А case of fulminant hepatitis against a background of paucity of the interlobular bile ducts

Summary

Paucity of interlobular bile ducts (PIBD) ranks second place after biliary atresia in the structure of cholestatic liver disease in children. Morphologically, PIBD is characterised by a reduction in the number of interlobular bile ducts in correlation with the portal hepatic tracts (ductopenia). Ductopenia can be found only upon morphological examination. A liver biopsy is the single most informative investigational tool for this. There are two known types of a paucity of biliary ducts – the syndromic type, which is associated with other congenital defects and the nonsyndromic type, with no other anomalies detected at birth. These may be classified as secondary and primary. Cytomegalovirus is the most frequent infectious etiology in the case of secondary nonsyndromic hypoplasia. Nonsyndromic hypoplasia is also considered to be an inherited autosomal recessive disease, as in many cases the parents of the affected children are relatives and the children’s siblings have the same disorder. The presented clinical case of a nonsyndromic form of PIBD was no exception. In the patient, this congenital anomaly complicated the course of acute hepatitis. PIBD, which was revealed during pathomorphology postmortally, played a leading role in the fulminant course of acute hepatitis in the child, who was thought to be healthy previously.

Key words:

paucity of interlobular bile ducts – fulminant hepatitis – cytomegalovirus infection – children

Introduction

Paucity of interlobular bile ducts (PIBD), synonyms hypoplasia of intrahepatic bile ducts, intrahepatic biliary atresia, ranks second place after biliary atresia in the structure of cholestatic liver disease in children. There are two known types of paucity of biliary ducts: the syndromic form, which is associated with other congenital defects and the nonsyndromic form with no other anomalies detected at birth [1]. The syndromic form of PIBD is associated with various extrahepatic anomalies. Previously, Alagille syndrome was synonymous with the syndromic form of PIBD. However, these terms are not now identical, because two syndromes belonging to the group of syndromic PIBD are well described in modern literature – Alagille syndrome and Williams syndrome [2]. We want to present a case of nonsyndromic form of PIBD with a fulminant course of the disease in a patient in whom it manifested as severe hepatitis at 3 years of age.

Case report A girl aged 3 years and 3 months was hospitalised in the infectious disease department of the Ternopil Children’s Hospital with complaints of severe skin and sclera jaundice, dark urine, clay-coloured stools and decreased appetite.

History of the present illness

The parents noticed the dark colour of her urine a week before hospitalisation. The skin and sclera jaundice appeared 4 days later. An urine test for bile pigments was performed the same day. An increased amount of urobilinogen and bilirubin was found. The parents admitted the intensification of jaundice, asthenic syndrome development (the girl became weak two days before hospitalisation) and an absence of appetite. A biochemical blood test revealed hyperbilirubinaemia with a pre-dominance of direct bilirubin and hypertransferasemia and the alkaline phosphatase levels significantly exceed-ed the norm. Hepatomegaly, free fluid near the right liver lobe in a volume of 13 ml was detected during ultrasound investigation of the abdominal cavity. She was hospitalised on the same day.

Epidemiological anamnesis

The child had no contact with patients who had had a similar illness within 1.5 months, no parenteral manipulations or operative treatment were performed during the last year.

Past history

The girl was born from the mother’s first pregnancy, with premature aging of the placenta, by term natural delivery. The birth weight was 3.3 kg. She was discharged home on the 3rd day after delivery. She had no illnesses during the neonatal period and was breastfed up to 1 year. Her physical and psychomotor development were adequate to her age and she was vaccinated according to the National Vaccination Schedule. Frequent ARIs (acute respiratory infections) were her only previous illnesses. Allergic anamnesis was unremarkable.

Objective examination

The child’s general condition was serious because of considerable jaundice, hepatomegaly and asthenic syndrome. Weight – 15.5 kg, height – 101 cm. The girl was conscious and had no sleep inversion. Her appetite was lower and her fluid intake reduced. Severe jaundice of the skin and mucous membranes was observed. Haemorrhagic syndrome was absent. There was no oedema of the subcutaneous tissue. The tongue was moist, coated with a white fur. Heart rate – 114 per minute, the tones were loud, rhythmic. Breathing through the nose was free, vesicular on auscultation, RR 26 per minute. The stomach was slightly bloated, not tender upon superficial palpation. The liver protruded from the right rib arch at 4 cm, was dense, and had a smooth surface. The spleen did not protrude from the rib arch. The urine was light brown – the faeces were light yellow and periodically greyish.

Preliminary diagnosis Hepatitis of unknown etiology, severe degree, acute course.

Laboratory and instrumental investigation results

Complete Blood Count: Hypochromic anaemia (red blood cells RBC – 4.05 T/l, haemoglobin (HGB) 105 g/L), which in dynamics became more severe (RBC – 3.10 T/l, HGB – 101 g/L); leukopenia 3.4 g/L with neutrophilia 51%, followed by leukocytosis 21.2 g/L with more severe neutrophilia 79%; thrombocytopenia 119 g/L, with drop to 33 g/L. Biochemical blood test: This showed an increase of the blood bilirubin level (167 μmol/L, subsequently up to 520 μmol/L), mainly due to a direct fraction (107.0 (later 304) μmol/L), alkaline phosphatase in the blood 962 IU/L (norm is < 348 IU/L), gama-glutamyl transferase 85 IU/L (norm is < 23 IU/L), alanine aminotransferase 605 (later 1505) IU/L, aspartate aminotransferase 162 (later 268) IU/L. The protein level was normal initially, then hypoproteinemia 40 g/L with hypoalbuminaemia 24 g/L developed, also hyperamilasemia 342 IU/L (norm is < 80 IU/L) developed. Coagulation test: It was normal at the beginning of the disease but later worsened significantly: prothrombin time 32.8 s (N 14–18 s), percentage of prothrombin 15% (N 70–130%), international normalised ratio 4.27 (N 0.85–1.15), activated partial thromboplastin time – no clot was formed (N 21.5–32 s) thrombin time – no clot was formed (N 15–19 s), fibrinogen 1.24 g/L (N 2–4 g/L), soluble fibrin monomer complex – absent (N up to 3.8 mg%). Blood tests for hepatitis: hepatitis A markers (immunoglobulin M (IgM) to hepatitis A virus), hepatitis B markers (polymerase chain reaction-deoxyribonucleic acid of hepatitis B virus), hepatitis C markers (polymerase chain reaction-deoxyribonucleic acid (PCR-DNA) of hepatitis C virus) – were negative. IgM to cytomegalovirus (CMV), IgM to the capsid antigen of Epstein-Barr virus (EBV), immunoglobulin G (IgG) early EBV antigens – were negative too. Screening for autoimmune hepatitis: ANA (immune ferment test method) < 1: 100, IgG antibodies to liver and kidney microsomes 1, (liver-kidney microsomal-1 autoantibodies, quantitative measurement) < 2 (negative result). General urine tests: They were without abnormalities. Test for helmints: It was negative. Coprogram: It described clay-coloured faeces with single digested and undigested fibres, absence of fatty acids, moderate amount of soap and mucus, leukocytes 3–4, single epithelial cells, a lot of bacteria. Ultrasound of the abdominal cavity: This revealed diffuse changes in the liver parenchyma. The walls of the hepatic veins were thickened, the diameter of the portal vein was 7 mm. Hepatomegaly (the sagittal size of the right lobe was 105 mm (+ 33 mm), of the left lobe – 75 mm (+ 38 mm)) was revealed. Oedema of the gallbladder was seen (spastic, size 5 × 1.5 cm, with no detected inner space, with thickened walls up to 5 mm). Oedema of the pancreas was noticed with enlarged sizes of its head, corpus and caudal part (15 × 11 × 19 mm). Ascites was detected with a small amount of fluid in the right hepatic angle and behind the bladder. The spleen was not enlarged (73 × 36 mm), the splenic vein was not dilated. The lymph nodes in the abdominal cavity and retroperitoneal space were not seen. In the dynamics, in 6 days, an abdominal ultrasound showed much severe hepatomegaly (the sagittal size of the right lobe was 120 mm (+ 48 mm), of the left lobe – 81 mm (+ 44 mm). The walls of the portal and hepatic veins were thickened, the diameter of the portal vein remained the same. Splenomegaly 83 × 42 mm (N up to 75 mm) appear-ed. Oedema of the pancreas (17 × 16 × × 16 mm) and its echogenicity increased. Oedema of the kidneys (right – 81 × 37 mm, left – 82 × 37 mm) and increased kidney echogenicity appeared. The kidneys’ cups and bowls were dilated. Oedema of the urinary bladder wall appeared. Ascites in comparison with the previous survey increased: free fluid was visualised in the hepatic and splenic angles of the abdominal cavity, between the loops of the intestine and in the small pelvis. A CT scan of the abdominal cavity and the small pelvis with intravenous contrast enhancement revealed signs of diffuse liver damage (hepatitis), collapsed gallbladder and ascites. An oesophagogastroduodenoscopy detect-ed superficial gastritis. The veins of the oesophagus were not dilated. Small portions of fresh bile began to secrete from the Vateri’s papilla after 10 ml of 25% magnesium sulfate administration through a biopsy channel.

Clinical diagnosis

Acute hepatitis, etiology which needs to be clarified. Fulminant hepatic failure, hepatic encephalopathy, 3rd degree, oedema-ascites syndrome. The girl was transferred to the intensive care unit due to hepatic encephalopathy a week after admission, where she was consulted by a hepatologist. The child was transferred to the Republican Centre of Hepatology 6 days later for further treatment. A positive CMV DNA blood test by PCR method in a repeated study was obtained. Despite intensive therapy, the girl’s condition deteriorated progressively. She died one month after initial hospitalisation.

Final pathomorphologic diagnosis

Basic Disease. Fulminant necrotic hepatitis with giant cellular pathomorphosis of the hepatocytes (ICD 10 – K 72). Background Disorders Congenital malformation: intrahepatic biliary hypoplasia with cholestasis and initial signs of liver cirrhosis. Cytomegalovirus infection. Complications: Ascites. Parenchymal dystrophy of the kidneys, myocardium. Induced aplastic anaemia. Haemorrhagic syndrome: multiple haemorrhages on the skin, lung haemorrhage, adrenal haemorrhage, gastro-intestinal bleeding. Secondary immunodeficiency. Candidiasis of the abdominal cavity.

Conclusion

Congenital pathology of the liver (intra-hepatic biliary hypoplasia) was found during an autopsy and pathomorphological examination of the child. It became an unfavourable background for hepatitis, which took a malignant fulminant course with hepatic failure and ascites. The disease was complicated by aplastic anaemia with haemorrhagic syndrome, which was the direct cause of the child’s death. Genetic counselling for the family and the supervision of a younger child, in whom nonsyndromic PIBD was diagnosed later, were recommended, due to what is likely a hereditary liver disorder.

Discussion

The nonsyndromic form of PIBD is a heterogeneous group of disorders. It may be classified into two groups: 1. patients with a definite etiology, which could be defined as secondary nonsyndromic hypoplasia, and 2. patients without a definite etiology, which could be defined as primary nonsyndromic hypoplasia [3]. Secondary nonsyndromic PIBD may be associated with various metabolic disorders, such as α-1-antitrypsin deficiency [3,4], cystic fibrosis [5], congenital disorders of bile acid metabolism [6], chromosomal defects (Down, Edward’s, or Turner syndrome) [7–9], hepatotoxins (carbamazepine, amoxicillin with clavulanic acid) and congenital bacterial or viral infection, especially cytomegalovirus, that results in progressive destruction of the bile ducts [3,10–13]. De Tommaso et al [3] have shown that possible CMV etiology of PIBD may lead to poor evolution of the pathology, which requires liver transplantation. In the presented case, a positive CMV DNA test detected etiology of nonsyndromic PIBD in the patient, so the course of her disease could predictably have been severe.

However, nonsyndromic PIBD is idiopathic in many cases, as it is impossible to evaluate the etiology of the disease [14].

Nonsyndromic hypoplasia is also considered an inherited autosomal recessive disease, as in many cases the parents of the affected children were relatives. The consanguinity rate was near 80% among them according to Koçak et al [6] and the patients’ siblings had the same disorder [6,13–15]. The inheritance was also positive in our case, when PIBD was proved in the patient’s sibling morphologically. She is now 2 years old and has had no clinical manifestations as yet.

Paucity of the intrahepatic bile ducts should be suspected in children with cholestasis. Clinically, intrahepatic cholestasis syndrome appears in the neo-natal period, less often during the early months of life. But some children, according to Koçak et al [6] may have late clinical presentation at the age of 1.5–2.5 years. Later development of clinical presentation (after 3 years) was discovered in our patient. Intrahepatic cholestasis usually presents with jaundice that has a greenish tinge, enlargement of the liver, non-permanent acholic stools and dark urine. Pruritus is a frequent symptom. In the future, up to the 4th to 6th months of life, the jaundice disappears and the colour of the stool and urine change to normal. However, itching of the skin appears, then intensifies and becomes the leading clinical symptom of the disease, while the other symptoms are intermittent [16]. Cholestatic syndrome was one of the leading clinical syndromes in the presented case.

As the disease progresses, children demonstrate a delay in physical development and signs of fat-soluble vitamin deficiency (rickets and osteopenia, muscle hypotonia, dry skin and mucous membranes, dimness and fragility of the nails and hair, ophthalmoplegia, petechiae and/or bleeding from the mucous membranes) [1,6,10].

Laboratory investigations usually detect conjugated hyperbilirubinae-mia, mild liver function test abnormalities [4,5,14] and cholestasis [2,15]. The biochemical blood results of our patient showed impaired liver synthetic function, cholestasis and severe cytolysis that worsened progressively.

The absence of symptoms, typical for Allagile syndrome, in the case of cholestasis is the reason for liver puncture biopsy and, according to indications, retrograde or percutaneous cholangiography to prove a diagnosis of nonsyndromic PIBD and differentiate it with biliary atresia. None of the variables of hepatobiliary involvement differs in the syndromic and nonsyndromic presentations of PIBD [15,17].

Percutaneous cholangiograms usually demonstrate in normal hepatic ducts, the common hepatic duct and the gall-bladder with normal drainage of the contrast to the duodenum. However, hypoplasia of the extrahepatic biliary tree could also be found in combination with intrahepatic bile duct paucity that proves their etiologic reliability. A combination of PIBD with biliary atresia has been described by Chiu et al [13].

Hepatobiliary scintigraphy may also be useful in cases of clinically suspected PIBD. It demonstrates delayed excretion of a radiotracer in bowel visualisation after 24 hours, consistent with delayed biliary excretion according to data from Figel et al [1].

Morphologically, PIBD is characterised by a reduction in the number of interlobular bile ducts in correlation with portal hepatic tracts (ductopenia) [3]. Ductopenia can be found only upon histological examination based on the ratio of the number of portal bile ducts to their total amount on the biop-sy. Liver biopsy is the single most informative investigational tool in this case. A normal ratio of interlobular bile ducts to the total number of portal tracts is within the range of 0.9–1.8 in healthy newborns. When the ratio of bile ducts to portal tracts is less than 0.5, a diagnosis of PIBD becomes indisputable [2]. Bile duct destruction is the common pathway leading to the paucity of biliary ducts.

Histologic investigation in nonsyndromic PIBD reveals a paucity of inter-lobular bile ducts, intracellular cholestasis and cirrhosis with regenerative nodules, mild to moderate portal tract fibrosis with giant cells and changed hepatocyte architecture with minimal to moderate inflammation in the portal tracts. In cases of PIBD associated with CMV infection specific pathognomonic inclusions in the liver, especially in the duct epithelium (but not in the parenchyma) will be present [11]. Liver fibrosis seems to be more severe in patients with cytomegalovirus infection [18]. Cirrhosis of the liver develops in more than 50% of the patients [2]. Typical morphological changes such as intrahepatic biliary hypoplasia, intracellular cholestasis and initial signs of liver cirrhosis were found in our patient.

The prognosis for patients is variable. There is no predictive histologic marker for prognosis. The outcome might depend on the degree of the damage severity. Kansu et al [14] describe two cases of a benign course of nonsyndromic idiopathic PIBD with clinical and biochemical resolution in 6 months but without histologic normalisation.

Liver transplantation is the method of choice in treating PIBD [15,17].

Conclusion

In the presented case, intrahepatic biliary hypoplasia was found due to an autopsy and pathomorphological examination of the child. In the patient, this congenital anomaly complicated the course of acute hepatitis. PIBD, which was revealed during the pathomorphology postmortally, played a leading role in the fulminant course of acute hepatitis in the child, who was thought to be healthy previously. The detection of CMV as an etiological factor in our patient proved the typically unfavourable outcome prognosis in comparison with idiopathic nonsyndromic PIBD.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for bio­­­­medical papers.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

Submitted: 2. 7. 2018

Accepted: 21. 7. 2018

prof. Halyna Pavlyshyn, Ph.D.

Ternopil State Medical University

M. Voli 1, Ternopil

Ukraine

halynapavlishin@gmail.com