Sickle Hepatopathy

Abstract

Sickle hepatopathy is an umbrella term describing various pattern of liver injury seen in patients with sickle cell disease. The disease is not uncommon in India; in terms of prevalence, India is second only to Sub-Saharan Africa where sickle cell disease is most prevalent. Hepatic involvement in sickle cell disease is not uncommon. Liver disease may result from viral hepatitis and iron overload due to multiple transfusions of blood products or due to disease activity causing varying changes in vasculature. The clinical spectrum of disease ranges from ischemic injury due to sickling of red blood cells in hepatic sinusoids, pigment gall stones, and acute/chronic sequestration syndromes. The sequestration syndromes are usually episodic and self-limiting requiring conservative management such as antibiotics and intravenous fluids or packed red cell transfusions. However, rarely these episodes may present with coagulopathy and encephalopathy like acute liver failure, which are life-threatening, requiring exchange transfusions or even liver transplantation. However, evidence for their benefits, optimal indications, and threshold to start exchange transfusion is limited. Similarly, there is paucity of the literature regarding the end point of exchange transfusion in this scenario. Liver transplantation may also be beneficial in end-stage liver disease. Hydroxyurea, the antitumor agent, which is popularly used to prevent life-threatening complications such as acute chest syndrome or stroke in these patients, has been used only sparingly in hepatic sequestrations. The purpose of this review is to provide insights into epidemiology of sickle cell disease in India and pathogenesis and classification of hepatobiliary involvement in sickle cell disease. Finally, various management options including exchange transfusion, liver transplantation, and hydroxyurea in hepatic sequestration syndromes will be discussed in brief.

Sickle cell disease (SCD) is one of the most common monogenetic disorders with an autosomal recessive inheritance that cause qualitative dysfunction of β chain of hemoglobin.¹ Sickle cells in red blood cells (RBCs) were first described by James Bryan Herrick in a dental student in Grenada in 1910 who presented with pulmonary symptoms.² It was shown by Linus Pauling et al. that sickle hemoglobin (HbS) had an altered electrophoretic mobility. They were first to describe it as a molecular disease in 1949. Vernon Ingram in 1957 described that this dysfunction occurs because of a single nucleotide substitution (A→T) that leads to replacement of glutamic acid by valine.^3,4 This results in formation of HbS, which has increased stiffness and tendency to sickle RBCs. Increased stiffness and deformability of RBCs lead to various acute and chronic complications of SCD including acute chest syndrome, stroke, pulmonary hypertension, blindness, priapism, nephropathy, and hepatopathy. Sickle cell hepatopathy is an umbrella term used to denote various acute and chronic liver involvements in SCD. Involvement of the liver in SCD is less common but may be life-threatening if not treated appropriately. This review will discuss in brief the epidemiology of SCD and sickle hepatopathy worldwide and in India. It will be followed by a brief discussion of clinical features, pathophysiology, and management of various acute and chronic syndromes included within the ambit of sickle hepatopathy in patients with SCD. Later various management options including contentious issues such as the role of liver biopsy and liver transplantation in this rare and life-threatening complication of SCD will also be outlined.

Epidemiology

About 5–7% of the whole world population is a carrier of a hemoglobinopathy.⁵ Globally, about 3,30,000 babies are born with a hemoglobinopathy out of which about 2,75,000 (over 80%) are due to SCD alone. Most (about 85%) of newborns affected with SCD are born in the African continent.⁶ Prevalence in the Indian subcontinent is second only to Africa.

Presence of HbS gives some protection from malaria, and hence, the gene has thrived in tropical regions.⁷ The highest prevalence in newborns with SCD is seen in middle- and low-socioeconomic countries.⁸ Early diagnosis and initiation of treatment is crucial, and without which, about 90% of children die in the first few years of life.⁹ Infectious complications are a common cause of increased mortality in SCD patients, and this fact underlines the importance of improving nutrition, hygiene, and proper infrastructure especially in these countries undergoing socioeconomic transition.^10,11 Few recent studies have clearly demonstrated the positive impact of early diagnosis, treatment, and improving overall hygiene on the overall outcome in these patients.12, 13, 14, 15

Because of recent increase in population mobility and migration seen all over the world, the prevalence of SCD has increased even in developed countries. Data from universal screening programs in the United States of America, the United Kingdom, and French overseas territories confirm this point.¹⁶ A recent study by Piel et al. ¹⁷ (2017) has estimated that with improved survival and population movements the overall global burden of SCD is increasing, with the annual number of SCD newborns being expected to increase from 300,000 to more than 400,000 between 2010 and 2050. The majority of these births are projected to occur in Sub-Saharan Africa. The prevalence of SCD in Nigeria and Democratic Republic of Congo is likely to increase, while it is likely to decrease in India.

Epidemiology of SCD in India

India has been ranked as the second worst-affected country in terms of predicted SCD births. The disease was first described in India about 70 years ago in the Nilgiri Hills of Tamil Nadu.¹⁸ Dunlop and Mazumdar¹⁹ at same time described presence of HbS in tea garden workers who were migrant tribal laborers from Orissa and Bihar. Initially, it was thought that the disease primarily occurs in tribal populations because of high rate of endogamy and prevalence of malaria in these areas. Later, SCD was identified in many states involving both the tribal and nontribal areas. The distribution of SCD is very much uneven, with pockets of increased prevalence in some regions. It is one of the major reasons why the true prevalence of disease is difficult to estimate. Highest prevalence is seen in western and central areas of India. In a rough approximation, the total number of SCD population may be about 1 in 20,000, and about 44,000 affected children are born every year carrying the gene. In addition, similar numbers of HbS/β-thalassemia children are also born accounting for third highest incidence of this abnormality in the world after Nigeria and Democratic Republic in Congo. About 42,016 (interquartile range: 35,347–50919) babies are estimated to be born with SCA in 2010. In India, the sickle β-globin gene variant (β^s) is mostly found amongst the scheduled tribe (ST) and scheduled caste (SC) population. These populations constitute about 25% of the whole population and the most socioeconomically disadvantaged population of India as per the census conducted in 2011. STs constitute 8.6% of the total population, which is about 67.8 million people in India. Madhya Pradesh, Maharashtra, Gujarat, Odisha, Rajasthan, Jharkhand, Chhattisgarh, Andhra Pradesh, West Bengal, and Karnataka account for about 83% of all ST population in India, and most of these live in rural areas.²⁰ Figure 1 summarizes district-wise distribution of the sickle cell gene among tribal populations in different states of India. The high prevalence of the β^s allele frequency within scheduled groups is probably due to a combination of three factors: (i) a potentially greater selection pressure on these groups from malaria;²¹ (ii) the high rate of endogamy is observed in the scheduled group;²² (iii) a competitive evolutionary exclusion of β^s occurs in certain nonscheduled groups.^23,24 The sickle cell carrier frequency in the scheduled population ranges from 1 to 40%, whereas that in the nonscheduled population is usually <5%.²⁵

Figure 1.

An overview of the prevalence of the sickle cell gene in tribal population in different states of India. HbS, sickle hemoglobin.

A recent spatial epidemiological study by Hockham et al.²⁶ showed the highest predicted frequency of the β^s allele up to about 10% occurs in central India extending from south-eastern Gujarat to south-western Odisha. In this belt, lower frequency of 2–6% was predicted in the Nagpur division of Maharashtra, whereas a still lower frequency of 1–2% was predicted in Konkan and Pune divisions. In south-eastern Rajasthan, Gujarat, and Odisha, the predicted frequency of the β^s allele is quite heterogeneous. In central India involving large parts of Madhya Pradesh and Chhattisgarh, the predicted frequency was around 4%. Another area with predicted high prevalence of the allele up to 12% was found in northwestern Jammu and Kashmir. Indian states with the lowest predicted frequency of the β^s allele (<1%) were found in the northeastern region. In some states, no data were available, and the predicted frequency was consistently less than <1%. These states include Haryana, Uttarakhand, Uttar Pradesh, Bihar, the central part of Karnataka, and Andhra Pradesh.

What is sickle hepatopathy?

Sickle cell hepatopathy or sickle hepatopathy encompasses a spectrum of liver disease arising from wide variety of insults to the liver in patients with SCD. SCD leads to significant morbidity because of cumulative multi-organ damage. One frequently witnesses proteinuria and renal impairment, elevated right-sided heart pressure, pulmonary hypertension, and high velocities on transcranial Doppler along with increased risk of stroke (in children).²⁷ Liver involvement in SCD has not been well characterized in terms of its natural history and pathogenesis, and all the abnormalities that occur as a consequence of the sickling process, including gall stone disease, hypoxic liver injury, hepatic sequestration, venous outflow obstruction, viral hepatitis (especially in multitransfused patient),hepatic crisis, and sickle cell intrahepatic cholestasis (SCIC), are described under a broad term of sickle hepatopathy.^28,29 Many authorities would like to reserve this term for a more serious presentation, currently classified as SCIC.^30,31 Several patients (up to a third) will have more than one pathophysiological abnormality.²⁹ In normal practice, the problem of accurate diagnosis is compounded by the fact that some authors have suggested that liver biopsy being contraindicated in acute settings.³² SCIC often presents acutely, whereas some patients may have recurrent episodes leading to chronic and progressive liver failure.

Epidemiology of sickle cell hepatopathy

The overall incidence of liver disease in patients with SCD is not well established, although liver dysfunction has been described in ~10% patients with SCD.³³ The major risk factor for developing liver disease in these patients involves multiple blood transfusions which lead to viral hepatitis (hepatitis B and C) and excessive iron stores. Abnormal liver function tests may be seen in about one third of the patients.³⁴ Various autopsy series have shown that hepatomegaly is seen in about 91% of SCD patients³⁵, whereas cirrhosis is seen in 16–29% patients.^35,36 The cause of cirrhosis is probably multifactorial related to viral infections, iron overload, or even due to the disease itself.

In a study of prevalence and pattern of sickle cell hepatopathy in hospitalized adult patients from a tertiary care hospital in Odisha, Ambika Mohanty et al. (unpublished) have studied 110 cases with SCD, and observed 34 patients (30.9%) had hepatic involvement. Of these, 29 patients had isolated hepatic involvement, and five patients were found to have both hepatic and biliary involvement. The common symptoms were fever, pain over the right upper abdomen, bone pain, and yellowish discoloration of eyes. The clinical spectrum of hepatic involvement in SCD ranged from jaundice, hepatosplenomegaly, and asymptomatic hyperbilirubinemia. Acute sickle cell crisis was seen in nine patients; hepatic sequestration crisis in two; persistent hyperbilirubinemia in ten; acute hepatitis in four; liver cirrhosis in two; acute intrahepatic cholestasis in two; and sickle cell cholangiopathy in one. Two patients died of liver failure.

The liver and biliary system in SCD

Sickle cell involves various organ systems including the central nervous system, respiratory system, and gastrointestinal tract (GIT). In the gastrointestinal system, clinical manifestations mostly occur owing to microvascular occlusion by sickle cells leading to acute abdominal crisis, acute abdominal pain, acute pancreatitis, peptic ulcer disease, and, rarely, mesenteric ischemia.^37,38 The liver and biliary system are one of the most common intra-abdominal systems involved in SCD. Involvement of the liver is seen in about 10–40% cases of sickle cell crisis.^39,40 Diagnosis and management of various hepatobiliary diseases remains challenging as the clinical spectrum of this condition ranges from relatively benign conditions such as gallstone disease to life-threatening acute liver failure (ALF). Classification, pathogenesis, clinical features, diagnosis, and treatment of various hepatobiliary diseases associated with the SCD are outlined in the following passages.

How much to investigate?

Liver involvement in patients with SCD may vary from mild jaundice to life-threatening conditions including acute liver failure (ALF) or acute on chronic liver failure (ACLF). When there is a suspicion of liver involvement in a patient with SCD, he or she should be evaluated carefully, keeping in mind that one third of such patients may have unrelated comorbidities. Thus common causes of liver disease in India, including viral hepatitis and drug-induced liver injury, must always be ruled out in these patients. Careful clinical assessment about alcohol, drugs, and presence of metabolic syndrome should be considered. Abdominal ultrasound examination including assessment of vessel patency and the biliary system should be routine with use of other imaging such as CT abdomen, magnetic resonance cholangiopancreatography (MRCP), and endoscopic ultrasound where required. Every patient depending on presentation must have screening for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, cytomegalovirus, Epstein–Barr virus, hepatitis A virus (HAV), and hepatitis E virus (HEV). Selected cases should also be tested for the antinuclear antibody, anti–smooth muscle antibody, anti–liver/kidney antibody, anti–soluble liver antigen, antimitochondrial antibody, alpha-fetoprotein levels, and ceruloplasmin/Wilson screening. Iron status assessment, serum ferritin, and MRI for the liver iron concentration are also the tests that will be needed in some cases. Hepatic injury due to SCD itself is a diagnosis of exclusion and should be considered only after carefully excluding these causes. Patients with severe hepatic involvement may present with coagulopathy and encephalopathy. In these patients, liver function, renal functions, coagulation parameters such as prothrombin time (PT) and the international normalized ratio (INR) should be closely monitored to take decision regarding need of liver transplantation. In the Indian subcontinent diseases, such as malaria, scrub typhus, leptospirosis, may mimic sickle hepatic crisis and should be excluded. Similarly, autoimmune hepatitis (AIH) and Wilson's disease (WD) may rarely have acute presentation such as sickle hepatic crisis. Thus, every patient with SCD presenting as acute hepatic crisis should be evaluated for AIH and WD. Hemoglobin electrophoresis should also be done in these critically ill patients at regular intervals to decide the need for exchange transfusion and also to monitor response to therapy. One should carefully weigh the risk–benefit ratio of obtaining the liver histology. It should be planned only if the results are likely to alter management. Liver biopsy via the transjugular route is preferred.

The role of liver biopsy for diagnosis

The histologic changes that occur in acute hepatopathy include sinusoidal obstruction due to sickling with variable proximal sinusoidal dilatation and variable centrilobular and hepatocyte damage. In more chronic cases, one may also find Kupffer cell hyperplasia with erythro phagocytosis and hemosiderosis, focal areas of necrosis, portal fibrosis, regenerative nodules, cholangiopathy, and, sometimes, biliary cirrhosis.^20,41,42 Some changes may be specific for certain situations. Mild centrilobular necrosis has been described in patients with sickle hepatic crisis.⁴³ Widespread anoxic necrosis was seen in two postmortem biopsies in patients with SCIC.⁴⁴ Other findings that may be seen on liver biopsies include perisinusoidal fibrosis, peliosis hepatis, and extramedullary erythropoiesis.⁴⁵ The degree of intrasinusoidal sickling does not correlate with the serum aminotransferase concentrations. It is possible that some of the sickling observed in liver biopsy specimen results from fixation with formaldehyde, which, in one study, increased the sickle cell count from mean of 12–48 percent.³⁴

However, it is to be noted that percutaneous liver biopsy in the setting of SCD has been historically noted to have high risk of bleeding complications. In the series by Zakaria et al.²³ 36% of patients undergoing percutaneous liver biopsy developed bleeding complications of which 28% died. The study was conducted at the Institute of Liver Studies at King’s College Hospital, a tertiary-care referral center. In this series of 14 patients, five had haemorrhagic complications after liver biopsy. Most of these complications occurred in patients undergoing liver biopsy during acute sickle cell hepatic crisis. Histopathology in these patients revealed sinusoidal dilatation and chronic venous outflow tract obstruction. Rest nine patients underwent liver biopsy as elective procedure and had no haemorrhagic complications. This can be explained by the fact that hepatic venous congestion is an important risk factor for postbiopsy hemorrhage.²³ In addition, poor hepatic reserve in patients with sickle cell crisis might have increased risk of bleed and difficult to control bleed. Although studies with transjugular liver biopsy (TJLB) are lacking, it can be concluded that liver biopsies should be reserved for selected cases during the acute syndromes. It should be done only when the procedure is likely to change management, for example, to diagnose AIH in young female with suggestive serology^46,47 or to diagnose coexistent WD in suspected cases. TJLB should be the preferred approach, but there is no published experience of this procedure in patients with SCD.

Classification

Patients with involvement of the hepatobiliary system in SCD can either present with an acute syndrome or chronic liver disease. Berry et al.²⁰ (2007) had described eight subgroups of patients, namely, acute hepatocellular necrosis, acute sequestration with cholestasis, cirrhosis, chronic hepatopathy, biliary obstruction, siderosis and extrahepatic iron overload, cholangiopathy, and venous outflow obstruction. However, clinically, it is useful to classify them as acute and chronic syndromes and further subdivide them based on pathophysiology. The acute involvement occurs during periods of vaso-occlusive crisis whereas the chronic complications tend to persist or even progress outside the crisis state. The spectrum and the severity of involvement usually depend on two factors: the severity of crisis and underlying hepatic reserve. The term sickle cell hepatopathy is used to describe the hyperbilirubinemia and liver dysfunction in patients with SCD. It can have varied pathophysiology. Intrahepatic sickling process can lead to ischemia, sequestration, and cholestasis.⁴⁸ Chronic liver damage may occur because of recurrent acute damage to hepatocytes/cholangiocytes related to ischemic crisis or simply gradual progressive damage to the liver leading to chronic liver disease independent of crisis episodes. Acute and chronic hepatobiliary manifestations with possible underlying pathology are summarized in Table 1.

Table 1.

Aetiopathogenesis and Various Acute and Chronic Hepatobiliary Manifestations of Sickle Cell Disease.

Underlying patholgy involved	Acute hepatobiliary disease	Chronic hepatobiliary disease
Related to sickling process	•Acute sickle hepatic crisis •Hepatic sequestration •Sickle intrahepatic cholestasis •Acute liver failure	•Chronic hepatic sequestration •Chronic cholestasis •Biliary-type cirrhosis
Related to multiple blood transfusion	•Viral hepatitis B	•Chronic viral hepatitis B and C •Iron overload
Miscellaneous complications	•Cholelithiasis and cholecystitis •Budd–Chiari syndrome •Hepatic abscess/biloma •Portal vein and mesenteric thrombosis	•Cholelithiasis and cholecystitis •Sickle cell cholangiopathy
Unrelated comorbidities	Hepatitis A and E	•Coincident chronic liver disease, for example, autoimmune hepatitis •Protein C and protein S deficiency •Zinc deficiency •Focal nodular hyperplasia •Malignant histocytosis •Primary sclerosing cholangitis

Acute hepatobiliary manifestations due to sickle cell vaso-occlusive crisis

Three common entities are described which occur owing to intrahepatic sickling of erythrocytes. They are acute sickle cell hepatic crisis, acute hepatic sequestration, and acute SCIC. In the patients who are admitted for acute vaso-occlusive crisis (severe pain in chest, abdomen, and joints), involvement of the liver is seen in about 39% of cases.⁴⁰

Acute Sickle Cell Hepatic Crisis

Acute sickle hepatic crisis affects about 10% of cases admitted with painful crises.⁴⁹ The disease is characterized by pain in the abdomen involving the right upper quadrant (RUQ) of the abdomen and fever. Clinical presentation may raise a suspicion of acute cholecystitis. Investigations will show leukocytosis, raised transaminases, and hyperbilirubinemia. The levels of aspartate transaminase (AST) and alanine transaminase (ALT) are usually elevated by 3–4 times the upper limit of the normal value. However, rise in transaminases of more than 1000 U/L may be seen in some cases. In contrast to acute cholecystitis, the liver is enlarged and tender.

Pathophysiology

Acute sickle hepatic crisis is believed to be due to sickling of erythrocytes causing sinusoidal obstruction.⁵⁰ The obstruction may be transient or prolonged which determines the degree of hepatic insult. Prolonged sinusoidal obstruction may result in hepatic infarction. In histology, sickle cell aggregates are seen in sinusoidal spaces. Depending upon the severity of the crisis, Kupffer cell hypertrophy and, in most severe cases, centrilobular necrosis may be seen.⁵¹

Biochemical Abnormalities

Biochemical features in acute sickle hepatic crisis are usually variable and only rarely correlate with the clinical or, even, histologic picture. The level of elevation of transaminases varies from 1 to 3 times normal to even thousands like in acute viral hepatitis. However, unlike acute viral hepatitis in which rise in transaminases remains for fairly prolonged duration, it rapidly comes back to the normal level in sickle hepatic crisis. The resolution of transaminitis is followed by the resolution of crisis. The serum bilirubin level is also elevated with a predominantly conjugated fraction but remains less than 15 mg/dL⁵¹. The biochemical parameters become normal in 3–14 days. Usually, there is no coagulopathy in acute sickle hepatic crisis.

Management

Management of acute sickle hepatic crisis is usually supportive with oxygenation and rehydration like other sickle crisis episodes. Prognosis is usually excellent.

Acute Hepatic Sequestration

It is an uncommon entity observed in some patients with SCD crisis.⁵² It is characterized by sequestration of a large number of erythrocytes in the spleen, in the pulmonary vasculature, and, rarely, in the liver. Clinically, this entity is characterized by an abrupt onset and severe RUQ abdominal pain, rapidly evolving to hepatomegaly and progressive pallor. Depending on the number of erythrocytes consumed by reticuloendothelial systems, the affected individuals may rapidly develop symptomatic anemia or even shock leading to increased mortality. There is acute fall in the hematocrit along with acute hepatomegaly.⁵³ The fall in hematocrit results in compensatory stimulation of the bone marrow resulting in an increased reticulocyte count. The hepatomegaly is usually smooth and massive.

Pathophysiology

There is sequestration of a large number of erythrocytes in the spleen, pulmonary vasculature, and liver. These erythrocytes are phagocytosed by Kupffer cells, which leads to dilatation of sinusoids and compression of the biliary tree.⁵² Liver biopsy often shows dilated sinusoids and trapped erythrocytes within. Rarely bile plugging and cholestasis may be seen, but hepatocyte necrosis is rare.

Biochemical Abnormalities

A predominantly conjugated pattern of hyperbilirubinemia, is common total serum bilirubin is usually less than 15 mg/dL. Because of compression of bile ducts, the serum alkaline phosphatase level may be elevated. However, rise in transaminases and the PT/INR is unusual.

Management

Management of acute hepatic sequestration is usually supportive. Simple transfusion/exchange transfusion or, rarely, hydration may reverse the condition. Monitoring hemodynamics and hematocrit during this recovery phase is crucial as the entrapped erythrocytes are returned to circulation. This may lead to hyperviscosity of blood with consequent heart failure, acute coronary syndrome, or cerebrovascular accident.⁵⁴ Phlebotomy may be required to prevent these complications if rapid rise of hematocrit is observed in the recovery phase.

Acute Intrahepatic Cholestasis/SCIC

It is the most severe of acute hepatic manifestations of SCD and resembles ALF. It carries high mortality. Mostly, patients with homozygous HbS disease are affected, although rarely seen with HbS beta thalassemia.55, 56, 57 Fortunately, it is rare with only a few cases reported so far. It presents initially as acute hepatic crisis with fever, RUQ abdominal pain, and deep jaundice but can rapidly evolve into ALF with raised a INR and hepatic encephalopathy. Renal failure and multiple organ failure may also follow.⁵⁸ Renal failure in this context may be due to circulatory disturbances secondary to liver failure or sickle cell nephropathy.⁵⁹ With improvement of liver function, renal function usually improves. Few cases of acute recurrent intrahepatic cholestasis have been described.⁶⁰

Pathophysiology

Pathophysiology involves diffuse sickling of erythrocytes in hepatic sinusoids leading to widespread ischemia. This leads to ballooning of hepatocytes and intracanalicular cholestasis as seen in histology.⁴⁴ In severe cases, there is widespread necrosis of hepatocytes with associated acute and chronic inflammation.

Biochemical Abnormalities

There is significant hyperbilirubinemia, mainly due to rise in the conjugated component. The level of total serum bilirubin as high as 273 mg/dL has been described.⁶¹ This high level of hyperbilirubinemia is due to a combination of three factors which include (a) ongoing hemolysis, (b) cholestasis, and (c) associated acute kidney injury. Transaminase levels are also significantly elevated with values reaching up to 1000 IU/L.⁶¹ The serum alkaline phosphatase level is elevated because of intrahepatic cholestasis. Coagulopathy with elevated PT and INRs and decreased fibrinogen is also commonly observed.

Management

Experiences with management of this fatal condition are based on case series and case reports. Simple blood transfusion and other supportive measures may reverse the condition. Reports of reversal of liver failure by the aggressive exchange transfusion strategy with red cells and fresh frozen plasma have been reported.^57,62 Target of this treatment strategy involves maintaining HbS < 20–30% and hemoglobin of 10 mg/dL to restore and maintain adequate tissue oxygenation. The role of liver transplantation in this context is controversial with only a few case reports described with variable outcomes. Logically the disease can be cured with a combination of liver and bone marrow transplantation. Associated acute kidney injury is proposed to be due to underlying liver disease, which usually improves with these measures. However, rarely, renal replacement therapy may be needed.

Ahn et al.²² in a review of 22 cases, with acute intrahepatic cholestasis presenting as liver failure, showed good response in 8 of 9 patients with exchange transfusion. One patient who did not respond died after liver transplantation. Two of 8 patients had recurrence that responded to exchange transfusion. Of the 13 patients in this cohort who did not undergo exchange transfusion, 11 died during initial hospitalization. These data indicate that exchange transfusion may offer potential therapeutic benefit. Nonresponders to exchange transfusion may indicate poor prognosis.^56,63

Liver Failure Without Histologic Changes

This entity is extremely rare with only few case reports described. It clinically presents like ALF.^64,65 Unlike ALF in patients without SCD, these patients have extremely high hyperbilirubinemia and PT with only mild rise in transaminases.⁶⁶ The condition is fatal without liver transplantation. Liver biopsies were performed only in a few cases, and these showed centrilobular necrosis in most cases and, rarely, cholestasis. Pathophysiology of this liver failure is not clearly understood.

Hydroxyurea in Sickle Cell Hepatic Crisis

Sickling of RBCs in SCD patients occur because of polymerization of deoxygenated hemoglobin S (α₂β₂^s) which makes it a rigid rod-like polymer that decreases flexibility of RBCs thus causing hemolysis. In vitro studies have shown that fetal hemoglobin (α₂γ₂), which lacks β chain, prevents sickling by inhibiting polymerization of hemoglobin S. Further, clinical studies have indicated that increasing fetal hemoglobin concentration may be beneficial in SCD patients.⁶⁷ It was incidentally discovered that administration of 5-azacytidine in adult baboons resulted in an increase in the fetal hemoglobin concentration.⁶⁸ Azacytidine exerts this effect by inhibiting methylation of deoxycytidine that reactivates synthesis of γ chains.⁶⁹ Various other cytotoxic drugs also showed similar effect.70, 71, 72 However, in view of ease of administration and relative safety, hydroxyurea has been used in various clinical trials.⁷³ Along with increasing concentration of fetal hemoglobin, hydroxyurea exerts antisickling effects by increasing water content of red cells⁷⁴, thus increasing their deformability⁷⁵ and decreasing adhesion of red cells to the endothelium.⁷⁶

Hydroxyurea has been shown to reduce the annual frequency and rate of hospitalization due to painful crisis.⁷⁷ However, its benefit in preventing hepatic sequestration and intrahepatic cholestasis is controversial. A single case of chronic hepatic sequestration responding to treatment with hydroxyurea has been reported.⁷⁸ Further studies are needed to prove its beneficial role in context of hepatic involvement of SCD.

The outline of management of sickle hepatopathy is provided in Figure 2.

Figure 2.

Suggested outline for management of sickle cell intrahepatic cholestasis (SCIC). Severity of jaundice should be carefully assessed as Gilbert's syndrome or G6PD deficiency–associated hemolysis may make the disease appear more severe than the degree of liver damage. Comorbid diseases as outlined in the text should be carefully ruled out. If patient shows features of acute liver failure, liver transplantation as an option should be considered. In all cases receiving multiple transfusions and having chronic hemolysis, management of iron overload should be part of treatment. The need for liver biopsy should be carefully assessed in view of risks involved, and lastly, some people have suggested use of ursodeoxycholic acid (UDCA) to improve biliary sludging in cholestasis. ACLF, acute on chronic liver failure; ALF, acute liver failure; SCD, sickle cell disease; SCIC, sickle cell intrahepatic cholestasis; EBT, Exchange Blood Transfusion.

Acute viral hepatitis in SCD

Patients with SCD suffer both from acute and chronic viral hepatitis. Acute viral hepatitis is caused by HBV and HAV. Clinical data regarding acute hepatitis by HEV in SCD are lacking. Clinical features of acute viral hepatitis in SCD patients are similar to those in other patients including fever, malaise, tender hepatomegaly, and jaundice. The AST/ALT level is elevated in thousands like patients without SCD. However, the serum bilirubin level is disproportionately elevated in SCD patients in view of underlying hemolysis which ranges from 8 to 64 mg/dL with an average of 45 mg/dL³³. Patients with SCD may be more prone to develop fulminant hepatic failure by HAV than the general population.⁷⁹ Thus, SCD patients should be immunized by HAV vaccine to prevent this fatal complication. Treatment remains same as that of the general population without SCD.

Various acute and chronic hepatobiliary manifestations of SCD are summarized in Table 2.

Table 2.

Summary of Common Acute and Chronic Hepatobiliary Diseases Related to Sickle Cell Disease.

Clinical scenario	Clinical features	Biochemical features	Pathophysiology	Management
Acute sickle hepatic crisis	Fever RUQ abdominal pain Jaundice Tender hepatomegaly	Bilirubin <15 mg/dL AST/ALT <300 U/L	Vaso-occlusive crisis	Supportive Hydration Transfusion Exchange blood transfusion
Hepatic sequestration	RUQ pain Rapidly progressive pallor Tender Hepatomegaly	Bilirubin up to 25 mg/dL Alkaline phosphatase up to 650 U/L	Vaso-occlusive crisis	Supportive Hydration Transfusion Exchange blood transfusion Phlebotomy for hyper viscosity syndrome during recovery
Sickle cell intrahepatic cholestasis	Fever RUQ abdominal pain Jaundice MOF Encephalopathy Bleeding diathesis	Bilirubin up to 273 mg/Dl AST/ALT/ALP up to thousands Prolonged PT/INR	Vaso-occlusive crisis	Supportive Hydration Transfusion Exchange blood transfusion ?LT
Iron overload	Variable	Elevated ferritin level MRI for Iron concentration	Related to multiple blood transfusion	Chelation therapy using deferoxamine, deferiprone and deferasirox when liver iron concentration >7 mg/gm present.
Gallstone disease	Asymptomatic Right upper quadrant pain Cholangitis Pancreatitis	Mild transaminitis in cholecystitis Hyperbilirubinemia and raised ALP in cholangitis Raised Amylase/Lipase in pancreatitis	Hemolysis	Cholecystectomy for symptomatic gallstones ERCP and CBD clearance for bile duct stones
Acute viral hepatitis	Fever, malaise Tender Hepatomegaly Fulminant hepatic failure with coagulopathy and encephalopathy	AST/ALT level elevated in thousands Bilirubin level disproportionately elevated	Similar to patients without SCD	As per guidelines proposed by AASLD
Chronic viral hepatitis (hepatitis B/C)	Variable	Variable	Similar to patients without SCD	As per guidelines proposed by AASLD
Sickle cell cholangiopathy	Obstructive jaundice, pruritus	Elevated AST/ALT/ALP levels	Ischemic injury to biliary tree due to recurrent sickle crisis	ERCP Liver transplantation

Note: SCD, sickle cell disease; AST, aspartate transaminase; ALT, alanine transaminase; RUQ, right upper quadrant; ERCP, endoscopic retrograde cholangiopancreatography; LFTs, liver function tests; AASLD, American Association for the Study of Liver Diseases; INR, International normalized ratio; PT, prothrombin time; MOF, Multiple Organ Failure; LT, Liver Transplantation; CBD, Common Bile Duct; ALP, Alkaline Phosphatase.

Chronic hepatobiliary manifestations of SCD

Recurrent ischemic attacks in patients with SCD lead to development of fibrosis and, even, cirrhosis.⁸⁰ The process of development of cirrhosis may be accelerated by viral infections and transfusion-related iron overload. In various autopsy series, cirrhosis has been detected in up to 29% of cases.^22,81 These patients may develop features of decompensated cirrhosis including ascites, variceal bleed, and encephalopathy.⁸² Patients may also develop ACLF when an acute insult, such as acute intrahepatic cholestasis, is superimposed on cirrhosis.^81,83 As blood supply of the bile duct is exclusively arterial, recurrent ischemic attacks may lead to chronic cholangiopathy.

Chronic Viral Hepatitis

Chronic viral hepatitis by HBV, HCV was common before universal screening for blood-borne viruses became routine practice, in view of frequent transfusion of blood products and immunodeficiency due to hyposplenism. However, with universal screening of blood products, the incidence of new infections has reduced. However, the burden of old infections persists. Patients with chronic hepatitis C is usually asymptomatic and may have only mild transaminitis. Antibodies against HCV have been detected in 10–20% patients with SCD. The risk of infection is increased in patients who receive multiple blood transfusions. In one study, the anti-HCV antibody was detected more often in patients receiving >10 packed red cell transfusion than in patients receiving <10 transfusion (23% vs 8%).⁸⁴ However, the natural history of chronic HCV infection and progression to cirrhosis is not known. In countries with high prevalence of hepatitis B, SCD individuals have a higher prevalence of chronic hepatitis B than that of the general population.⁸⁵

Assessment of necroinflammatory activity and fibrosis in this population is difficult in SCD patients in view of inherent risks involved with percutaneous liver biopsy in these patients. In an Egyptian series, 10 patients with HCV and 12 patients with HBV underwent liver biopsies. The features in liver biopsy include features of sickle cell hepatopathy (sinusoidal dilatation, erythrophagocytosis, and Kupffer cell hyperplasia) along with features of chronic hepatitis. Three patients with HBV had features of cirrhosis.⁸⁶ The role of non invasive markers and transient elastography to detect fibrosis has not been validated in this population.⁸⁷ Treatment of chronic HBV and HCV infection is similar to that of patients without SCD as advocated by the American Association for the Study of Liver Diseases.

Chronic Intrahepatic Cholestasis

Only a single case report⁶⁰ has described a patient with SCD and very high serum bilirubin (>88 mg/dL) due to chronic intrahepatic cholestasis. There was no fever/abdominal pain/hematological evidence of hemolysis. There was a dramatic response to exchange transfusion in this patient. After exchange transfusion, his serum bilirubin level fell to 10 mg/dL. However, on follow-up, he developed repeated episodes of hyperbilirubinemia, requiring regular exchange transfusion to keep his hemoglobin S level <20% to prevent intrahepatic cholestasis.

Transfusion Iron Overload

Iron overload is considered as a major cause of end-organ damage in patients receiving multiple blood transfusions in various hemoglobinopathies. In patients with thalassemia major, the heart, the liver, and endocrine glands are commonly affected with heart failure being the major driver of mortality. However, unlike thalassemia major, iron overload in patients with SCD mainly affects the liver, and involvement of the heart and endocrine organs is less common. Iron overload in SCD occurs because of various factors including blood transfusion and intravascular hemolysis. Iron overload predominantly affects the reticuloendothelial system and, rarely, hepatocytes in contrast to hepatocellular iron deposition in hereditary hemochromatosis.⁸⁸ The resulting hemosiderosis leads to hepatic inflammation, fibrosis, and, finally, cirrhosis.⁸⁹

Hepatic iron content (HIC) can be measured by using liver biopsy or noninvasive methods such as MRI (FerriScan).^90,91 There is usually an excellent correlation between FerriScan and liver biopsy⁹¹, which has obviated the need for liver biopsy to asses HIC. Normal HIC ranges from 0.4 to 2.2 mg/g of dry liver weight. Extrapolating from data of patients with hereditary hemochromatosis, HIC values < 7 mg/g of dry liver weight are not associated with hepatic pathology whereas values > 14 mg/g are consistently associated with liver fibrosis.⁹²

In a study of 27 children with SCD receiving blood transfusion, liver biopsy done before commencement of iron chelation therapy revealed that higher HIC correlated with number of transfusions and higher degree of hepatic fibrosis.⁹³ However, another study in 40 adult patients with SCD who underwent liver biopsy showed presence of fibrosis in 28% patients which correlated high HIC. However, few patients with high HIC did not have fibrosis, indicating interplay of other factors as well in development of hepatic fibrosis.⁹⁴ In addition, iron overload can occur despite the use of iron chelating agents. Iron overload can occur even in patients without blood transfusion suggesting the role of additional factors such as chronic hemolysis.⁹⁵ On long-term follow-up of patients with chronic liver disease and SCD, levels of direct bilirubin and serum ferritin are independent predictors of mortality.⁹⁴

Management

All patients with SCD on multiple blood transfusions should be periodically screened for iron overload. The most important factors to be considered while screening are number of blood transfusions, spot ferritin, and mean ferritin levels. These high-risk patients should be periodically screened for iron overload preferably by FerriScan. Iron overload can be minimized in these patients by using exchange blood transfusion rather than simple blood transfusion. The other method involves use of iron chelating agents including deferoxamine, deferiprone, or deferasirox.⁹⁶

Hepatobiliary Manifestations Due to Gall Stones

Gallstones are a common occurrence in SCD patients because of hemolysis. About 15% of children and 58% of adults with SCD have gall stones.^97,98 Associated choledocholithiasis is seen in 18% cases. Symptomatic biliary tract disease occurs in about 20% cases.

Pathophysiology

Gallstones are mainly made up of black pigment stones rather than brown pigment stones due to elevated excretion levels of bilirubin.⁴⁹ Hemolysis causes increase in excretion of unconjugated bilirubin from heme catabolism, precipitation of bilirubin, and growth of bilirubinate crystals, thus leading to formation of gallstones. Because of presence of calcium bilirubinate, up to 50% of these stones are radio-opaque.⁹⁹

Clinical Presentation

Like in the general population, cholelithiasis is usually asymptomatic in SCD. History of intermittent abdominal pain in response to a fatty meal may be elicited. Otherwise most of the cases are detected when patients develop complications such as acute cholecystitis and choledocholithiasis. Again in view of small size and increased friability, these pigmented stones only rarely produce biliary duct obstruction and cholangitis.

Biochemical Abnormalities

In acute cholecystitis mild transaminitis may be seen. Serum bilirubin and alkaline phosphatase are usually normal. In choledocholithiasis, there is mild transaminitis and raised alkaline phosphatase depending upon degree of biliary obstruction. An incremental hyperbilirubinemia is a better predictor of choledocholithiasis in SCD rather than raised alkaline phosphatase or the dilated biliary duct. This is in contrast to cholesterol choledocholithiasis, in which biliary dilatation and raised alkaline phosphatase are the most important predictors.⁴⁹

Imaging

Cholelithiasis can be easily detected by ultrasonography of the abdomen. However, it is less useful to detect cholecystitis and pancreatitis. MRCP may be needed to detect choledocholithiasis. With widespread availability of CT scans, it has become the imaging modality of choice to diagnose acute or chronic cholecystitis and pancreatitis.

Management

Management of acute cholecystitis, cholangitis, and gall bladder empyema remains similar to that of patients without SCD. However, these patients should be prescribed broad-spectrum antibiotics covering Salmonella species and anaerobic organisms. After recovery from the acute episodes, elective cholecystectomy should be done to prevent further acute attacks. The role of elective cholecystectomy in asymptomatic individuals remains controversial. Preoperative optimization of patients with exchange transfusions or transfusions to maintain HbS< 30% and Hb-10 mg/dL is necessary to prevent acute sickle crisis.

Sickle Cell Cholangiopathy

It is a form of ischemic cholangiopathy and may be encountered in patients with SCD. In the presence of abnormal biliary imaging with hyperbilirubinemia, it becomes imperative to rule out sickle cholangiopathy.

Pathophysiology

The mechanism of development of sickle cell cholangiopathy involves ischemic injury to the biliary tree due to recurrent sickle cell crisis, involving end arteries supplying the biliary tree, causing hypoxic injury.^100,101 Although initial attack causes bile duct dilatation, recurrent sickle cell crisis ultimately leads to biliary strictures involving both intrahepatic or extrahepatic bile ducts. Liver biopsies show cholestasis, ischemic bile duct necrosis, and biliary fibrosis.

Biochemical Abnormalities

Patients with sickle cell cholangiopathy show hyperbilirubinemia with variable elevation of alkaline phosphatase and transaminases.

Clinical Features

Most common presentation of sickle cell cholangiopathy in early stages is cholestatic jaundice. In a study of 224 SCD patients with cholestatic jaundice who underwent 242 endoscopic retrograde cholangiopancreatography, about one quarter of the patients had dilated bile ducts.¹⁰² The other common causes of dilated bile ducts, such as choledocholithiasis and malignant obstruction, must be excluded before labeling these patients as patients with sickle cell cholangiopathy. With progression of the disease, strictures become more pronounced, and along with these symptoms of obstructive jaundice such as pruritus, clay colored stool and high colored urine appear. Patients can develop ascending cholangitis. With further progression, patients may develop biliary cirrhosis.

Management

Endoscopic biliary drainage may be needed in symptomatic patients with biliary strictures. The role of ursodeoxycholic acid in this setting is unknown. Patients having recurrent cholangitis and cirrhosis may need liver transplantation, although its role remains controversial.

Miscellaneous conditions associated with SCD

Many patients with SCD have been found to have low protein C and protein S levels.^103,104 It may reflect decreased hepatic production or a consequence of increased consumption. Low levels of these anticoagulant factors may increase the risk of stroke.¹⁰⁵

Zinc deficiency is also common (up to 44%) among patients with SCD possibly because of excessive excretion of zinc due to impaired renal tubular handling.106, 107, 108 It may be aggravated when deferoxamine therapy is used.¹⁰⁹ Zinc being a cofactor for ornithine transcarbamylase, a urea cycle enzyme,¹¹⁰ SCD patients are also likely to have hyperammonemia,¹¹¹ which can be corrected by administration of zinc.112, 113, 114 Zinc supplementation has been reported to significantly decrease the number of sickle/pain crises. Zinc regulates copper absorption from GIT, and hence, enhanced copper absorption and increased ceruloplasmin levels may be seen with zinc deficiency.^111,115

Few other hepatic comorbidities have been described in patients with SCD. These include hepatic infarction,¹¹⁶ pyogenic liver abscess, Budd–Chiari syndrome,^117,118 AIH,^119,120 focal nodular hyperplasia,^121,122 malignant histocytosis,¹²³ primary sclerosing cholangitis, and mesenteric thrombosis.¹²⁴

Liver transplantation in SCD

Liver transplantation in patients with SCD presenting with ALF, ACLF, or end-stage liver disease remains a matter of particular interest. The experience of performing liver transplant in these patients is very limited. Until now, only 20 cases of liver transplantation have been reported with 15 adults and 5 pediatric cases. Most common indication of liver transplantation in these cases was acute intrahepatic cholestasis presenting as ALF. In two cases, liver transplantation was performed in view of sclerosing cholangitis (likely sickle cholangiopathy). Reported outcomes in these cases have been variable with higher incidences of vascular (mainly thrombotic) and infectious complications. Long-term follow-up data in most of these cases are lacking. The most comprehensive follow-up data included six adult patients (five for acute intrahepatic cholestasis and one for ALF related to AIH). One patient died in the immediate postoperative period because of severe rejection. In rest five, 1-year survival was 83%, and 5 year survival was 44%.⁸¹ Peritransplant hematologic management in these cases included aggressive exchange transfusion to maintain HbS less than 30% and hemoglobin 8–10 mg/dL up to 6 months of transplantation and less than 40% after 6 months. Of these recipients, exchange transfusion was stopped in two and continued with hydroxyurea. An interesting observation was that the explant liver in all these cases was cirrhotic. Another important point to consider is these patients have significant cardiopulmonary comorbidities which may make them ineligible for transplant. A patient with HbS/β-thalassemia and cryptogenic cirrhosis also underwent liver transplantation with a stormy outcome.¹²⁵ Perioperative transfusions were used to keep hemoglobin S levels below the critical level, but in spite of this early graft function remained poor with very low levels of factor-V at days 1 and 5. On day 7, serum bilirubin climbed to 44 mg/dL. Graft dysfunction was also seen at 6 months due to a sickle hepatic crisis leading to multiple infarcts in transplanted liver, but subsequently graft function improved.

A living related liver transplantation has also been carried out in a child with ALF due to SCIC syndrome. The child did not do well and developed outflow obstruction forcing retransplantation three months later. The child eventually succumbed to vascular complications related to SCD.¹²⁶

It is clear that liver transplant can only take care of the hepatic morbidities temporarily and patient continues to have these crisis episodes ultimately affecting the transplanted liver again. The role of the combined stem cell and liver transplant in these cases remain to be evaluated.

Prevention of liver disease

In patients with SCD, one third may have concomitant cause of liver injury. These include acute and chronic viral hepatitis, AIH, WD, or liver injury due to iron overload. These diseases should be treated as patients without SCD. To prevent iron overload, optimal use of iron chelating agents should be done. Hydoxyurea, by increasing levels of HbF, reduces various complications in sickle cell patients, such as painful crisis, acute chest syndrome, priapism, and stroke. It may also reduce need of blood transfusion. However, role of hydroxyurea in prevention of SCIC is uncertain, and it has not been shown to influence frequency of hepatic sequestration crisis.^127,128

Hepatic involvement in SCD is not uncommon in India. Most of these patients have mild elevated transaminase levels and unconjugated hyperbilirubinemia due to hemolysis. Severe manifestations such as SCIC are less common. These patients should be evaluated to rule out common causes of liver disease prevalent in the region including viral hepatitis, AIH, and alcoholic hepatitis. In tropical countries such as India, infections such as malaria, enteric fever, and scrub typhus may also present with similar features such as sickle hepatopathy and should be excluded. Liver involvement due to SCD is usually episodic. These episodes may be severe enough to cause ALF which may need liver transplantation. These patients require frequent red cell transfusion to tide over crisis such as acute chest syndrome and stroke. Frequent transfusions may lead to secondary iron overload which can also affect the liver, although this complication has reduced significantly with use of chelating agents. In addition, hemolysis in patients with SCD increases risk of developing pigmented gall stones and complications such as acute cholecystitis, choledocholithiasis, cholangitis, and pancreatitis. These conditions should be treated similar to those without SCD. However, before cholecystectomy, the hemoglobin level should be built up to 10 g/dL to prevent development of crisis episodes. Ischemic injury to bile ducts may lead to biliary strictures which require endoscopic biliary drainage. With increased safety of blood transfusion and advanced methods of exchange transfusion the hepatic crisis is being managed in a better way. However, the method and indications of doing liver biopsy during these episodes of crisis remain a matter of controversy. Use of hydroxyurea in these patients to prevent hepatic crisis remains unclear. Liver transplantation in SCIC is controversial, and further studies are warranted to establish role of combined liver and bone marrow transplantation.

Credit author statement

Dibyalochan Prahraj: Review of literature, Data curation, Writing- Original draft preparation; Anil Chandra Anand: Conceptualisation, Visualization, Supervision, Validation, Rewriting- Reviewing and Editing.

Conflicts of interest

The authors have none to declare.

Funding

None.