Cholestasis in hepatitis E virus infection

Abstract

Hepatitis E virus (HEV) infection causes acute hepatitis, chronic hepatitis, particularly in compromised hosts, and various extrahepatic manifestations. HEV infection is reportedly associated with biliary-pancreatic diseases, such as gallstones, cholangitis, choledocholithiasis, and acute pancreatitis. Severe jaundice and prolonged cholestasis are also atypical manifestations of HEV infection. The mechanism and genes involved in cholestasis, namely sinusoidal uptake of blood, bile salt synthesis and secretion from hepatocytes to the canaliculus, have been elucidated. HEV infection triggers severe jaundice and prolonged cholestasis in patients with genetic variants in adenosine triphosphatase phospholipid transporting 8B1, adenosine triphosphate-binding cassette (ABC) protein B4, ABCB11, Myosin VB, and/or farnesoid X receptor (FXR/NR1H4). Although prolonged cholestasis associated with these gene mutations does not seem to be specific to HEV infection, these mutations may be risk factors related to the severity of HEV infection. The use of the pregnane X receptor agonist rifampicin and the peroxisome proliferator-activated receptor activator bezafibrate may be useful for the treatment of cholestasis. These studies provide new insights into understanding the mechanisms of severe jaundice and prolonged cholestasis caused by HEV infection.

Key Words: Genomic mutations; Cholestasis; Farnesoid X receptor; Hepatitis E virus; Jaundice

Core Tip: Hepatitis E virus (HEV) infection triggers severe jaundice and prolonged cholestasis in patients with genetic variants in adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1), adenosine triphosphate-binding cassette (ABC) protein B4, ABCB11, Myosin VB and/or farnesoid X receptor (FXR/NR1H4). Genomic mutations associated with hepatocanalicular transporter proteins occasionally cause cholestasis. HEV infection may trigger severe jaundice and prolonged cholestasis in patients with these genomic mutations.

INTRODUCTION

Hepatitis E virus (HEV) infection causes acute hepatitis, chronic hepatitis, especially in compromised hosts, and various extrahepatic manifestations[1-3]. Severe jaundice and prolonged cholestasis are occasionally observed in patients infected with HEV[4-6]. As these conditions lead to hepatic failure, their exact mechanism, diagnosis, treatment, and measures are important issues to explore.

HEV infection is reportedly associated with biliary-pancreatic diseases, such as gallstones, cholangitis, choledocholithiasis, and acute pancreatitis[7-13]. Severe jaundice and prolonged cholestasis are also atypical manifestations of HEV infection. Although HEV infects a wide range of species, such as human, pigs wild boars, deer rabbits and camels, HEV genotypes 1/2 infect only humans and related to outbreaks of hepatitis E in developing countries and HEV genotypes 3/4 cause zoonosis and associate with sporadic and autochthonous HEV infection in developed countries[1-3]. Although severe jaundice generally seems to be associated with HEV genotype 1 infection[4], Drexler et al[6] reported that autochthonous HEV genotype 3 is prevalent in adults in Germany[14,15] and that HEV infection triggered intrahepatic cholestasis. However, their study was limited because they did not examine the HEV genotypes[6].

SINUSOIDAL UPTAKE OF BLOOD, BILE SALT SYNTHESIS AND SECRETION FROM HEPATOCYTES TO CANALICULUS

Several binding proteins transport energy independently from the blood to hepatocytes, helping to maintain low concentrations within these cells. In contrast, canalicular transport proteins facilitate energy-dependent transport processes across the canalicular membrane, moving substances from hepatocytes to bile[16].

Soluble carrier organic anion transporter family 1B1 [SLCO1B1/organic anion transport protein 1B1 (OATP1B1)], SLCO1B3/OATP1B3, SLC10A1/Na taurocholate cotransporter protein (NTCP), SLC22A1/organic cation transporter 1 (OCT1), multidrug resistance protein family 3/adenosine triphosphate (ATP)-binding cassette (ABC) protein C3, MRP4/ABCC4, and organic solute transporter-α/β (OST-α/β) play roles as cell surface membrane transporters in the sinusoidal uptake of bile salts and other organic and inorganic ions from plasma to hepatocytes[16]. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) act as nuclear receptors in this step[16].

As cell surface membrane transporters, bile salt export pumps/ABCB11, multidrug resistance protein 2 (MRP2/cMOAT/ABCC2), familial intrahepatic cholestasis 1/ATP8B1, multiple drug resistance protein 3/ABCB4, ABC G5/G8 and MDR1/ABCB1 transport bile salts, organic cations, phospholipids, organic anions, and cholesterol, respectively, from hepatocytes to canaliculi[16]. FXR, PXR, constitutive androstane receptor, and peroxisome proliferator-activated receptor alpha (PPARα) also play roles as nuclear receptors in this step[16].

Cystic fibrosis transport regulator (CFTR), apical sodium-dependent bile salt transporter/SLC10A2 and OST-α/β are cell surface membrane receptors located on the apical side of cholangiocytes, the apical side of the ileum, and the basolateral side of the ileum[16]. Myosin VB (MYO5B) motor domain mutations, which can cause the mislocalization of canalicular proteins in hepatocytes, are associated with progressive familial intrahepatic cholestasis 6[17,18]. In the ileum, FXR also functions as a nuclear receptor[16].

CHOLESTASIS AND GENOME MUTATIONS

Rotor syndrome is associated with mild hyperbilirubinemia and is caused by biallelic pathological variants in both the SLCO1B1 and SLCO1B3 genes, resulting in defective OATP1B1 and OATP1B3 in the sinusoidal membrane and preventing bilirubin uptake by hepatocytes[19]. NTCP is also well known as a cell surface receptor candidate for hepatitis B virus[20], and NTCP mutations are associated with hypercholanemia[21]. MRP2/cMOAT is the gene responsible for Dubin–Johnson syndrome[22]. Thus, genome mutations in these transporters, which are involved in the transport of bilirubin, bile salts, phospholipids, and the formation of bile, could result in human cholestatic diseases[16].

Drexler et al[6] described two patients with HEV infection and severe hyperbilirubinemia. The 39-year-old patient had no medical history, whereas the 58-year-old patient had already experienced an episode of jaundice in his early twenties. Liver disease or jaundice were not reported in the families of either patient. Interestingly, next-generation sequencing of their genomic DNA revealed that both patients had genetic variants in ATP8B1, ABCB4, ABCB11, and MYO5B. The latter patient also had a heterogeneous pathogenic mutation, predisposing this individual to cholestatic variants in NR1H4 (FXR)[6], which is a bile acid sensor that links the enterohepatic circuit and regulates bile acid as well as systemic lipid metabolism[23].

Krawczyk et al[24] reported the presence of two procholestatic polymorphisms, the c.3084 [GG] variant within ABCB11, and the c.711 [AT] variant of ABCB4, in a 36-year-old female with hepatitis A virus (HAV) infection and prolonged cholestasis. Prolonged cholestasis associated with these gene mutations did not seem to be specific to HEV infection[6,25].

HYPOTHESIS OF HEV INFECTION LEADING TO CHOLESTASIS

In general, the mechanism of cholestasis progress through three types: prehepatic, hepatic and posthepatic. Therefore, possible mechanism by which HEV infection leads to cholestasis seems also similar (Table 1). Hemolysis and bilirubin overload cause the prehepatic-type of cholestasis in patients with hepatitis E[26,27]. Inherited genome mutations and co-infection with other virus and drugs cause hepatic-type of cholestasis in patients with hepatitis E[6,28]. Biliary duct obstruction causes posthepatic-type of cholestasis in patients with hepatitis E[7-13,29]. Attention should be given to causes of cholestasis than the genome mutations.

Table 1 Possible mechanisms of cholestasis in patients with hepatitis E.

Types/cause	Proteins involved	Ref.
Prehepatic-type/bilirubin overloads, hemolysis		[26,27]
Hepatic-type/impaired conjugation, impaired uptake (hepatitis or inherited genome mutations), impaired canalicular secretion (hepatitis, drugs, sex hormones or inherited genome mutations)	(Sinusoidal uptake of blood, etc.) SLCO1B1, SLCO1B3, SLC10A1, SLC22A1, MRP3, MRP4, OST-α/β, FXR, PXR (Transport of bile salt, etc.) BSEP, MRP2, FIC1, MDR3, ABC G5/G8, MDR1, FXR, PXR, CAR, PPARα	[6,28]
Posthepatic-type/ductular diseases (primary biliary cholangitis, primary sclerosing cholangitis or biliary duct obstruction by gallstones or malignancies)	(Secretion from hepatocytes to canaliculus) CFTR, ASBT, OST-α/β, MBO5B, FXR	[7-13,29]

SLCO1B1: Soluble carrier organic anion transporter family 1B1; SLCO1B3: Soluble carrier organic anion transporter family 1B3; NTCP: Na taurocholate cotransporter protein; OCT1: Organic cation transporter 1; MRP3: Multidrug resistance protein family 3; OST-α/β: Organic solute transporter-α/β; FXR: Farnesoid X receptor; PXR: Pregnane X receptor; BSEP: Bile salt export pumps; MRP2: Multidrug resistance protein 2; FIC1: Familial intrahepatic cholestasis 1; MDR3: Multiple drug resistance protein 3; MDR1: Multiple drug resistance protein 1; CAR: Constitutive androstane receptor; PPARα: Peroxisome proliferator-activated receptor alpha; CFTR: Cystic fibrosis transport regulator; ASBT: Apical sodium-dependent bile salt transporter; MBO5B: Myosin VB.

TREATMENT OF CHOLESTASIS IN PATIENTS WITH HEV INFECTION

Drexler et al[6] reported that 150 mg rifampicin or 400 mg bezafibrate daily was effective for treating intrahepatic cholestasis triggered by HEV infection. Rifampicin, a PXR agonist, is also an effective treatment for cholestatic pruritus[30]. Bezafibrate, a PPAR activator, is also a therapeutic option for patients with primary biliary cholangitis [31]. Ursodeoxycholic acid and/or steroids may be useful for the patients with cholestasis triggered by HEV infection[32,33]. Seladelpar, a PPAR delta agonist may offer potential benefits[34].

Several clinical practice guidelines for cholestasis may be useful for the diagnosis and management of cholestasis[35,36]. Anti-HEV drugs, such as ribavirin, could also be useful for the treatment for patients with HEV infection and cholestasis[1,3].

RISK FACTORS RELATED TO THE SEVERITY OF HEV INFECTION

The severity of HEV infection is associated with host factors (older age, genetic factors related to cholestasis, etc.), viral factors (viral load, HEV genotype, nucleotide mutations of HEV genomes, etc.), and other factors (HIV co-infection, chronic liver disease, metabolic disease, etc.)[3]. Immune status and nutritional status are also risk factors related to the severity of HEV infection[28]. Immunosuppressed patients may face higher risks and malnutrition may affect disease severity[28].

Patients with acute HEV infection were reported to be older (mean age 56.1 years) than those with HAV infection in Japan[37]. Among metabolic disease, diabetes mellitus and hypertension affect disease severity[38-40]. Although there have been no reports of specific genome mutations related to the disease severity of HEV infection, several genome mutations associated with HEV infection-triggered intrahepatic cholestasis have been reported[6].

HEV genotype 1 infection is associated with poor fetal outcomes among pregnant women[41]. Although HEV genotype 3 infection is prevalent in Japan, fulminant hepatitis occurs more frequently in individuals with HEV genotype 4 (6/74; 8.1%) than in those with HEV genotype 3 (1/128; 0.8%)[42]. Special populations, such as pregnant women, could have a risk for HEV infection and cholestasis[41].

As excessive drinking may exacerbate liver damage, leading to acute-on-chronic liver failure caused by HEV infection[3], alcohol history is also important. Environmental factors, such as sanitation conditions, drinking water quality are also risk factors. Occupational exposures are also important as certain occupations may increase HEV infection risk and severity. Extrahepatic conditions, such as renal function, may affect prognosis[1,3]. Timely diagnosis and treatment may affect disease progression.

In patients with a history of jaundice, host genome mutations associated with cholestasis may be helpful in the clinical setting of HEV infection and other liver diseases[6,43,44]. Attention should also be given to these factors related to the severity of HEV infection. Further research should be needed to fill up the current knowledge gaps, to solve potential research questions, to determine the relative importance of these risk factors, and to point out that there may be other undiscovered risk factors.

CONCLUSION

Genomic mutations associated with hepatocanalicular transporter proteins occasionally cause cholestasis. HEV infection may trigger severe jaundice and prolonged cholestasis in patients with these genomic mutations. Among the patients with autochthonous HEV infection, genetic variants in ATP8B1, ABCB4, ABCB11, and MYO5B, which are related to cholestasis, may contribute to disease severity. These findings provide new insights into the mechanisms underlying severe jaundice and prolonged cholestasis in patients infected with HEV.