Sickle cell hepatopathy: An underrecognized and undertreated cause of chronic liver disease

Abstract

INTRODUCTION

Sickle cell hepatopathy (SCH) refers to the diverse patterns of acute and chronic liver injury associated with sickle cell disease (SCD). SCH is not an uncommon complication of SCD, with a current estimated cirrhosis prevelance of 30%.^1,2 Despite this, there remains no consensus on appropriate disease management. In this review, we focus on the chronic liver disease (CLD) manifestations of SCH and summarize the evidence on pathophysiology, clinical phenotypes and describe the factors that contribute to the underdiagnosis of SCH-CLD.

Genetics and pathophysiology of SCH

SCD describes a group of inherited disorders resulting from a single point mutation involving the β-globin gene of the hemoglobin protein. This substitution of abnormal hemoglobin S (HbS) β-globin chains for normal hemoglobin A β-globin chains manifests as a spectrum of clinically significant hemoglobinopathies. The most common and severe genotype of SCD is the homozygous state (HbSS) of SCA and occurs when patients inherit 2 copies of the HbS gene and exhibit higher concentration of HbS (>85%) within erythrocytes. The pathophysiology of disease burden in SCD is determined by the interplay of specific cellular variables, including higher concentrations of HbS in erythrocytes and, therefore, increased burden of deformed red blood cells during episodes of physiological and pathological deoxygenation of erythrocytes. Under conditions of low oxygen tension, intracellular polymerization of HbS occurs whereby cell membrane distortion produces the characteristic “sickling” of the red blood cell. The “sickled” erythrocytes become entrapped in microcirculation and as they aggregate and adhere to vascular endothelium, inflammatory mediators are produced—culminating with the pathognomonic features of SCD that include vaso-occlusion, hemolysis, and tissue ischemia.

The etiological mechanism by which SCH-CLD develops is only partially understood. The HbSS genotype is known to be associated with severe clinical manifestations of SCD that are mainly divided into vaso-occlusive and hemolytic phenotypes. These factors—in addition to transfusion-related hemosiderosis and viral hepatitis—are known to contribute to progressive liver dysfunction in this patient population.^3,4 Hepatopathy ultimately develops as a result of vaso-occlusive–mediated vasculopathy whereby diffuse sinusoidal sickling leads to hepatocyte ischemia and ballooning; ballooning of hepatocytes promotes sinusoidal obstruction and ultimately intracanalicular and intraductal cholestasis. Persistently abnormal biochemical liver tests are seen even in the absence of an acute crisis with “benign” predominately conjugated hyperbilirubinemia and mild elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. This suggests synergistic progressive hepatobiliary injury due to ischemia and cholestasis-mediated toxicity. Recent evidence based on murine models of SCD demonstrated that cycles of ischemic-reperfusion injury in the setting of recurrent episodes of intrahepatic “sickling” resulted in an upregulation of genes involved in inflammation and fibrosis. When compared to controls, the SCD mice demonstrated biochemical and histopathological evidence of CLD with hyperbilirubinemia, elevated liver biochemistries (alanine aminotransferase and aspartate aminotransferase), elevated liver stiffness measurement (LSM), hepatomegaly, sinusoidal ischemia, ductular-type reaction, and fibrosis. Although the current literature involving humans is limited to case series and small cohort studies that largely include postmortem and explanted livers, similar histopathological features of hepatobiliary injury were found.⁵

Diagnosis and management of SCH-CLD

Liver biopsy remains the gold standard in diagnosing fibrosis. However, given concern for increased bleeding risk in SCD, biopsy is often deferred—likely further contributing to underdiagnosis of SCH-CLD. Noninvasive techniques including serum biomarkers and advanced imaging, have emerged as promising alternatives in assessing for hepatic fibrosis across a spectrum of diffuse liver disorders. Existing data based on observational studies do identify patterns of liver injury seen in SCH that can provide insight into groups at risk of having a progressive CLD course.³ Bortolotti et al⁶ found that patients with the HbSS genotype exhibited clinical manifestations of severe liver disease, higher cholestatic indices (gamma glutamyl transferase, alkaline phosphatase, and total and direct bilirubin), and imaging suggestive of hepatic fibrosis with increased echogenicity on abdominal ultrasound and higher LSM on vibration-controlled transient elastography (VCTE) when compared to other genotypes. Previously, the use of VCTE in assessing for liver fibrosis in SCH was controversial. Increased LSM that is seen in patients experiencing a vaso-occlusive crisis did not correlate with histopathologic features of advanced fibrosis. More recently, evidence suggests that VCTE (Figure 1) in combination with SCH-associated serum biomarkers of liver injury [alkaline phosphatase, gamma glutamyl transferase, conjugated bilirubin(CBili)] are reliable in screening and surveillance of SCH-CLD.⁷ When using previously described VCTE thresholds for liver stiffness, that is, optimal cutoffs for significant fibrosis (F2) at >7.9 kPa, severe fibrosis(F3) at >10.3 kPa, and cirrhosis (F4) at 12 kPa, positive correlation between LSM in steady state SCH-CLD and stage of fibrosis was demonstrated.^7–11 Further studies explored the accuracy of hepatitis C-validated VCTE thresholds for fibrosis in SCH-CLD. In the study by Ben Yakov and colleagues, the use of a higher threshold LSM of 8.5 kPa was found to be associated with increased specificity (75%) and positive predictive value (31%) in detecting significant fibrosis when compared to LSM cutoff of 7.5 kPa (specificity 66%, positive predictive value 25%).

FIGURE 1.

Proposed algorithm for the diagnosis and management of sickle cell hepatopathy. *, Given evidence suggestive of combined use of non-invasive testing for screening and surveillance of SCH in asymptomatic patients with abnormal diagnostic or clinical findings consistent with underlying chronic liver disease. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; CBili, conjugated bilirubin; GGT, gamma-glutamyl transferase; LSM, liver stiffness measurement; US, ultrasound.

The current management for SCH remains largely supportive with efforts at disease mitigation largely limited to the acute manifestations of disease (Table 1). SCD-associated intrahepatic cholestasis is a rare but potentially fatal manifestation of SCH that results from the previously described intrahepatic “sickling” that is exaggerated and thought to result from widespread sinusoidal sickling and culminating in profound ischemia, cholestasis-mediated hepatic toxicity, and not uncommonly fulminant liver failure. It is frequently described as an acute presentation of a vaso-occlusive crisis involving the liver that is characterized by an onset of nonspecific constitutional symptoms accompanied by progressive right upper quadrant abdominal pain, coagulopathy, encephalopathy, and marked cholestasis with CBili ~ >24 mg/dL. Essential to mitigating significant mortality risk in SCD-associated intrahepatic cholestasis is early recognition and prompt treatment, which involves an aggressive exchange transfusion strategy of keeping HbS levels to <20%–30%, correction of underlying coagulopathy, and consideration for liver transplantation in cases refractory to medical therapy.^4,12,13

TABLE 1.

Spectrum of acute and chronic clinical manifestations of sickle cell hepatopathy¹²

	Clinical presentation	Liver biochemistries	Management
Acute hepatic sequestration	RUQ pain, progressive hepatomegaly, worsening anemia (↓Hct >>Hgb)	Often normal AST, ALT; Total bilirubin ≤24 mg/dL; ALP ranges from normal to 5 × ULN.	Mainly with supportive management and exchange transfusions.
Acute sickle hepatic crisis	Fever, RUQ pain, tender hepatomegaly, jaundice	AST, ALT ≤300 IU/L; Total Bilirubin ≤15 mg/dL (mostly CBili), normal or mildly elevated ALP.	Mainly supportive management
Acute sickle cell intrahepatic cholestasis	Fever, RUQ pain, tender hepatomegaly, and jaundice with frequent progression to ALF	AST, ALT >1000 IU/L, Total bilirubin> 100 mg/dL (mostly CBili); ALP ranges from normal to >1000 IU/L.	Mainly supportive. early, aggressive correction of coagulopathy; exchange transfusion; liver transplant.
Acute viral hepatitis	Asymptomatic or nonspecific constitutional symptoms with associated hepatomegaly, RUQ pain, and jaundice.	AST, ALT >1000 IU/L, total bilirubin ≤15 mg/dL, normal or mildly elevated ALP.	Supportive or antiviral therapy if indicated.
Chronic sickle cell intrahepatic cholestasis	Jaundice	Total bilirubin ≤100 mg/dL; normal or mildly elevated AST, ALT, ALP.	Regular exchange Transfusions
Cholelithiasis	Biliary colic; acute cholecystitis(fever, RUQ pain with + murphy’s sign, jaundicea).	Normal or mild elevations in aminotransferases, total bilirubin, and ALP.	Cholecystectomy
Hepatic iron overload	Asymptomatic or sequala of chronic liver disease.b	Normal or mild elevations in aminotransferases, total bilirubin, and ALP.	Iron chelation; avoidance of transfusions as able; liver transplant if progression to cirrhosis.
Chronic viral hepatitis	Asymptomatic or sequela of chronic liver disease.	Normal or mild elevations in aminotransferases, total bilirubin, and ALP.	Direct acting antiviral therapy for hepatitis C; for chronic hepatitis B, treatment recommendations based on AASLD guidelines.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALF, acute liver failure; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CBili, conjugated bilirubin; Hct, hematocrit; Hgb, hemoglobin; RUQ, right upper quadrant; ULN, upper limit of normal.

^aGiven similarities in clinical presentation, it can be difficult to differentiate between acute sickle hepatic crisis and acute cholecystitis and additional diagnostic testing beyond biochemical labs and abdominal ultrasound is often required to make the diagnosis.

^bHepatomegaly, edema, palmar erythema, spider angiomas, encephalopathy, sarcopenia, gynecomastia, and ascites.

Barriers to SCH-CLD care in adults

Disproportionate research funding

Unlike other rare heritable diseases such as cystic fibrosis, management of cystic fibrosis in adulthood has been limited by a disproportionate allocation of resources to fund clinical research in the development of disease-specific therapies and in the establishment of SCD-specific surveillance programs and patient registries.^14–16 Between 2008 and 2018, federal funding and disease-specific research was significantly less for SCD when compared to cystic fibrosis despite overall lower health care costs and being more than two-thirds as prevalent. Our recent search of the NIH RePORTER Database identified a single-study investigating SCH for FY 2019-2022.¹⁵ Altogether, disparate funding in SCD is likely a principal driver in the under-recognition of SCH-CLD—contributing to delayed diagnosis and a lack of SCH-specific management and therapeutic strategies.¹³

Absence of diagnostic criteria

The heterogeneity in phenotypic expression of SCH-CLD creates challenges in developing consensus diagnostic criteria. Additionally, although abnormal liver biochemistries are common in SCD, there is little guidance on further diagnostic workup in asymptomatic patients. There is consistent evidence in the literature that in asymptomatic cohorts with CLD resulting from varying etiologies (viral hepatitis, cystic fibrosis, and NAFLD), normal/near normal liver biochemistries can occur in the setting histopathological and sonographic findings consistent with fibrosis.^17–19 Noninvasive techniques including serum biomarkers and advanced imaging have emerged as promising alternatives in assessing for hepatic fibrosis across a spectrum of diffuse liver disorders. Models combining noninvasive biochemical, serological, and elastographic tests can provide complementary information on underlying hepatic dysfunction and improve the diagnostic accuracy in predicting progressive fibrosis (Table 1); these can, in turn, provide guidance on workup for SCH (Figure 1).^6–9,11

CONCLUSIONS

The factors giving rise to the under-recognition and undertreatment of SCH are multifaceted and arguably interconnected. Strategies to address barriers in SCH-CLD require robust SCD funding to create validated diagnostic criteria for SCH-CLD as well as the establishment of a surveillance-registry partnership.