Early plasmapheresis in type 2 benign recurrent intrahepatic cholestasis: A case report and review of literature

Abstract

BACKGROUND

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive liver disease, causing episodic cholestasis with intense pruritus. This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2, offering rapid symptom relief and early termination of cholestatic episodes. It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies.

CASE SUMMARY

A 43-year-old male with BRIC type 2 presented with fatigue, jaundice, and severe pruritus, triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection. Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase. First-line pharmacological treatments, including cholestyramine and rifampicin, failed. Endoscopic nasobiliary drainage was ineffective, prompting initiation of plasmapheresis. This intervention rapidly relieved pruritus, with complete biochemical normalisation after 11 sessions. Two years later, a similar episode occurred, and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks. The patient tolerated the procedure well, with no adverse effects observed. Follow-up showed no signs of cholestasis recurrence.

CONCLUSION

Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2, particularly when initiated early in cholestasis.

Key Words: Cholestasis; Benign recurrent intrahepatic 2; Plasmapheresis; Pruritus; Cholestasis; Bile salt export pump; Case report

Core Tip: This case report highlights the successful use of early plasmapheresis in managing a patient with pruritus due to a cholestatic episode of benign recurrent intrahepatic cholestasis type 2, triggered by severe acute respiratory syndrome coronavirus 2 infection. Plasmapheresis provided rapid relief from severe pruritus when first-line therapies failed and, when reinitiated early during a consequent flare, significantly accelerated recovery from cholestasis. While the procedure’s invasiveness and associated costs underscore the importance of careful patient selection, prompt initiation should be considered in therapy-refractory cases to optimize outcomes.

INTRODUCTION

Benign recurrent intrahepatic cholestasis (BRIC) is a group of rare inherited cholestatic liver diseases caused by autosomal recessively inherited mutations in one of the canalicular bile acid transporter genes, leading to various degrees of dysfunctional bile acid excretion. Two types of BRIC are described: (1) Type 1 involves pathogenic mutations in the ATPase Phospholipid-Transporting 8B1 gene, coding for the familial intrahepatic cholestasis 1 (FIC1) protein, leading to FIC1 deficiency; and (2) Type 2 is caused by mutations in the adenosine triphosphate-Binding Cassette Subfamily B Member 11 (ABCB11) gene, which codes for the bile salt export pump (BSEP)-transporter and leads to BSEP deficiency[1,2]. Clinically, both types present similarly, with relapsing episodes of cholestasis characterised by pruritus, jaundice, fatigue and elevated biochemical markers of cholestasis. However, since FIC1 is also extrahepatically expressed, other manifestations such as hearing loss, pancreatitis and steatorrhea can occur[3]. In BRIC, cholestatic episodes spontaneously resolve after several weeks to months, and there is no progression to liver cirrhosis and failure. Indeed, BRIC most commonly arises from missense mutations causing partial protein deficiencies, explaining the more favourable prognosis. Conversely, mutations that more severely impair protein function, such as nonsense mutations, lead to more severe phenotypes known as progressive FIC (PFIC)[2,4]. PFIC is characterised by progressive and continuous cholestasis, liver cirrhosis, and liver failure[2,5].

Given its generally benign clinical course, the treatment of BRIC is symptomatic and supportive[6]. While most patients respond well to pharmacological or endoscopic therapies, some experience refractory symptoms that severely impair quality of life. Additional therapeutic options for these patients are highly required. This case report describes the successful use of plasmapheresis in a BRIC type 2 patient during a cholestatic episode, resulting in rapid symptomatic relief and improved biochemical parameters. Early reinitiation of plasmapheresis during a subsequent flare several years later resulted in quick resolution of the cholestatic episode.

CASE PRESENTATION

Chief complaints

A 43-year-old Caucasian male patient presented with fatigue, insomnia, and severe pruritus persisting for four weeks.

History of present illness

The patient's symptoms began three weeks after a mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which did not require treatment. He reported worsening pruritus and jaundice, with no resolution of symptoms despite the use of antihistamines (levocetirizine 5 mg 2 times/day per os). His condition was further complicated by fatigue and sleep disturbances due to severe itching.

History of past illness

The patient was diagnosed with BRIC type 2 at the age of 22 years, confirmed by genotyping that revealed compound heterozygosity in the ABCB11 gene (p.E297G; p.I1227F). He had experienced multiple episodes of spontaneous, self-limiting cholestasis over the years. These episodes usually resolved within several months without progressing to liver cirrhosis or failure.

Personal and family history

The patient had no significant personal or family history of liver disease outside his BRIC diagnosis. There was no family history of genetic liver disorders, and no close relatives had similar symptoms. The patient reported occasional alcohol use and had no history of smoking, drug or herbal (ab)use.

Physical examination upon admission

On examination, the patient was jaundiced but otherwise in a stable condition (blood pressure 17.7 kPa/10.3 kPa, regular heartbeat 88/minute, SpO₂ 98% on room air, temperature 36.3 °C). No abdominal tenderness, hepatosplenomegaly, or other abnormal physical findings were noted.

Laboratory examinations

Laboratory results revealed significantly elevated total bilirubin (16.7 mg/dL) and direct bilirubin (14.3 mg/dL). Alkaline phosphatase (ALP) levels were 2.9 times the upper limit of normal (ULN), while transaminases were mildly elevated (less than 1.5 × ULN). Gamma-glutamyl transferase (GGT) levels were within normal limits. Other routine blood tests and urine analyses were unremarkable. There were no signs of active infection.

Imaging examinations

Abdominal ultrasound and magnetic resonance cholangiopancreatography showed no abnormalities in liver structure or biliary ducts, and no evidence of gallstones or liver masses.

FINAL DIAGNOSIS

A recurrent cholestatic flare in a patient with BRIC type 2, triggered by a mild SARS-CoV-2 infection.

TREATMENT

Initial management included cholestyramine (4 g 4 times/day per os) and rifampicin (150 mg 4 times/day per os), which proved ineffective in alleviating pruritus. Endoscopic nasobiliary drainage (ENBD) was attempted but discontinued due to relapsing obstruction and lack of therapeutic benefit. As a third-line intervention, intermittent plasmapheresis was initiated six weeks after the onset of the cholestatic episode. Centrifugal apheresis (COM.TEC Fresenius-Kabi) was performed, extracting 4000 mL of plasma and replacing it with a 5% albumin solution (Alburex 5, CLS Behring). This resulted in rapid reduction of pruritus. The procedure was well tolerated and there were no adverse effects observed. The patient was scheduled for further “on-demand” plasmapheresis sessions, based on pruritus recurrence. In total, 11 plasmapheresis sessions were conducted over a three-month period, after which biochemical markers of cholestasis resolved completely (Figure 1).

Figure 1 Evolution of biochemical parameters during two cholestatic episodes in a patient diagnosed with BRIC type 2. ALP: Alkaline phosphatase; ENBD: Endoscopic nasobiliary drainage; PP: Plasmapheresis; ULN: Upper limit of normal.

OUTCOME AND FOLLOW-UP

Two years after the first episode, following another mild SARS-CoV-2 infection, the patient experienced a new cholestatic episode marked by severe pruritus. Laboratory results showed early signs of cholestasis, including mildly elevated total bilirubin (1.5 mg/dL), direct bilirubin (0.8 mg/dL), and ALP (2.4 × ULN), while GGT levels remained normal. In between both episodes, the patient had been symptom-free with normal laboratory results. The patient refused pharmacological therapy and after shared decision-making, plasmapheresis was re-initiated early, within 10 days of symptom onset, using the same apheresis protocol. We asked the patient to track his mean pruritus levels on a numerical rating scale both in the morning and in the evening. As anticipated, reinitiation resulted in rapid amelioration of pruritus (Figure 2). Moreover, markers of cholestasis now also rapidly normalized, within two weeks of treatment initiation (Figure 1). Consequently, plasmapheresis could be discontinued after just two sessions. The patient remained symptom-free and there was no recurrence of cholestasis during further follow-up for more than one year.

Figure 2 Pruritus evolution during the second cholestatic episode in a patient diagnosed with BRIC type 2. Pruritus was assessed separately in the morning and evening using a numerical rating scale ranging from 0 (‘no itch’) to 10 (‘worst imaginable itch’), where the patient assessed their mean pruritus level. NRS: Numerical rating scale; PP: Plasmapheresis.

DISCUSSION

This case report highlights the successful use of (early) plasmapheresis in managing a patient with therapy-refractory BRIC type 2. Notably, our findings underscore the potential of plasmapheresis not only to relieve symptoms but also to expedite recovery when initiated early during cholestatic episodes.

BRIC type 2 is a phenotype of an inherited cholestatic liver disease caused by genetic BSEP deficiency which disrupts hepatocanalicular bile salt transport. BRIC is generally considered a benign condition, as it typically does not progress to liver cirrhosis, although rare cases of progression to more severe cholestasis have been reported[7]. Consequently, treatment for BRIC primarily focuses on symptomatic relief.

Among conventional treatments, rifampicin is most studied for BRIC-related pruritus, demonstrating moderate efficacy[8-12]. Rifampicin most likely suppresses pruritus through its role as pregnane X receptor agonist, which modulates pruritogenic pathways[3]. However, antihistamines, cholestyramine and ursodeoxycholic acid have shown very limited effectiveness in alleviating BRIC-related pruritus[3,6]. For pharmacological therapy-refractory cases, ENBD has proven effective, offering rapid amelioration of pruritus intensity[13-17]. However, ENBD is an invasive procedure that carries a risk of post-endoscopic retrograde cholangiopancreatography pancreatitis[17], and some patients may still experience refractory symptoms. Moreover, it is hypothesized that ENBD may be less effective in BRIC type 2, where bile salt secretion-dependent bile flow is hampered[18]. In our patient, recurrent obstructions and treatment failure led to discontinuation of ENBD.

Plasmapheresis proved to be an effective third-line intervention in this patient. The procedure involves the extracorporeal removal and replacement of plasma components, either with an albumin solution or with donor plasma[19]. Previous case reports have demonstrated similar results in therapy-refractory BRIC-associated pruritus[9,20-23] although not all patients respond uniformly[15]. Although it is an invasive procedure, the safety profile is favourable and reported side effects such as hypotension and hypofibrinogenemia are typically mild and correctable[19,24]. Our patient tolerated the procedure well, with no adverse effects observed. Our findings corroborate the potential utility of plasmapheresis as an effective and safe procedure. Similarly, its beneficial effects were also reported in other therapy-refractory cases of cholestatic liver disease such as intrahepatic cholestasis of pregnancy[25-27], primary biliary cholangitis[19,24,28,29] and drug-induced cholestasis[30-34].

Likewise, other extracorporeal elimination techniques, including liver dialysis systems such as the molecular adsorbent recirculating system and the Prometheus system, were reported to be effective in therapy-refractory pruritus in BRIC[35-37]. However, these methods are highly complex and have very limited availability, whereas plasmapheresis offers a simpler and more widely accessible alternative for extracorporeal elimination.

The mechanism behind the beneficial effects of plasmapheresis on pruritus are poorly understood, primarily because the pathogenesis of cholestatic pruritus itself is incompletely elucidated. Current evidence points to a role for autotaxin (ATX), a circulating lysophospholipase D that is responsible for the production of lysophosphatidic acid (LPA)[38]. Serum levels of LPA and ATX are positively correlated with cholestatic pruritus intensity. Interestingly, plasmapheresis decreases ATX activity[25,39]. Also rifampicin directly interferes with the ATX pathway and decreases serum ATX levels[40]. However, the causative association of ATX and LPA to cholestatic itch is questioned and further research should unravel other factors that may play a more significant role in the pathogenesis of pruritus. Nevertheless, it seems that the beneficial effects of plasmapheresis are mediated by the removal of pruritogens that accumulate in the systemic circulation[38].

In BRIC specifically, the early initiation of plasmapheresis during a cholestatic flare appears to have additional benefits. During the second episode, we observed early recovery in our patient upon early reinitiation of plasmapheresis, an observation that was also noted in similar cases[6,9-11,22], although not every case reported accelerated recovery[20]. Interestingly, both flares in our patient were preceded by SARS-CoV-2 infection. Halawi et al[5] showed that in up to one half of BRIC-mediated episodes for which a trigger could be identified, a recent infection was the attributable factor. Proinflammatory cytokines released during infection may downregulate BSEP expression and the expression of other hepatocanalicular transport proteins[41-43]. Consequently, the proinflammatory environment during infection might predispose to BRIC-mediated cholestasis. Plasmapheresis effectively removes proinflammatory cytokines[44] which might have interfered with this pathophysiological cascade, expediting recovery.

While this case report provides compelling evidence for plasmapheresis as a treatment for therapy-refractory BRIC, the possibility that the early resolution of cholestasis during the second flare was due to an abortive attack[10] rather than the therapeutic effect of plasmapheresis cannot be excluded. Furthermore, its invasive nature and associated costs underscore the importance of careful patient selection. Nevertheless, the decision to initiate plasmapheresis should not be delayed in cases where pharmacological therapy and ENBD fail to improve pruritus, or in centres where ENBD is unavailable. Given the absence of studies directly comparing the efficacy of plasmapheresis with ENBD, further research is essential to delineate the role of plasmapheresis in the management of BRIC.

The management of cholestatic pruritus is advancing rapidly. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has recently been recommended as a first line therapy for adult patients with cholestatic pruritus[3,38]. However, its efficacy in the context of BSEP deficiency remains to be established. Odevixibat, an ileal bile acid transporter inhibitor that interferes with the reuptake of conjugated bile acids in the gut, has shown promising results in early randomized controlled trials for reducing pruritus in PFIC patients[45]. Additionally, chemical chaperones such as 4-phenylbutyrate (4-PB) provide the potential for mutation-specific therapy by correcting folding- and trafficking- deficient variants of the BSEP protein. Notably, 4-PB has demonstrated success in case reports involving patients with BRIC type 2[46-48].

Future research should prioritize understanding how therapeutic responses vary according to specific genetic mutations and their functional consequences. Given the genetic heterogeneity of BSEP deficiency, elucidating the relationship between genotype and treatment outcomes could pave the way for more tailored and effective therapies[18,47].

CONCLUSION

Plasmapheresis represents a promising option for treating therapy-refractory BRIC type 2. It is an effective, rapid-acting and safe procedure for achieving symptom relief and biochemical recovery. Furthermore, it is a potential accelerator of recovery when initiated early during a cholestatic episode. Given its invasiveness and associated costs, plasmapheresis should be reserved for patients unresponsive to first-line therapies, although initiation should not be delayed. As there are no direct comparative studies, the choice between plasmapheresis and ENBD should consider patient preferences, success of prior treatments, and local expertise.