BACKGROUND

Progressive familial intrahepatic cholestasis (PFIC) syndromes are autosomal recessive disorders characterised by defects in transporters of conjugated bile acids into the bile canaliculus. In both subtypes cholestasis starts early and patients suffer from severe pruritis and, due to conjugated hyperbilirubinaemia, from jaundice.1^–3 In addition to the disorders in which patients have low serum γ-glutamyltranspeptidase (GGT) levels (PFIC1 and PFIC2), a late-onset benign progressive disease (benign recurrent intrahepatic cholestasis, BRIC) has also been recognised.3^,4 Human herpesvirus type (HHV)-6 is not only the causative agent of exanthema subitum, but is also associated with a spectrum of diseases, including febrile convulsions, encephalopathy and liver disease, including acute liver injury and fulminant hepatitis.5^–8

HHV-6 infection, usually acquired in early childhood, is widespread, as shown by the presence of specific antibodies in >90% of healthy adults.9^,10

We present a case that shows the difficulties in the differential diagnosis between HHV-6-related hepatitis and PFIC.

CASE PRESENTATION

The patient presented at the age of 1 month. He had been delivered spontaneously after 40 weeks’ gestation. At birth he weighed 3100 g. No perinatal complications had occurred and he was breast-fed. The mother had been on ampicillin for 1 week due to fever without any specific symptoms before the child’s admission to our unit with jaundice and raised aminotransferases.

Physical examination revealed mild hepatomegaly and no splenomegaly. He had no history of drug or toxin exposure. Metabolic diseases were ruled out by normal values of the following tests: serum levels of α1-antitrypsin, ceruloplasmine, ammonium, lactic acid, wet test, fasting blood sugar, reducing substances in urine and organic acids in urine. Ultrasound found no alterations of liver, biliary tree, gallbladder and pancreas; the portal flow was normal.

Aspartate aminotransferase (AST) was 309 IU/l (normal 40 IU/l), alanine aminotransferase (ALT) 224 IU/l (normal 40 IU/l), alkaline phosphatase 1158 IU/l (normal up to 1200 IU/l), GGT 148 IU/l(normal 40 IU/l), total bilirubin 9.33 mg/dl (normal 0.25–1.00 mg/dl) and conjugated bilirubin 6.63 mg/dl (normal 0.08–0.25 mg/dl).

INVESTIGATIONS

HHV-6 DNA was found in blood and saliva; IgG anti-HHV-6 were found in serum. Other infectious agents, including cytomegalovirus, parvovirus B19, Epstein–Barr virus, adenovirus and herpes simplex virus-1 and -2 were negative. A diagnosis of HHV-6 hepatitis was made.

In the following weeks, AST and ALT values remained raised while GGT levels progressively fell reaching normal values after 45 days.

At the age of 4 months the child was still jaundiced and pruritus appeared. There was a relative failure to thrive with both weight and height at the 10th percentile with persistent AST and ALT elevation. At the age of 5 months a liver biopsy was done. Histology revealed chronic hepatitis with fibrosis, bridging necrosis, giant cell transformation of liver cells, long-lasting cholestasis. Immunohistochemistry did not show the expression of canalicular bile salt export pump (fig 1). PFIC2 gene analysis ruled out common mutations. A diagnosis of progressive familiar intrahepatic cholestasis type 2 was made.

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Figure 1

Bile salt export pump (BSEP) deficiency. (A) Bland canalicular cholestasis (arrows) and multinucleated giant hepatocytes (arrowheads). Haematoxylin and eosin. (B) Fine portal-to-portal and central-to-portal fibrotic sapta. Masson trichrome. (C) Immunohistochemistry for BSEP shows absent marking at canalicular margins while control (D) stains adequately. PAP method.

DIFFERENTIAL DIAGNOSIS

Neonatal hepatitis

• toxic

• viral

• metabolic.

Human herpesvirus type 6 infection with liver injury

Intrahepatic cholestasis

• pfic1

• pfic2

• bric1

• Disorders of bile acids synthesis.

OUTCOME AND FOLLOW-UP

The patient is now 7 months old. Cholestatic jaundice continues to be present and pruritus is still the most notable symptom. AST, ALT, GGT and bilirubin are monitored every 3 weeks.

He has had no infections during follow-up, is being vaccinated and his neurological development is normal for his age.

DISCUSSION

HHV-6 infection is quite frequent in children, and, although associated with liver disease in some, may be occasionally found in others without liver disease.11 Our case demonstrates that our first diagnosis, merely based on the detection of viral sequences in blood and saliva, was incorrect. A careful follow-up allowed the right diagnosis to be made, ie, PFIC, a rare disease that affects 1 in 90 000 living births world-wide. Treatment of PFIC disease is mainly supportive (ursodeoxycholic acid and antipruritic drugs), and liver transplantation is necessary in most cases.1 The role of partial biliary diversion is debated.1