Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Abstract

BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

Novel missense mutation in VPS33B is associated with isolated low gamma‐glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome

“…Infantile low/normal GGT cholestasis comprises a series of monogenic defects. Except for ARC syndrome, other defects usually manifest a spectrum of familial cholestasis of different severity, or varied phenotypes from intractable watery diarrhea to isolated cholestasis (Bull & Thompson, ; Chen et al, ). In addition, hereditary diseases that typically result in multiorgan disorders may manifest isolated hepatopathy at times.…”

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

“…Given that patients with ALGS and PFIC have intrahepatic accumulations of bile acids that can damage tissues in the liver and spill over into systemic circulation, SBD procedures were developed to interrupt enterohepatic circulation and reduce the bile acid pool in these patients. 8,15 SBD is often associated with reductions in serum bile acids and pruritus as well as improvements in sleep disturbance, quality of life, fibrosis and growth. [53][54][55] In the case of PFIC, most of the currently available data on SBD are based on ATP8B1-and ABCB11-deficient patients.…”

“…4,5 Cholestasis is defined as the impaired formation or flow of bile in the hepatobiliary system and may be intrahepatic (involving hepatocytes, bile canaliculi or intrahepatic bile ducts) or extrahepatic (involving the bile ducts outside the liver or the gallbladder). [6][7][8] In cholestasis, which can present with features of jaundice or pruritus, the accumulation of bile acids may damage liver cells such that fibrotic and inflammatory pathways are activated that lead to liver injury. 1,2,6 Common cholestatic liver diseases include Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia in children and primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) in adults.…”

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

“…Notably, biochemical criteria of hepatotoxicity in adults with cholestatic disease may not apply to paediatric populations due to development‐related differences in the normal ranges of common liver tests including total bilirubin, aminotransferases, and ALP from early infancy through the pubertal growth spurt. In addition, certain hereditary cholestatic liver diseases in infants and children are not associated with the characteristic rise in GGT that are seen in PBC or PSC and cannot be relied upon as a marker of cholestatic injury . During growth in normal paediatric study subjects, ALP levels are affected by fluctuations of the enzyme derived from bone.…”

“…In addition, certain hereditary cholestatic liver diseases in infants and children are not associated with the characteristic rise in GGT that are seen in PBC or PSC and cannot be relied upon as a marker of cholestatic injury. 169 During growth in normal paediatric study subjects, ALP levels are affected by fluctuations of the enzyme derived from bone. Changes of ALP in paediatric patients are also typically observed with vitamin D deficiency.…”