A 6-month-old boy presented with progressive jaundice, dark urine and generalized pruritus for one month

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A 6-month-old boy of non-consanguineous parents admitted to the Department of Pediatric Gastroenterology with the complaints of progressive jaundice, dark urine and generalized pruritus for one month. The boy was well up to five months of age. Then he developed jaundice which was progressive in nature with intermittent pale colored stool along with dark urine. His mother also complaints for generalized pruritus which was severe in intensity (disturbing sleep and daily activities) without any diurnal variations. There was no history of sib death or family history of a similar type of illness.

Physical examination revealed he was moderately icteric, scratch mark present over the whole body and mild (2 cm) firm hepatomegaly present with normal physical development.
The laboratory data included normal complete blood counts except leucocytosis mostly lymphocyte. Serum total bilirubin was 8.8 mg/dL (conjugated bilirubin 5.1 mg/dL), alanine transaminase 26 U/L and gamma-glutamyl transferase 22 U/L, prothrombin time, activated partial thromboplastin time and international normalized ratio were within normal limit. Serum cholesterol level was 133 mg/dL. Anti-HAV IgM was negative. Urine R/E was normal and urinary reducing substances were nil. Renal functions, X-ray spines and echo-cardiography were normal. Ultrasonography of the abdomen showed mild hepatomegaly. Slit lamp examination of eyes showed no abnormality. Liver biopsy was done and histopathological examination revealed the paucity of interlobular bile ducts (out of eight portal tracts examined, two had bile duct) (Figure 2A and B). Bile duct to portal tract ratio was 0.25. The hepatocytes were mildly swollen and occasional sinusoid contained bile plugs.
Based on history, physical findings and laboratory investigations with liver biopsy our diagnosis was nonsyndromic interlobular bile duct paucity.

Provisional Diagnosis
Nonsyndromic bile duct paucity

Differential Diagnosis
Dr. A. S. M. Bazlul Karim: The differential diagnoses were the following:

Alagille syndrome
Alagille syndrome is an autosomal dominant, multisystem developmental disorder. It is a familial disease with wide variability in its clinical presentation. Majority of the patients present before six months of age with jaundice and failure to thrive or cardiovascular symptoms. Cholestasis is manifested by jaundice and pruritus, present in 96% of cases. Jaundice presents as a conjugated hyperbilirubinemia in the neonatal period and the magnitude of the hyperbilirubinemia is minor compared to the degree of cholestasis. Severe cholestasis results in the formation of xanthomas, especially on the extensor surfaces of the fingers, the palmar creases, nape of the neck, popliteal fossa, buttocks, and around inguinal trauma sites. These lesions are persisting but may gradually disappear after 10 years of age. The presence of interlobular bile duct paucity and at least 3 of 5 clinical features are necessary for the diagnosis: Chronic cholestasis, cardiac disease, ocular abnormalities, skeletal abnormalities, and characteristic facies. In infants, less than 6 months of age, when the bile duct paucity is usually absent, three or four clinical features should be adequate to make the diagnosis. In a family with one definite proband, other members with two and even one feature are suggestive to have Alagille syndrome. 1-3 Dr. Akter: After evaluating patient's clinical presentations, the physical findings and investigations results, liver biopsy was done and send for histopathological examination. Histopathology report showed the paucity of interlobular bile ducts (out of eight portal tracts examined, two had bile duct and bile duct to portal tract ratio was 0.25 cm. The hepatocytes were mildly swollen and occasional sinusoid contained bile plugs. The diagnosis was made based on the histopathologic examination of the liver. Clinical features described in Alagille syndrome were not present in our case except cholestasis which led us to a diagnosis of nonsyndromic interlobular bile duct paucity.

Nonsyndromic bile duct paucity
Dr. Parisa Marjan: The patient presented with jaundice and pruritus. Why it is not a case of progressive familial intrahepatic cholestasis (PFIC)?
Dr. Akter: Progressive familial intrahepatic cholestasis is a clinical syndrome of intrahepatic cholestasis which presents in infancy or early childhood. PFIC1 and PFIC2 usually present symptoms within the first 3 months of life and PFIC3 present at early adulthood whereas our patient presented at 5 months of his age. Along with cholestasis patients with PFIC1 can present with deafness, pancreatic insufficiency, cholelithiasis, and diarrhea. These features were not present in our case. Serum gamma-glutamyltranspeptidase activity is elevated in PFIC3 but in our case it was normal. Progressive familial intrahepatic cholestasis usually runs in families, which was not so in our case. For these reasons the possibility of progressive familial intrahepatic cholestasis is ruled out. 4-8 Dr. Archana Shrestha Yadav: Have you put biliary atresia at your differential diagnosis?
Dr. Akter: No. Biliary atresia can also present with jaundice with pruritus but it commonly present in the neonatal period with persistent pale stool. Our patient presented with jaundice, pruritus, intermittent pale stool and hepatomegaly at his 5 th months. The typical histopathological findings of biliary atresia are inflammation, portal tract fibrosis, cholestasis, and bile duct proliferation which were also absent in our case.  Dr. Mondal: What is the prognosis of this patient?
Dr. Akter: The prognosis of nonsyndromic bile duct paucity is highly variable and the patient can be categorized into two groups according to their outcome: Those with progressive disease and those with a benign course. Evolution to cirrhosis of the liver in infancy is infrequent but higher than in the cases of syndromic paucity. 12, 13

Discussion
Dr. Wahiduzzaman Mazumder: Cholestasis refers to the consequences of reduction or interruption of the bile flow or its constituents at any level from hepatocyte to the duodenum and is defined serologically as prolonged conjugated hyperbilirubinemia. It is classified as extrahepatic and intrahepatic in causes. Intrahepatic cholestasis may results from the defective mechanism of bile formation due to bacterial, protozoal and viral infections, also may have a metabolic or toxic origin. It also can be secondary to an abnormality of biliary secretion as a result of hepatocyte dysfunction or abnormal excretion of bile. The paucity of intrahepatic bile ducts can cause cholestasis which comprises about 6.7% of the causes of intrahepatic cholestasis. 1, 14, 15 Bile duct paucity is defined as the absence or marked reduction in the number of interlobular bile ducts within portal tracts. It is a significant abnormality causing intrahepatic cholestasis in children. 2, 4, 12 Histopathologically, it is expressed as the ratio of the number of interlobular bile ducts to the number of portal tracts. In normal children, this ratio is 0.9 to 1.8 and a ratio <0.5, 0.6, or 0.9 is considered hypoplasia or the paucity of intralobular bile duct in the pediatric age group. Although the etiopathogenesis is not clear, three theories have been proposed for ductal paucity: Congenital absence of bile ducts, partial atrophy or primary duct destruction. It is an important problem that is faced commonly in the pediatric age group.
Clinically the paucity of intrahepatic bile ducts is classified as syndromic (which is called Alagille syndrome), or nonsyndromic. 1 The nonsyndromic bile duct paucity which is seen rarely may idiopathic or can be associated with congenital infections (cytomegalovirus, rubella) metabolic disorders (alpha-1 antitrypsin deficiency, cystic fibrosis Niemann-Pick type C, Zellweger syndrome), nutriational (total parenteral nutrition), endocrine disorders (hypopituitarism), chromosomal defects (Trisomy 17, 18 and 21), immunologic disorders, altered bile acid metabolism and chronic rejection of transplants. [16][17][18][19][20] Alagille syndrome or arteriohepatic dysplasia is diagnosed on the basis of interlobular bile ductular paucity in the liver histology with any three of five major features such as cholestatic liver disease, consistent cardiac disease, skeletal abnormalities (butterfly vertebrae), ocular abnormalities (posterior embryotoxon) and a characteristic Alagille (triangular) facies. 5  The mainstay of treatment is symptomatic relief of pruritus, optimization of nutritional status, and management of complications of chronic liver disease. All the infants and children who presented with cholestasis were treated with fat-soluble vitamins. Ursodeoxycholic acid has been used for the management of pruritus as it stimulates bile flow by increased liquidity of bile. Additional antipruritic medications including hydroxyzine, diphenhydramine, rifampin, naltrexone, and cholestyramine alone or in combination may also be used. Newer study shows that omega-3 polyunsaturated fatty acid can be effective as a potent choleretic agent for children with nonsyndromic paucity. If the medical treatment failed to relief prutitis, surgical interventions such as biliary diversion and ileal bypass have been done. Liver transplantation should be done in patients with complications of end-stage liver disease and hepatocellular carcinoma, intractable and refractory pruritus despite medical management. 10, 11 The prognosis of nonsydromic bile duct paucity is highly variable. The patient can be separated into two groups according to their outcome: Those with progressive disease and those with a benign course. 21 Progression to cirrhosis has been reported to occur in 45% of patients while in patients with Alagille syndrome it is seen in only 14% of cases. 28 The syndromic form shows clinical and biochemical improvement whereas development of cirrhosis is common in the nonsyndromic form. 4 However, complete clinical and histopathological resolution are also described in nonsyndromic form. Berezin et al (1995) 29 reported a neonate with nonsydromic bile duct paucity in whom biochemical resolution occurred at 5 years of age, development of normal bile duct also seen in this case. Kansu et al (1998) 12 reported a 2 months old infant and a 20 days old neonate with nonsydromic bile duct paucity, clinical and biochemical resolution were seen in both patients about six months after diagnosis. The 2 nd one shows histological improvement after 18 month but 1 st one doesn't show histological improvement even after 2 years.

Follow-up
Our patient improved clinically and the biochemical resolution was seen about 1 year after diagnosis but repeat liver biopsy cannot be performed.

Final Diagnosis
Nonsyndromic bile duct paucity