Evaluation of unexplained clinical features of hepatic diseases through biopsies among hospitalized children: A cross-sectional study in Lahore, Pakistan

Objectives: There are variations in therapeutic regimens of different liver diseases. The accurate diagnosis ensures prompt recovery from these diseases. The present study aimed to evaluate the underlying causes of unexplained signs and symptoms associated with liver diseases through biopsies. Methods: A retrospective study was conducted in a public child care specialty of Lahore, Pakistan. The data was collected from medical records of the patients who were index hospitalized with unexplained clinical presentation of liver disease between 1st July, 2017 and 31st December, 2017. Data were analyzed by using Statistical Packages for Social Sciences (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.), and Microsoft Excel (MS Offi ce 2010). Results: Overall, the records of 53 patients were selected for the study. Most of them were 11 to 15 years of age. The patients were presented with unexplained hepatomegaly (60.4%) and jaundice (40.7%) during index hospitalization which made them eligible for liver biopsy (LB). The fi ndings of LB revealed that the underlying causes of liver diseases in most of the cases were metabolic (33.9%) and infl ammatory disorders (22.6%). Majority of the patients were ≤4 years of age, however cryptogenic cirrhosis (39.1%) was commonly found in >10 years of age. Although most of the patients were suffering from metabolic disorders (p-value=0.07) and liver cirrhosis (p-value=0.08) but these were not statistically signifi cant. Conclusion: LB was benefi cial in evaluating the etiologies of unexplained signs and symptoms of liver diseases. It was found that glycogen storage diseases and liver cirrhosis were the most common etiologies of liver diseases among pediatric patients. But etiologies like metabolic and infl ammatory diseases were insignifi cantly associated with gender. Research Article Evaluation of unexplained clinical features of hepatic diseases through biopsies among hospitalized children: A cross-sectional study in Lahore, Pakistan Ibtasam Ahmad1, Muhammad Haris1, Amnah Javed1 and Muhammad Azhar2* 1FMH College of Medicine and Dentistry, Lahore, Pakistan 2CMH Medical and Dental College, Lahore, Pakistan *Address for Correspondence: Muhammad Azhar, MBBS, CMH Medical and Dental College, Lahore, Pakistan, Tel: 092-307-2578263; Fax: 09262-9255243; Email: dr.azharalvi003@gmail.com Submitted: 11 May 2018 Approved: 10 September 2018 Published: 11 September 2018 Copyright: © 2018 Ahmad I, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited


Introduction
Children are at high risk of developing liver diseases but the level of severity is different in each case. Such patients are presented with elevated liver function tests (LFTs) [1]. The standard technique in diagnosis of various pediatric liver diseases is histopathological examination of tissue i.e. Liver biopsy (LB) [2]. The liver injury among children is primarily the result of various metabolic, developmental and infectious disorders which may lead to mortality or life-threatening morbidities [3]. There are different treatment options available for each pediatric liver disease [4]. The percutaneous approach of LB is used to identify pediatric hepatic problems [5]. An accurate and prompt diagnosis is essential for proper disease management. For instance, if a child presents with cholestasis then an accurate diagnosis is necessary to differentiate between idiopathic neonatal hepatitis (INH) and biliary atresia (BA). This is because of the reason that INH can be treated with pharmacological therapies while early surgical methods are crucial for BA [6]. Also, LB is bene icial in differentiating among cholestasis, hepatitis, steatosis, vascular abnormalities, in iltrative disorders, infectious and metabolic diseases on the basis of histopathological features [7]. This technique is not only useful in diagnosis of primary hepatobiliary disorders, and secondary problems but also gives a clear representation of prognosis of various hepatic diseases [8,9]. The immune-mediated complications and genetic disorders can be detected through LB on the basis of Immuno histochemical (IHC) procedures [10]. The bene icial aspects of LB can be increased by overcoming several limitations like inadequate sample size and inappropriate correlation of hepatic morphology and medical history [11,12].
The present study aimed to evaluate the underlying causes of the unexplained signs and symptoms associated with liver diseases through biopsies among pediatric patients.

Study design and setting
A retrospective, cross-sectional study was conducted in a public child care specialty of Lahore, Pakistan. The selected setting was a tertiary care hospitals with liver and gastroenterology departments where health services are provided to the children (<18 years of age). The characteristics of the selected hospital were summarized in table 1.

Study population and sample size
The records of 114 patients admitted in liver and gastroenterology wards were scrutinized. The patients were included in the study if they were 1 month to 15 years of age, index hospitalized, presented with clinical features associated with liver diseases, not suffering from any drug induced liver disease and acute or chronic disorder, had unexplained abnormal results of LFTs, never underwent liver transplant and had gone through ultrasound-guided percutaneous LB using spring cut semi-automated needle. The records of 53 patients ful illed our inclusion criteria and consequently selected for the study.

Data collection
A data collection tool was used to collect the data. The questionnaire was structured and consisted on four parts: 1) general characteristics (age and gender) of the patient, 2) clinical sign and symptoms, 3) indings of other unexplained abnormal results of tests (coagulation pro ile, ultrasound, complete blood count (CBC) and LFTs), and 4) histopathological indings of LB.
Data were collected between 1 st July, 2017 and 31 st December, 2017 according to the objectives of the study. The investigational team included general medical practitioner and a trained nurse. All the investigators received the same training prior to the survey for the collection and validation of data. During the survey, one investigator illed out the investigational form and the other reviewed the data. The expert opinion of an experienced radiologist and histopathologist was also taken into account when needed.

Data analysis
The descriptive statistics (frequency and percentage) were applied on characteristics of study population, etiologies and histopathological indings. The frequencies of each etiology were calculated separately and in combination with the age group or gender. The signi icance of the data was evaluated by Fisher's exact test and Chi square test taking p<0.05 as the value of signi icance. Data were analyzed by using Statistical Packages for Social Sciences (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) and Microsoft Excel (MS Of ice 2010).

Ethical approval
Ethical approval was obtained from the Medical Research Ethics Committee (MREC) of Nishtar Medical College, Multan (Reference: 05-2017/REC, dated May 11, 2017). The permission to conduct this study was also obtained from the administrator of the healthcare setting.

Results
The medical records of 53 patients were investigated for the study. Among them, 69.8% (n=37) were male, 43.4% (n=23) were of age 11 to 15 years and 73.6% (n=39) were presented with more than 4 signs and symptoms of liver disease (Table 2).
The histopathological indings after LB revealed that metabolic 33.9% (n=18) and in lammatory 22.6% (n=12) disorders were the most common underlying causes of liver diseases. Among them, 13.2% (n=7) of the cases were found with glycogen storage disease and 9.4% (n=5) were having liver cirrhosis, respectively (Table 4).
In patient's ≤10 years of age, metabolic storage disorders were most commonly found while among >10 years of age in lammatory hepatitides was the most commonly found etiology (Table 5).
There was no signi icant difference observed among pediatric patients on the basis of gender (p-value >0.05). Although most of the patients were suffering from metabolic disorders (p-value=0.07) and liver cirrhosis (p-value=0.08) but these were not statistically signi icant (Table 6).

Discussion
The indings of current study revealed that metabolic and in lammatory disorders were the major etiologies among pediatric patients having unexplained clinical features of hepatic disease. Percutaneous LB is a safe and ef icacious method in early detection of disease and prior to initiate the therapeutic regimen.    This method evaluates extent of liver injury and gives valuable information when clinical features (e.g., hepatomegaly) and other diagnostic tests (e.g., LFTs) provide unexplained results [13]. The incidence of hepatic diseases among pediatric patients is inconsistent with age e.g., autoimmune, infective and in iltrative causes are common in pediatric patients of older age groups while BA and INH are more prevalent among younger patients. The underlying causes of hepatic disorders depend on various factors like the particular characteristics of study population, accessibility of diagnostic facilities and trends in medical practices. The present study revealed that metabolic and in lammatory disorders were among the underlying causes of liver diseases among pediatric patients. A Pakistani study revealed hemochromatosis as an etiology behind liver injury among 30% of the study population [14]. The possible explanation of it might be the referral pattern because many patients underwent bone marrow transplantation. Another study found neonatal hepatitis among 20.3% of the pediatric patients which is quite high in comparison of the present study [15]. This is due to the referral pattern as the patient load in the current study setting was very high.
The incidence of liver disorders is also dependent on geographical variations and characteristics of study population. A study conducted on 51 children in India having 2 days to 12 years of age revealed glycogen storage diseases (GSD) and metabolic disorders as the underlying causes among many sufferers of Wilson's disease [13]. The prompt diagnosis of asymptomatic patients and the genetic counselling of parents can be bene icial in decreasing prevalence of these diseases in the future [16]. Among the previously published studies, the variation in the incidence of chronic hepatitis is in the range of <10% to >90% [15,[17][18][19]. While in a Nigerian study Schistosomiasis (37.5%) was found to be the most common etiology of hepatic diseases especially in tropical regions [20].
The liver cirrhosis is attributed to end-stage hepatic disease. It is characterized as degeneration of parenchymal cells, hepatic ibrosis, nodular regeneration and portal hypertension. The incidence of liver cirrhosis is found to be more common in developing countries as compared to underdeveloped regions (e.g., Pakistan) [21]. Similarly, liver cirrhosis was found in 16.9% of the study population in the current study. The variation of 10% to 41.8% has been found in the reported incidence of cirrhosis among previously published studies [14,[22][23][24]. The onset of cirrhosis can be prevented if the accurate and prompt diagnosis is made possible of high risk population (e.g., younger age group). Irrespective of age and extent of hepatic injury, many metabolic and genetic diseases may cause harmful effects on liver. Hence, the advancement in the ield of genetics is pivotal in inding pathophysiology and new diagnostic strategies for inherited hepatic disorders [25].

Strength and Limitations
The present study shows the ef iciency of percutaneous liver biopsy technique in evaluating the unexplained sign, symptoms and abnormal results of other diagnostic tests among patients suffering from liver diseases.
The indings of present study cannot be generalized to entire country because of the small sample size and shortened length of study period.
As the data is retrospective in nature so the outcomes of LB can't be evaluated.

Conclusion
The present study concluded that histopathological indings during biopsy was bene icial in evaluating the etiologies of unexplained signs and symptoms of liver diseases. Metabolic and in lammatory disorders were the most common etiologies of liver diseases among these patients. But these etiologies showed no signi icant association with age and gender. Hence, the ef icient management of liver diseases demands the facility of prompt and accurate diagnosis for patients especially of high risk population.