Retrospective assessment of hepatic involvement in patients with inherited metabolic disorders: nine-year single-center experience

Introduction

Inherited metabolic diseases (IMDs) are single gene disorders caused by enzymatic defects in metabolic pathways in which cumulative incidence is estimated as high as 1/800 [1]. IMDs include a heterogeneous group of conditions that can affect multiple organs, including the liver. Metabolic liver diseases have been categorized the signs and symptoms as hepatomegaly; hepatocellular disease with either elevation of transaminases or frank acute liver failure; cholestasis; steatosis; fibrosis or cirrhosis; and liver tumors. Previous studies have found that among the approximately 1,000 IMD documented to date are more than 140 distinct types (such as lysosomal storage disorders, glycogen storage disorders, and mitochondrial storage disorders) that can potentially affect the liver [2]. Approximately one-third of cases presenting with hepatomegaly, acute hepatic insufficiency, cirrhosis, or cholestasis during childhood can be attributed to IMDs [3]. Studies have reported that IMDs are accountable for two-thirds of cases involving acute hepatic insufficiency in children below the age of two and around 10–15 % of cases in children below the age of 18. The mortality rate in these cases has been reported in the range of 22–65 % [2]. Another report suggests IMDs contribute to approximately 8–13 % of all liver transplant cases in childhood [2], [4].

Considering the high birth rate (1,079,842 in 2021) and the frequency of consanguineous marriages (23.4 %) in Turkey, we speculated that the prevalence of inherited metabolic disorders in patients presenting with liver involvement would be higher than in other countries [5].

In this study, we aimed to identify some clinical, laboratory, and radiological features that could serve as red flags for diagnosing IMDs in cases with hepatic involvement in childhood.

Materials and methods

Results

Discussion

A significant proportion of inherited metabolic disorders are accompanied by hepatic involvement. The findings of the present study emphasize the significance of a positive family history, physical examination findings, as well as radiological findings in predicting the diagnosis of IMDs. Although blood laboratory tests such as hyperammonemia and hyperlactatemia were detected more frequently in the IMDs group, laboratory parameters were insignificant in predicting IMDs.

Due to the autosomal recessive inheritance nature of IMDs, consanguineous marriage in parents and the presence of a sibling with a diagnosis of IMD increase the likelihood of a diagnosis of IMD [6], [7]. In a study examining patients with a diagnosis of IMD and hepatic involvement, 57.8 % were children of a consanguineous marriage, 24.5 % had a sibling diagnosed with IMD and 21 % had lost a sibling to the disease [8]. In another study involving patients who were initially followed up for hepatic insufficiency and later diagnosed with IMD, approximately 50 % had a positive family history of IMDs, and the study also reported a sensitivity of 75 % and a specificity of 66.7 % for a positive family history as a predictive factor for IMD [9]. The findings of the present study concur with existing literature, underscoring the significance of garnering a comprehensive family history, particularly in populations where consanguineous marriages are prevalent. In addition, in our study, the presence of a sibling diagnosed with IMD, and the history of the sibling’s death were determined as essential parameters in the prediction of IMDs.

Inherited metabolic disorders can manifest with various clinical symptoms. Dysmorphism can also be detected in most IMDs. Although there are many inherited metabolic diseases in which dysmorphism and liver disease occur together, the main ones include peroxisomal diseases, lysosomal diseases, mitochondrial diseases, and congenital glycosylation defects [10]. In our study, dysmorphism was more common in the IMDs group and was the most important physical examination finding in the prediction of IMDs. This parameter is so significant because the most common diagnoses in our research population are inherited metabolic disorders of complex molecules and mitochondrial disorders. Diagnoses such as mucopolysaccharidosis, GM1 gangliosidosis, and Zellweger syndrome, which are under the leading diagnostic group of inherited metabolic disorders of complex molecules, have been reported with well-defined dysmorphism in the literature [11], [12].

Gastrointestinal problems are common in IMDs. Loss of appetite and vomiting are widespread in attacks of organic acidemia and urea cycle disorders, which are acute intoxication-type hereditary metabolic diseases. Swallowing difficulties are common in lysosomal diseases and mitochondrial diseases. Gastroesophageal reflux and constipation are severe problems in IMDs accompanied by hypotonicity. However, diarrhea is less common in IMDs than other GI problems [11], [12]. In our study, diarrhea was detected more frequently in the group without a diagnosis of IMDs. In multivariate analysis, the absence of diarrhea was a strong enough result to predict IMDs.

Laboratory findings can guide clinicians in diagnosing IMDs [5]. Elevated total and conjugated bilirubin levels are common in patients with galactosemia, hereditary fructose intolerance and mitochondrial disorders [5], [12]. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found to be higher than 100 IU/L in 41 % of patients with urea cycle disorders (14), and there have been previous studies reporting elevated ALT, bilirubin, INR and ammonia levels to be commonly observed in IMDs that result in acute hepatic insufficiency [13], [14]. In the present study, acute hepatic insufficiency was identified in 14.6 % of the patients. No significant difference was observed between Group 1 and Group 2 in terms of hepatic insufficiency. Therefore, the two groups had no significant difference in related blood parameters. Elevated serum lactate can be detected in mitochondrial diseases, glycogen storage diseases, and gluconeogenesis defects [15]. In our study, lactate was found to be higher in Group 1 than in Group 2. This is because mitochondrial diseases are the second largest group in our patient population. Hyperammonemia can be seen in any case of primary liver failure. However, hyperammonemia may be an important finding in IMDs, including urea cycle disorders, organic acidemias, fatty acid oxidation defects, and some mitochondrial diseases [16]. Although hyperammonemia was found to be higher in the group diagnosed with IMDs in our study, no significant results were obtained in the prediction of IMDs. Hyperammonemia can be observed in many other conditions, such as infection affecting the liver, anatomical problems, primary diseases of the liver, and toxicity, and that it is nonspecific. It is unsurprising that the group with more frequent abnormalities in urine reducing substance, carnitine/acylcarnitine profile, and urine organic acids, which are the first tests to indicate IMDs in the presence of pathological results, is Group 1.

Abdominal imaging findings of IMDs are valuable in specificating and suspecting diagnoses. An assessment of the echogenicity of the liver can also guide the diagnostic process. In patients with galactosemia, no increase in liver echogenicity is typically observed, while increased hepatic echogenicity has been reported in patients with glycogen storage disorders and hereditary fructose intolerance [17], [18]. An earlier study reported a change in parenchymal echogenicity in 41 % of the patients followed up for glycogen storage disorder type 1, 25 % of patients with glycogen storage disorder type 3, and 11 % of patients with glycogen storage disorder types 6 and 9 [19]. Hepatomegaly also can be seen in lysosomal diseases, glycogen storage diseases, gluconeogenesis defects, mitochondrial diseases, and congenital glycosylation defects [6], [20]. In our study, the most significant finding on abdominal ultrasonography was hepatomegaly. The fact that the most common diagnosis is inherited metabolic disorders of complex molecules may explain this situation. However, it is surprising that the splenomegaly finding expected in lysosomal storage diseases shows no difference between the two groups. The presence of hepatic nodules and cirrhosis are other findings that can be useful in a differential diagnosis. A study involving 38 patients diagnosed with tyrosinemia type 1 reported that 87 % of the sample were identified with a granular appearance in the liver, half of the patients had multiple hypoechoic nodules, 53 % of patients had hyperechoic nodules and cirrhosis was detected in 34 % of the cases [21]. A review of literature revealed cirrhosis to be the most frequently observed condition in conjunction with aminoacidopathies and carbohydrate metabolism disorders, alongside other IMDs [22]. When all the parameters, which were not significant when looked at individually, were gathered under one roof, the presence of any pathological finding on abdominal ultrasonography was seen more frequently in Group 1 than in Group 2, and this parameter appeared to be the only significant radiological parameter in the prediction of IMDs. Another issue that should be emphasized is that while hepatomegaly is detected in 42.7 % of patients on physical examination, this rate is 53.3 % on ultrasound. In other words, evaluating the organomegaly of a patient being examined for IMDs only through physical examination may cause the finding to be missed in some patients. For this reason, it is essential to perform radiological imaging and interpret it together with other clinical findings.

We present here a comprehensive analysis of the 9-year experience of our tertiary healthcare facility, which is dedicated to the diagnosis, treatment and follow-up of patients with IMDs. The present study revealed significant hepatic involvement in 33 % of the pediatric patients monitored in the Department of Pediatric Metabolism. The present study assessed physical examination findings, laboratory test results, and radiological imaging studies to evaluate hepatic involvement in different subgroups of patients with IMDs, and these comprehensive evaluations presented valuable diagnostic data for the distinction of various diagnostic subgroups. One significant limitation of the this study is related to the inaccessibility of various laboratory parameters due to missing data in the records and the retrospective nature of the study.

The assessment of patients presenting with a suspected IMD for hepatic involvement at the time of the initial presentation and during follow-up can play a crucial role in guiding the diagnostic process. The accurate diagnosis and the subsequent prompt initiation of treatment are vital for the reduction of morbidity and mortality, especially in patients with treatable IMDs who present with acute hepatic insufficiency. In young children presenting with prominent hepatic involvement, it is important to consider the possibility of a yet-to-be-diagnosed IMD. The present study clarifies the need for further multicenter, prospective and long-term studies.