Pathways Case Record: Sickle Cell Disease and Hepatopathy: A Case of Multiple Insults Leading to Liver Disease
In This Case Study
- A 29-year-old man with a history of sickle cell disease (SCD) complicated by hepatopathy and multiple intracranial aneurysms presented with rising bilirubin levels and concerns for recurrent liver injury
- He was diagnosed with SCD at 8 months old and was treated with red blood cell (RBC) transfusions and pain medication throughout his childhood
- Of note, he drank bush tea daily throughout his childhood. In his mid-20s, he began treatments with hydroxyurea
- The Pathways Consult Service at Massachusetts General Hospital took up the case and focused on the potential association between SCD and liver disease
A 29-year-old man with a history of sickle cell disease (SCD) complicated by hepatopathy and multiple intracranial aneurysms presented with rising bilirubin levels and concerns for recurrent liver injury. He was diagnosed with SCD at 8 months old and was treated with red blood cell (RBC) transfusions and pain medication throughout childhood. Of note, he drank bush tea daily throughout his childhood. In his mid-20s, he began treatments with hydroxyurea. Around the same time, abnormal liver biochemical studies revealed acute liver failure due to acute intrahepatic cholestatic liver injury which led to an orthotopic liver transplant. Six years later, he presented at the hospital again with an acute gastrointestinal bleed and evidence of liver injury. Correction of biliary stricturing (narrowing of the bile duct) improved bilirubin levels. One year later, he showed elevated bilirubin levels and was admitted for a repeat liver biopsy and further evaluation.
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There was no evidence of a worsened biliary stricture, allograft rejection or acute thrombus, and no identified medications that might damage the liver on his recent medications list. Liver biopsy revealed sinusoidal congestion with sickled RBCs, marked iron deposition, an increased number of ductules secondary to ischemia, and fibrosis. Notably, the current biopsy was more consistent with chronic vascular hepatopathy with increased fibrosis when compared to his biopsy a year prior.
The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the potential association between SCD and liver disease, which was driven by two questions: (1) why did SCD prominently affect our patient's liver rather than other organs/vascular beds, and (2) what existing and emerging therapeutic strategies could be used to treat his hepatopathy?
Background and Diagnosis
Sickle cell disease is an inherited disorder of hemoglobin in which the mutant hemoglobin (hemoglobin S) proteins crystalize at low oxygen tension, leading to distortions in RBCs morphology with a C-shape like a sickle. These sickle cells become sticky compared to the round phenotype seen in healthy RBCs. This increases the risk of sickled RBCs becoming stuck in small vessels and blocking blood flow. Abnormal liver function tests are common in SCD as seen by moderate elevation in bilirubin levels but are not always indicative of liver disease. Sickle cell hepatopathy is an umbrella term used to describe the collection of liver diseases that some patients with SCD develop, and it ranges from obstruction of vasculature and subsequent ischemia to complications of multiple blood transfusions (e.g., excessive accumulation of iron deposits) to toxicity induced by medications and other agents (e.g., NSAIDs, herbal supplements, antibiotics, etc.) (Clin Liver Dis).
The predominant source of acute or chronic liver disease in SCD is a vascular blockage due to sickling. It is likely that the primary source of damage in our patient was vascular occlusion leading to ischemia due to multiple episodes of sickling. The requirement of frequent blood transfusion to keep his hemoglobin S under 30% likely led to iron overload in the liver (Hematology Am Soc Hematol Educ Program). Iron-induced inflammation is known to cause liver injury through the generation of reactive oxygen species which inflict oxidative stress on hepatocytes. Iron additionally acts on the vasculature by depleting nitric oxide and leading to endothelial dysfunction (Nat Chem Biol). A high iron load has been associated with fibrosis and cirrhosis. Frequent transfusions likely created a vicious cycle of iron deposition-induced endothelial dysfunction and sickling injury, leading to the need for a liver transplant and the development of liver disease in his donor liver.
Chemical-induced liver injury can be caused by agents such as antibiotics, NSAIDs, steroids, glucocorticoids and herbal supplements. Relevant to our patient, bush tea, a commonly consumed home remedy in several African and Caribbean countries, has been linked to liver disease (J Clin Anesth). Case reports in children correlate cirrhosis following chronic ingestion of bush tea (Ethiop Med J). The tea leaves contain pyrrolizidine alkaloids which are metabolized by cytochrome P450 into pyrrole derivatives. These pyrrole derivatives behave as alkylating agents to induce hepatotoxicity. Although bush tea consumption may have contributed to liver disease prior to his liver transplant, it likely did not play a role in his most recent hospital admission.
SCD is known to cause complications in the heart, kidney, liver, gallbladder, eyes and bones due to the difficulty of sickled RBC to flow through small blood vessels. If SCD can impact so many organs, why did our patient have such a relative propensity for sickling in his hepatic vascular bed, especially since sickle cell hepatopathy by vaso-occlusion is a less common phenomenon? Perhaps his native endothelium accounts for an increased risk of hepatic sickling. While literature is limited regarding the specific relationship between the vasculature and sickling, further exploration may prove fruitful. Thus, the Pathways Service hypothesized that multiple predisposing factors (sickled RBC, iron overload, hepatotoxicity and endothelial factors) caused damage to our patient's liver—both his original native liver and his later transplanted allograft.
Summary and Future Steps
Lifelong management of SCD can lead to a myriad of downstream problems, including liver disease. RBC phenotype and iron overload due to multiple transfusions likely led to liver dysfunction in our patient's transplanted liver. In addition to the continuation of hydroxyurea, we would recommend a focus on current disease-modifying therapy to curtail further sickling and limit future ischemic damage to the liver. The recently FDA-approved drugs for SCD, voxelotor (N Engl J Med) and crizanlizumab (N Engl J Med), have demonstrated benefits by reducing vaso-occlusive events and may be beneficial to our patient. Erythropoietin, which promotes the formation of RBCs and is used to treat anemia, may assist in combating the iron overload seen in the patient (Vox Sang). A better understanding of the role of pre-existing phenotypes (endothelium) and treatments in SCD complications may improve the future standard of care for these patients and reduce reoccurrence following transplantation.
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