Benign recurrent intrahepatic cholestasis 1

Other Names: BRIC1; Summerskill syndrome; Cholestasis, benign recurrent intrahepatic 1; Recurrent familial intrahepatic cholestasis 1; Mild ATP8B1 deficiency

Benign recurrent intrahepatic cholestasis 1 (BRIC1) is characterized by episodes of liver dysfunction called cholestasis, during which the liver cells have a reduced ability to release a digestive fluid called bile. Because the problems with bile release occur within the liver (intrahepatic), the condition is described as intrahepatic cholestasis. Episodes of cholestasis can last from weeks to months, and the time between episodes, during which there are usually no symptoms, can vary from weeks to years. Most people with BRIC1 have their first episode of cholestasis in their teens or twenties.

Epidemiology

BRIC is a rare disorder. Although the prevalence is unknown, this condition is less common than the related disorder PFIC, which affects approximately 1 in 50,000 to 100,000 people worldwide.

Cause

Mutations in the ATP8B1 gene cause BRIC1. The ATP8B1 gene provides instructions for making a protein that helps to control the distribution of certain fats, called lipids, in the membranes of liver cells. This function likely plays a role in maintaining an appropriate balance of bile acids, a component of bile. This process, known as bile acid homeostasis, is critical for the normal secretion of bile and the proper functioning of liver cells. Although the mechanism is unclear, mutations in the ATP8B1 gene result in the buildup of bile acids in liver cells. The imbalance of bile acids leads to the signs and symptoms of BRIC1. The factors that trigger episodes of BRIC are unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

BRIC1 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Some people with BRIC1 have no family history of the disorder. These cases arise from mutations in the ATP8B1 gene that occur in the body's cells after conception and are not inherited.

Signs and symptoms

Most people with BRIC1 have their first episode of cholestasis in their teens or twenties. Symptoms often present with severe itchiness, followed by yellowing of the skin and whites of the eyes (jaundice) a few weeks later. Other general signs and symptoms that occur during these episodes include a vague feeling of discomfort, irritability, nausea, vomiting, and a lack of appetite. A common feature of BRIC1 is the reduced absorption of fat in the body, which leads to excess fat in the feces (steatorrhea). Because of a lack of fat absorption and loss of appetite, affected individuals often lose weight during episodes of cholestasis.

Diagnosis

Laboratory Studies Consistent with ATP8B1 Deficiency

• Serum concentrations of cholesterol are usually not elevated (an unusual finding in cholestasis).
• Serum concentrations of total bile acids are elevated.
• Fast-atom bombardment ionization mass spectrometry (FAB-MS) analysis of urine. Normal bile acid species present in elevated concentrations indicate normal bile acid synthesis and conjugation. In ATP8B1 deficiency FAB-MS shows elevated levels of normal bile acid species without unusual bile acid species.

• Gas-chromatography / FAB-MS analysis of bile. Depletion of dihydroxy-bile acid species (principally chenodeoxycholic acid) is compatible with ATP8B1 deficiency .

• Note: Such analyses of bile and urine should be conducted, if possible, more than two weeks after the last administration of ursodeoxycholic acid (see Management). The presence of this choleretic, an exogenous dihydroxy-bile acid, in bile and urine samples may make interpretation of results more difficult.

• Sweat chloride. Concentration of electrolytes in sweat may be elevated.

• Liver Biopsy

• Findings typical of severe ATP8B1 deficiency at presentation are bland intracanalicular cholestasis and scant intrahepatocytic cholestasis.

• Molecular genetic testing

Treatment

Standard pharmacologic therapies for pruritus associated with cholestasis (e.g., ursodeoxycholic acid, cholestyramine, and/or rifampin) may be temporarily effective but in the long term are relatively ineffective in severe disease. Nutritional therapy and supplementation of fat-soluble vitamins are useful in severe cholestasis.

In severe disease, partial external biliary diversion (PEBD) surgery may reduce pruritus. In some individuals it even slows or reverses progression of hepatic fibrosis. Alternative surgical procedures include ileal exclusion, partial internal biliary diversion, and external diversion with a button device. When liver disease fails to respond to this type of surgery or progresses to cirrhosis in patients with severe ATP8B1 deficiency, orthotopic liver transplantation (LTX) is necessary for long-term survival; however, particular complications are relatively common after LTX.

Additional treatment options are available for milder disease, including temporary measures such as nasobiliary drainage and extracorporeal liver support therapy, which may shorten a bout of cholestasis.

NIH genetic and rare disease info

• NIH info on Benign recurrent intrahepatic cholestasis 1

Benign recurrent intrahepatic cholestasis 1 is a rare disease.

Benign recurrent intrahepatic cholestasis 1 Resources
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