This observational study was carried out at the Paediatric Hepatology and Gastroenterology Units of Cairo University Children's Hospital, Cairo, Egypt, over a 6-mo-period (between June 2013 and December 2013). Forty-eight children with an established diagnosis of IBD were included in the study. The diagnosis of IBD was based upon clinical, laboratory, endoscopic and histopathological features.

The study protocol was approved by the Research Ethics Committee of the Paediatrics Department, Faculty of Medicine, Cairo University, Egypt. The research was conducted in accordance to the Helsinki Declaration. All patients were enrolled in the study after an informed consent was obtained from their parents/guardians.

All patients < 18 years of age of both sexes with an established diagnosis of IBD were included. The clinical and laboratory data were retrospectively retrieved from 44 patients’ files, and 4 newly diagnosed patients were prospectively enrolled during the study period. Patients were excluded if any crucial data was missing in their files.

Detailed history taking was carried out, including: (1) Age at the time of presentation; (2) Age at the time of IBD diagnosis; (3) Meticulous family history of IBD in other siblings or parents; (4) History of comorbid conditions other than IBD; (5) Symptoms suggestive of HB manifestations [jaundice, abdominal distension, pruritus, gastrointestinal (GI) bleeding]; (6) Age at the start of treatment and age at the time of onset of HB manifestations; and (7) Medication history [aminosalicylate, azathioprine, corticosteroids, methotrexate, infliximab and/or drugs for associated diseases such as colchicine for Familial Mediterranean fever (FMF)].

The patients’ anthropometric measurements (weight and height) were plotted on Egyptian growth curves (Standard Egyptian Growth, 2008)[14], and the corresponding Z-scores were obtained.

All patients were subjected to meticulous clinical examination focusing on the signs of hepatic complications (jaundice, palmar erythema, spider nevi, lower limb oedema, and abdominal examination for organomegaly and ascites).

All patients were evaluated by liver chemistry, including the following: (1) Total and direct serum bilirubin; (2) Alanine aminotransferase (ALT); (3) Aspartate aminotransferase (AST); (4) Alkaline phosphatase (ALP); (5) Gamma glutamyl transpeptidase (GGT); (6) Serum albumin; and (7) Prothrombin time (PT) and concentration and international normalized ratio.

Abdominal ultrasound was performed in all patients using a greyscale device (FUKUDA-DENSHI; FF Sonic-400 Tokyo, Japan) to assess the liver size, texture, and echogenicity, dilatation of the intra-hepatic biliary radicals, gallbladder size, content and wall thickness, focal lesions, hepatic vasculature, and the presence of ascites. Splenic size was also assessed.

Serum immunoglobulin G (IgG), antinuclear antibody (ANA), smooth muscle antibody (SMA), anti-liver kidney microsomal 1, anti-neutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae antibody testing was performed in selected cases suspected of having autoimmune hepatitis (AIH) and/or primary sclerosing cholangitis (PSC). Viral markers were assessed for patients suspected of having hepatitis B virus (HBV) or hepatitis C virus (HCV) infections.

Diagnostic and follow-up upper and lower GI endoscopic examinations were performed for all patients to confirm the diagnosis of IBD and to monitor the treatment response. The gross endoscopic appearance as well as the histopathological examination of mucosal biopsy specimens withdrawn at the time of GI endoscopy was the cornerstone for IBD diagnosis in our patients. Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) was performed in cases suspected of having PSC or overlap syndrome (AIH and PSC).

The data were tabulated and statistically analysed. Qualitative data were expressed as numbers and percentages, and were compared by the chi-square test or Fisher's exact test when appropriate. Quantitative data were expressed as the mean ± SD, median and interquartile range, minimum and maximum, and were compared by the Student’s t-test or the Mann-Whitney U test. In all tests, a probability (P) value was considered significant if less than 0.05.

Based on the classic clinical findings, gross endoscopic appearance and microscopic histopathological features, we recruited 48 patients with IBD during this relatively short period from a large tertiary referral centre for all of Egypt. Twenty-nine (60.4%) patients were male; 24 (50%) had UC, 11 (22.9%) had CD, and 13 had IBD-U. The mean age at the time of presentation was 8.14 ± 4.02 years, while the mean age at the time of study enrolment was 10.16 ± 4.19 years.

The most common clinical presentation was recurrent abdominal pain in 47 patients (97.9%), followed by chronic diarrhoea with tenesmus and rectal bleeding (Table 1). None of our patients presented with ulcerating perianal disease. There was a positive family history of IBD in 9 patients (18.75%), representing other affected siblings. Twelve patients (25%) had other associated diseases: 11 had FMF, and 1 patient had systemic lupus erythematosus (SLE).

Regarding the symptoms suggestive of HB manifestations of IBD, 2 patients had jaundice associated with dark-coloured urine. Eighteen patients (37.5%) presented with abdominal distension, which may also have been attributed to IBD itself. One of our patients presented with pruritus, and none had manifestations of portal hypertension. Upper GI endoscopy confirmed the absence of oesophageal varices. The mean age at the onset of hepatic complications in our patients diagnosed with IBD was 12.10 ± 3.51 years.

The median (range) weight and height by Z score were -1.0 (-5.0-3.0) and -1.2 (-6.6-1.7), respectively. Sixteen patients (33.4%) were on the 3^rd percentile or lower in weight, while 13 (27.1%) had short stature.

Abdominal examination showed that 16 patients (33.3%) had abdominal distension, 6 of whom (12.5%) had only hepatomegaly, with mean ± SD size of the liver in the right midclavicular line and midline of 4.83 ± 1.72 and 5.33 ± 2.94 cm, respectively. Two patients (4.2%) had splenomegaly and none had ascites.

With regard to administered medications for the treatment of IBD at the time of study enrolment: (1) Thirty-five patients (72.9%) were receiving mesalamine; (2) Twelve (25%) received salazopyrine; (3) Twenty-six patients (54.2%) were receiving corticosteroids; (4) Twenty patients (41.7%) received azathioprine; (5) Four patients (8.35%) received methotrexate; and (6) Only one patient received infliximab.

In addition, 11 patients (22.9%) who were diagnosed with FMF received colchicine.

Liver chemistry revealed that 3 patients (6.25%) had elevated liver enzymes, 2 patients (4.2%) had direct hyperbilirubinaemia, and 10 patients (20.8%) had hypoalbuminaemia that may also have been attributed to IBD, as none of the patients had coagulopathy (Table 2). Abdominal ultrasonography revealed that 10 patients (22.7%) had a bright echogenic liver (Figure 1), which may suggest fatty infiltration. Two patients (4.5%) had dilated intrahepatic biliary radicals. Two patients (4.5%) had thickened gallbladder walls, while 4 patients (9.1%) had splenomegaly. None had ascites.

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Figure 1 Abdominal ultrasound of a patient with inflammatory bowel disease showing increased liver echogenicity.

Therefore, the overall frequency of HB manifestations in this study was 27.1% (13 patients). Of these 13 patients, 2 had cholestatic jaundice, elevated transaminases and elevated ALP and GGT, and both were confirmed to have PSC by MRCP (Figure 2) and percutaneous liver biopsy (Figure 3). One of these 2 patients had elevated serum IgG levels, positive ANA and positive SMA, and was diagnosed with PSC/AIH overlap syndrome. Another patient with elevated liver enzymes was diagnosed with SLE and had a concomitant HCV infection. He was recently treated for HCV with oral direct acting antivirals (sofosbuvir/ledipasvir) and achieved sustained virological response followed by normalization of his liver functions. Ten patients had echogenic liver by ultrasound: 3 of them were receiving steroids, 3 patients had malnutrition with poor growth, and 4 patients had both risk factors.

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Figure 2 Magnetic resonance cholangiopancreatography of a patient with inflammatory bowel disease and primary sclerosing cholangitis showing dilatation of the intra- and extra-hepatic biliary tree with multiple strictures (arrows).

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Figure 3 Histopathological findings of a liver biopsy specimen from a patient with inflammatory bowel disease showing the features of primary sclerosing cholangitis. A: Diffuse bile ductular proliferation "Onion skin" fibrosis around affected ducts, concentric collagen fibre deposition; B: Same findings by Masson's trichrome stain which imparts a blue color to type 1 collagen against a red background of hepatocytes; C: Aggression of inflammatory cells towards the biliary epithelium and the portal area is markedly expanded with lymphoplasmacytic inflammatory cellular infiltrate (all photos H&E, Original magnification × 400).

Regarding the 6 patients (12.5%) who had hepatomegaly, two had PSC, 3 had fatty liver, and the remaining patient had HCV infection.

Screening for HB manifestations of IBD is mandatory, as many of these complications could be initially asymptomatic. HBV and HCV should not be overlooked and should be screened for in patients with IBD, as these patients have multiple risk factors for HCV acquisition including endoscopies, blood transfusion and recurrent hospitalizations. Therefore, it is necessary to implement mass screening for HCV in these high-risk groups especially in an endemic country such as Egypt. Health education for parents and patients should be carried out to increase knowledge on the nature of the disease and treatment options. Genetic research on the diagnosis of very early-onset IBD and family screening should be emphasized.

Inflammatory bowel disease (IBD) is a systemic illness that can present with multiple extra-intestinal manifestations. Hepatobiliary (HB) disorders associated with IBD are not uncommon. From an aetiopathogenic perspective, there are multiple layers of evidence suggesting that these disorders are not isolated entities and may share mechanistic pathways. All of these disorders usually manifest with abnormal hepatic biochemical tests. Of the HB complications of IBD, primary sclerosing cholangitis (PSC) carries the most significant clinical implications and remains a highly challenging disease to manage.

Recently, the reported incidence of IBD in paediatrics has increased dramatically. The HB manifestations of IBD have been well studied in children in the industrialized and developed countries. On the other hand, there is a paucity of studies on IBD in low- and middle-income countries (LMICs) such as Egypt.

The main objective was to determine the frequency of HB manifestations in Egyptian paediatric patients with IBDs, to achieve an early diagnosis in order to obtain prompt treatment. Moreover, the risk factors associated with the occurrence of HB complications in patients with IBD were determined.

This study was carried out at the Paediatric Hepatology and Gastroenterology Units of Cairo University Children's Hospital over a 6-mo-period. Patients younger than 18 years of age of both sexes were included. The available data were retrieved from the files of patients diagnosed with IBD as well as newly diagnosed patients. The collected data included a full medical history such as name, age, sex, residence, meticulous family history of IBD and other associated autoimmune illnesses; history of jaundice; abdominal distention; pruritus; bleeding; a history of blood transfusion; and a detailed medication history. A meticulous clinical examination was performed, including the assessment of anthropometric measures and a general and detailed abdominal examination. Laboratory investigations, such as CBC, complete liver functions (ALT, AST, total and direct bilirubin, ALP, GGT, albumin and PT) were performed in all patients. In addition, serum immunoglobulin G, antinuclear antibody, smooth muscle antibody, anti-liver kidney microsomal 1, anti-neutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae antibody were performed for selected cases suspected of having autoimmune hepatitis (AIH) and/or PSC. Viral markers were assessed in patients suspected of having hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Abdominal ultrasound was performed in all patients. Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography was performed for cases suspected of having PSC. Percutaneous liver biopsy was performed when indicated.

We recruited 48 paediatric patients with IBD. Twenty-nine (60.4%) patients were male. Twenty-four (50%) had UC, 11 (22.9%) had CD, and 13 patients had IBD-U. The median (range) of the weight and height by Z score were -1.0 (-5.0-3.0) and -1.2 (-6.6-1.7), respectively. Sixteen patients (33.4%) were on the 3^rd percentile or lower for weight, while 13 (27.1%) had short stature. The most common clinical presentation was recurrent abdominal pain, which was present in 47 patients (97.9%), followed by chronic diarrhoea with tenesmus and rectal bleeding. None of our patients presented with ulcerating perianal disease. There was a positive family history of IBD in 9 patients (18.75%). Twelve patients (25%) had other associated diseases: 11 had FMF, and one patient had systemic lupus erythematosus. Therefore, the overall frequency of HB disorders in this study was 27.1% (13 patients). Two patients had cholestatic jaundice, one of them was diagnosed with PSC, and the other patient had PSC/AIH overlap syndrome. Three (6.3%) patients had elevated liver enzymes. Ten (20.8%) patients had echogenic liver suggesting fatty changes.

HB manifestations in paediatric patients with IBD in LMICs are more common than those in the industrialized countries. Investment in research for confounding factors in LMICs is cost-effective, including family genetic studies that can offer an early diagnosis of IBDs in general and specifically for very early-onset IBD. The importance of awareness of the implications and causes of abnormal hepatic biochemical tests in IBD patients is due to the wide range of possible complications and risks associated with the medications used to treat and manage them. Hepatic biochemical tests should be routinely performed in these patients. When abnormalities are detected, a prompt step by step diagnostic approach should be followed until an aetiology is reached. The frequency of HB manifestations in our patients was not low and may be affected by the type of treatment modality and malnutrition. The highest proportion was found in those suffering from an echogenic liver by abdominal ultrasound, and many of these patients received corticosteroids.

Screening for HB manifestations of IBD is mandatory, as many of these complications may be initially asymptomatic. Complete liver function tests and abdominal ultrasound should be performed on a regular basis. A high index of suspicion of PSC should be raised in patients who present with an unexplained cholestatic jaundice or elevated ALP levels. An echogenic liver detected by abdominal ultrasound requires thorough assessment of the patient’s growth and medication history. Liver biopsy may be needed in selected cases for the definitive diagnosis of NAFLD. Drugs used to treat IBD should be administered cautiously, as a majority of them can potentially cause hepatotoxicity. HBV and HCV should be screened for in patients with IBD especially in endemic areas such as Egypt. Patients with IBD have multiple risk factors for HCV and HBV acquisition, including repeated endoscopies, transfusion of blood products and recurrent hospitalizations. Genetic research should include the diagnosis of very early-onset IBD and screening of similar cases in families.