Endoscopic nasobiliary drainage: an effective treatment option for benign recurrent intrahepatic cholestasis (BRIC)

Abstract

Benign recurrent intrahepatic cholestasis (BRIC) is characterised by recurrent episodes of jaundice, severe pruritus and low or normal serum γ-glutamyltransferase activity lasting from several weeks to months. BRIC is an autosomal recessive disorder caused by the mutation in either of the two hepatic transporter genes—ATP8B1 or ABCB11 gene. The disease is very well known for episodic flare of jaundice with cholestatic symptoms that are spontaneous or perpetuated by acute insults, followed by self-recovery. There is no proven medical therapy and rarely does it progress to progressive familial intrahepatic cholestasis (PFIC) or biliary cirrhosis. BRIC may be associated with nephrolithiasis, diabetes or pancreatitis. Here, we report a case of BRIC with spontaneous flare and further complicated by drug-induced liver injury with disabling cholestastic symptoms, who underwent endoscopic nasobiliary drainage and was completely relieved of the distressing symptoms.

Background

Benign recurrent intrahepatic cholestasis (BRIC) is a rare disease with frequent exacerbations which cause distressing symptoms. Endoscopic nasobiliary drainage (ENBD) is a novel therapy which can lead to permanent resolution of the symptoms and can be the treatment of choice.

Case presentation

A 23-year-old male with no family history of jaundice presented with complains of intermittent jaundice associated with severe pruritus and clay coloured stools since 2 years. He also complained of  steatorrhoea and night blindness during the episodes. The symptoms would exacerbate during periods of stress or minor illness. His symptoms would last for 4–5 months and then would be asymptomatic for 2–3 months before recurrence. He visited multiple hospitals and was treated with ursodeoxycholic acid, cholestyramine, high dose of hydroxyzine, rifampicin, naltrexone, but all failed to improve his symptoms. He then received complementary alternative medicine for 15 days leading to aggravation of the above symptoms and presented to our hospital.

On examination, there were excoriation marks all over the body but predominantly distributed over palms and lower limbs. There were no signs of liver cell failure and there was no organomegaly.

Investigations

Investigations revealed serum bilirubin of 11.9 mg/dL with a predominant direct fraction of 6.7 mg/dL. Aspartate amiotransferase (AST) and alanine aminotransferase (ALT) were mildly elevated with AST being 77 IU/L (normal ~5–40 IU/L) and ALT of 58 IU/L (normal ~10–40 IU/L). High alkaline phosphatase of 213 IU/L (normal ~32–92 IU/L) and normal γ-glutamyltransferase (γ-GT) of 57 (normal ~7–64 IU/L) were seen. Hypoalbuminaemia (2.8 g/L(normal ~3.5–5.5 g/L)) and prolonged INR (2.03) secondary to anorexia and steatorrhoea were seen (figure 1).

Figure 1.

The laboratory parameters and clinical features in relation to endoscopic nasobiliary drainage (ENBD) placement. (A) Total serum bilirubin (mg/dL). (B) Serum alkaline phosphatase (SAP-32-92 IU/L), gamma glutamyl transferase (GGT-7-64 IU/L). (C) Prothrombin time-International normalised ratio (PT-INR). (D) ENBD placement, improvement in itching, night blindness and stool colour. Dotted line indicates—ENBD removed.

Autoimmune markers, typical (HAV, HBV, HCV, HEV) and atypical hepatotropic (EBV, HSV and CMV) viral markers were negative. Serum copper and ceruloplasmin were normal. Ultrasonography revealed a normal liver echo texture and non-dilated biliary system. Magnetic resonance cholangiopancreatography confirmed the normal intrahepatic and extrahepatic bile ducts (figure 2). Liver biopsy showed centrilobular cholestasis with mild inflammation and mild periportal fibrosis (figure 3).

Figure 2.

Imaging in benign recurrent intrahepatic cholestasis. (A, B) Magnetic resonance cholangiopancreatography imaging of the abdomen showing normal intrahepatic and extrahepatic ducts. (C) Fluoroscopic image showing nasobiliary drain.

Figure 3.

H&E stained section of core biopsy specimen obtained from the liver lesion. Liver biopsy showing (A and B) portal areas with mild inflammatory infiltrate and liver parenchyma showing cholestatic features. ×200. (C) Mild portal fibrosis highlighted by Masson’s trichrome, 200.

Diagnosis

After ruling out all the causes of cholestatic jaundice and based on history of recurring jaundice and histopathology showing intrahepatic cholestasis with preserved architecture, he was suspected to have BRIC based on Tygstrup et al ¹ criteria.

Treatment

In view of protracted course and failure of medical therapy and on the basis of limited literature, we undertook a trial of ENBD to hasten the bile drainage (figure 2). He was supplemented with vitamin K for raised INR and vitamin A orally for the symptoms.

Outcome and follow-up

Patient showed improvement in jaundice, itching and night blindness. Nasobiliary drainage was removed after 7 days. Patient has been asymptomatic for five consecutive months.

Discussion

BRIC and progressive familial intrahepatic cholestasis (PFIC) form a part of spectrum of familial intrahepatic cholestatic disorders. The prevalence of BRIC is largely unknown but is said to be rarer than PFIC which occurs in 1/50 000–1/100 000 births.² BRIC is a rare autosomal recessive disorder characterised by repeated self-limiting episodes of severe pruritus and jaundice lasting from several weeks to months. The disease may begin in childhood or adulthood.² It usually begins with malaise, cholestatic jaundice with mild transaminitis and hence can be misdiagnosed as acute viral hepatitis. The episodes can be preceded by influenza-like illness or viral gastroenteritis or drugs which act as precipitants.² It is a benign disease as it does not lead to progressive liver dysfunction or cirrhosis but is the cause for high morbidity. The patients can be severely jaundiced and can have pruritus, steatorrhoea and weight loss. Even in the presence of cholestasis the serum γ-glutamyltransferase activity is not elevated. The diagnostic criteria suggested by Tygstrup was the presence of episodes of pruritus and jaundice with biochemical and histological evidence of cholestasis, symptom-free intervals lasting months to years, absence of known cause of cholestasis and normal bile ducts on cholangiography, all of which were seen in our patient.¹

Minuk and Shaffer³ showed that BRIC is not mediated by a circulating cholestatic agent, but rather is secondary to an intrinsic abnormality in hepatocyte bile salt secretion. BRIC can be caused by the mutation in either of the two hepatic transporter genes: the ATP8B1 gene, coding for familial intrahepatic cholestasis-1 (FIC1; BRIC type 1), or the ABCB11 gene, coding for the bile salt export pump (BSEP; BRIC type 2).^{2 3} ATP8B1 acts as an aminophospholipid flippase. Thus, the defect in ATP8B1 reduces transport of bile acids in the liver and the gut, which results in cholestasis and watery diarrhoea. Missense mutations in ATP8B1 leads to BRIC and non-sense frameshift mutations lead to PFIC-1. BSEP is a P-glycoprotein, defect of which leads to impaired bile salt secretion, accumulation of bile salts in hepatocytes and subsequent hepatocellular injury, apoptosis or necrosis.

Histopathology in BRIC-2 shows intrahepatic cholestasis with mild inflammation but otherwise preserved normal liver architecture and no ductular reaction. In contrast, PFIC shows intracanalicular cholestasis, giant cell transformation and varying degree of fibrosis and frank cirrhosis in advanced disease. On immunohistochemistry, loss of BSEP staining is noted. However, there is substantial polymorphism in BSEP noted and hence it is not pathognomonic hallmark feature of BRIC-2 or PFIC-2.²

There is no proven treatment for this disease. Various medical approaches have been tried which include ursodeoxycholic acid, corticosteroids and bile acid-binding resins but without much success.⁴ Rifampicin and colestimide have been reported to be successful in few cases. Refractory cases of jaundice with pruritus (for BRIC exacerbation) have been treated with albumin dialysis.^{5 6}

Surgical approach to this disabling disease includes partial biliary diversion similar to PFIC. It is effective in improving the jaundice and pruritus, but may be associated with a high incidence of stoma-related complications. Minimally invasive laparoscopic external biliary diversion is an innovative method and showed good long-term benefit without complication in paediatric patients as case report.⁷

Endoscopic nasobiliary drainage is a type of transpapillary external drainage wherein the distal end of the long tube is left in the bile duct and the proximal end emerges out through the nose. It is a well-established way of biliary decompression which is most often used in acute cholangitis.⁸ The main advantage of ENBD is the real-time monitoring of drainage status. Report of ENBD as an effective therapy has been shown in few case series and is encouraging. Some series even showed the effects to be long lasting without any further attack of jaundice even though the nasobilliary drainage is one time and usually for 1 week, for which the exact mechanism is unknown. Stapelbroek et al ⁹ demonstrated a reduction in the total bile acid levels (100–200 μmol/L pretreatment) that get normalised by day 3 along with resolution of pruritus. The postulated mechanism behind effectiveness of ENBD for BRIC includes forced bile drainage, block in the enterohepatic circulation and subsequent reduction in the hydrophobic bile acid pool. But the same thing could be achieved by placing a stent as well; advantage of ENBD over a stent is not known. Plausible explanation is that the stent-mediated biliary drainage is internal where there can be reabsoprtion of bile acids while ENBD is external leading to rapid decline in bile acid pool. This is supported by the fact that increased levels of phospholipids other than phosphatidylcholine, particularly sphingomyelin, in the bile drained by ENBD and disruption of the phospholipid gradient.⁹

Our patient did not undergo any genetic testing; however the long-standing history, recurrent cholestatic jaundice episode, no imaging or histological abnormality is in favour of BRIC. He had acute worsening probably due to drug-induced liver injury. He was diagnosed based on classical clinical features, liver function tests and histology. ENBD improved the symptoms as well as the quality of life. There are hardly few cases of BRIC reported from South-East Asia to achieve a successful cure of this highly morbid disease with ENBD.

Learning points.

• Benign recurrent intrahepatic cholestasis, though referred as benign can lead to distraught for the patient and needs early clinical suspicion.

• Medical management may not be successful in all.

• Endoscopic nasobiliary drainage can be the treatment of choice for patients with refractory symptoms