatopathy represents a potentialcontraindication for percutaneous liver biopsy. Blood.2003; 101 (1): 101-103.

12. Mekeel KL, Langham MR Jr, Gonzalez-Peralta R, Fujita S,Hemming AW. Liver transplantation in children withsickle-cell disease. Liver Transplantation. 2007; 13(4):505-508.

13. Maha M Mahera, C Amany H. Mansourb. Study of chronichepatopathy in patients with sickle cell disease. Gastro-enterology Research. 2009; 2(6): 338-343.

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