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GASTROENTEROLOGY AND NUTRITION: Edited by Bradley Barth

Managing abnormal liver tests in children with inflammatory bowel disease

van Rheenen, Patrick F.

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Current Opinion in Pediatrics: October 2021 - Volume 33 - Issue 5 - p 521-529
doi: 10.1097/MOP.0000000000001045
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Abstract

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with the principal forms being Crohn's disease and ulcerative colitis. A heterogenous group of hepatobiliary manifestations can occur in IBD, ranging from a transient liver test abnormality to life-threatening liver failure [1,2▪,3]. Liver test abnormalities, which refers to levels outside the laboratory reference range, may already be present at diagnosis, or develop throughout the course of the disease. They tend to develop silently without any symptoms, or appear in combination with nonspecific symptoms (such as fatigue, nausea, anorexia, or pruritis) that go unnoticed in the patient with IBD. It is, therefore, important to perform a basic panel of liver blood tests in the treatment-naive patient with suspected IBD, and to repeat this periodically throughout the follow-up [4,5].

Children with IBD have an estimated risk of just under 10% to develop an immune-related liver disease, including primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC) or autoimmune hepatitis (AIH) [6]. Several drugs used in the treatment of IBD have been implicated in causing liver injury, with thiopurines, allopurinol, methotrexate, and anti-TNF agents being the most common but liver injury in children taking these drugs is rare. The diagnosis of drug-induced liver injury (DILI) relies largely on excluding other rare causes of liver injury (Table 1). In the following sections, we provide a step-wise approach for investigating children with IBD who have an incidental finding of abnormal liver tests. 

T1
Table 1:
Causes of abnormal liver tests in children with inflammatory bowel disease and the accompanying biochemical profile
FB1
Box 1:
no caption available

STEP 1: WHAT IS CONSIDERED A LIVER BLOOD TEST?

A basic panel of liver tests in children should include alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), and total serum bilirubin (TSB), together with tests of synthetic function, including albumin and the international normalized ratio (INR).

Alanine aminotransferase

ALT values outside the laboratory reference range suggest hepatocyte injury. ALT is more liver-specific than aspartate aminotransferase (AST), which is also present in cardiac and skeletal muscle, kidney, and brain. In children with a disproportionate elevation of AST compared with ALT, testing for creatine phosphokinase could help to detect muscle-derived AST. Establishing normal ranges for ALT in the paediatric population has been challenging because of differences in the definition of healthy controls and interlaboratory variability. A recently published article that included over 8000 healthy Chinese children and adolescents showed that the true upper limits of normal (ULN; 30 U/l for boys and 24 U/l for girls) are significantly lower than previously thought [7].

Gamma glutamyl transferase

GGT is abundant in the liver, and also present in the kidney and intestine but not in bone.

In adults, GGT is measured to confirm the hepatic origin of an alkaline phosphatase elevation [8,9]. In children, on the other hand, GGT is the better marker for injury to biliary epithelium. Alkaline phosphatase is frequently elevated because of nonhepatic causes, such as rapid growth or vitamin D deficiency. The ULN for GGT was recently established in a cohort of over 3000 healthy German children and adolescents and is 27 U/l for boys and 18 U/l for girls [10].

Total serum bilirubin

Total serum bilirubin constitutes unconjugated and conjugated fractions. Elevations of either fraction lead to a rise in the total bilirubin concentration. A rise in the unconjugated fraction, in the absence of haemolysis, is almost always Gilbert's syndrome, and is not associated with liver disease or ill health. Conjugated hyperbilirubinemia, on the other hand, is usually caused by parenchymal liver disease or obstruction in the biliary tract.

In healthy children and adolescents, the ULN for TSB is 1.0 mg/dl (17 μmol/l) irrespective of gender, and the unconjugated fraction is approximately 70% [11].

Markers of liver synthesis

Markers of hepatocellular function are albumin and PT. Albumin is exclusively synthesized by the liver and has a half-life of 3 weeks. Albumin concentrations (normal range 35–52 g/l) [12] are reduced in many clinical situations, including sepsis, systemic inflammation, malabsorption, and protein-losing enteropathy.

PT better reflects the actual synthetic function than albumin as it may already be prolonged within 24 h after significant liver injury. As the reagents to perform the PT vary between laboratories, PT is better expressed as an international normalized ratio (INR) to standardize results across different laboratories. The normal range of INR is 0.9–1.2 [13].

STEP 2: RETEST LIVER BIOCHEMISTRY (OR PROCEED WITH LIVER AETIOLOGY SCREEN)?

The first abnormal liver test should be interpreted with caution as it may not represent the true time of liver injury onset. The liver injury may already be advanced or subsiding when first identified. Grading of the liver test elevation is important to determine the timing of the next diagnostic step. The classification shown in Table 2 is based on the National Cancer Institute's grading system of Common Toxicity Criteria for Adverse Events [14]. This system is useful for signal detection and identification of changes in liver tests at the individual level, although the cut-offs are somewhat arbitrary.

T2
Table 2:
Grading of liver test elevations

Retesting liver biochemistry is necessary to evaluate whether the liver injury is progressing or regressing. In the context of a child with IBD, who has no symptoms referable to liver disease and who has mild liver test elevations, it is reasonable to retest after 1 month. Mild abnormalities that persist after 1 month require further investigation. Moderate to marked elevations, or mild elevations combined with clinical symptoms (such as fatigue, pruritis, right upper quadrant pain, anorexia, and oedema in lower extremities) should trigger immediate investigations of the aetiology [9].

STEP 3: RECOGNITION OF THE BIOCHEMICAL PATTERN

The first abnormal liver test is generally the basis for establishing the liver injury type. The ratio between ALT and GGT can help recognizing the pattern and may point towards a different set of differential diagnoses [15]. A hepatocellular profile is characterized by a disproportionate elevation of ALT compared with GGT. Common causes include viral hepatitis, autoimmune hepatitis, and nonalcoholic fatty liver disease (NAFLD). In the absence of positive clues for these disorders, an evaluation for Wilson's disease and alpha-1antitrypsin deficiency is warranted. A cholestatic profile is a disproportionate elevation of GGT compared with ALT, with or without elevated TSB. Common causes include PSC and bile stones. DILI can present with a hepatocellular, cholestatic or mixed pattern (Table 1).

STEP 4: DISCONTINUE THE POTENTIALLY IMPLICATED DRUG?

Most drugs used for treatment of IBD have the potential to cause DILI [16]. Attributing abnormal liver tests to any of these drugs requires systematic evaluation. The Roussel Uclaf Causality Assessment Method is the most widely used tool to assess the likelihood of DILI [17]. Regardless of the method used, the major diagnostic elements include time to liver test abnormality after the implicated drug has been started (latency), resolution after the drug is stopped (dechallenge), recurrence on re-exposure (rechallenge) and previous information on the drug's potential for hepatotoxicity (likelihood) [18▪▪]. Table 3 shows that each IBD drug causes its own typical liver injury, also known as ‘signature’. Differences in drug signatures are most strikingly related to differences in latency and biochemical injury pattern [19].

T3
Table 3:
Drugs used for the treatment of inflammatory bowel disease and the phenotype of liver injury they inducea

Critical thresholds of liver test elevations that should trigger immediate discontinuation of the implicated drug are not well established. The biochemical observation by the late Hyman Zimmerman that drug-induced hepatocellular jaundice is a potentially life-threatening event has evolved into one of the most important clinical measures of hepatic safety [20]. Hy's Law, as it is affectionately referred to, states that ALT greater than 3× ULN in combination with TSB greater than 2× ULN in the absence of cholestatic injury should prompt immediate drug discontinuation [20,21]. In addition to this stopping rule, discontinuation of therapy is also advised in cases of marked ALT elevation (>5× ULN) for more than 2 weeks in the absence of symptoms, or ALT greater than 3× ULN in combination with fatigue, nausea, vomiting, and right upper quadrant pain [21].

Rechallenge of a patient to a drug thought to be responsible for DILI is usually not advisable for fear of inducing an even more severe reaction. The strategy of switching to another drug in the same or related class to avoid recurrent hepatotoxicity is frequently executed in clinical practice but formal studies are lacking. Where no alternative therapies are available, re-exposure to the implicated drug will provide essential information to improve future care for the individual patient [20]. A drug rechallenge should be planned as an ‘N-of-1 clinical trial’. The SPENT checklist is recommended to ensure that relevant trial details have been considered [22▪▪].

STEP 5: LIVER AETIOLOGY SCREEN

The timing of extended differential diagnostic actions depends on the severity of liver test elevations, as shown in Table 2. In fact, only in case of mildly raised liver tests and a high index of clinical suspicion that this is because of intercurrent illness, it is reasonable to retest liver biochemistry and delay the aetiology screen (Fig. 1). Moderate-to-marked elevations, mild abnormalities that persist after 1 month, and mild abnormalities co-occurring with liver-related symptoms should trigger immediate investigations of the aetiology.

F1
FIGURE 1:
Step-wise approach for investigating children with inflammatory bowel disease and liver test elevations.

The biochemical profile of the liver test abnormalities, as depicted in Table 1, may be useful to narrow down the extended aetiology checklist (Table 4).

Table 4 - Aetiology table and accompanying diagnostic work-up for children with IBD and nonacute abnormal liver blood tests
Causes Diagnostic tests
Immune-related liver disease
 Autoimmune hepatitis (AIH) Auto-antibodies (antimitochondrial, antismooth muscle, antinuclear and antiliver-kidney-microsome)
Immunoglobulin G
Liver histology (interface hepatitis)
Primary sclerosing cholangitis (PSC) MR cholangiopancreatography
 Autoimmune sclerosing cholangitis (ASC) Auto-antibodies (antimitochondrial, antismooth muscle, antinuclear and antiliver-kidney-microsome)
Immunoglobulin G
MR cholangiopancreatography
Liver histology (interface hepatitis and bile duct involvement)
Viral hepatitis
Hepatitis A (IgM)
Hepatitis B (HBsAg, anti-HBc IgM, anti-HBs)
Hepatitis C (Anti-HCV, HCV RNA)
Hepatitis E (IgM, HEV RNA
Cytomegalovirus (IgM, CMV-DNA)
Epstein--Bar virus (IgM, EBV-DNA)
Drug-induced liver injury (DILI)
 Thiopurines Thiopurine metabolite levels [6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)]
Nonalcoholic fatty liver disease (NAFLD)
 Hepatic steatosis caused by obesity BMI, ultrasound
 Hepatic steatosis caused by starvation BMI, ultrasound
Biliary obstruction
 Bile stones Ultrasound
 Choledochal malformation Ultrasound
Vascular liver disease
 Portal or hepatic vein thrombosis Doppler-ultrasound
Other
 Celiac disease Celiac antibodies
 Wilson disease Bloodmarkers (ceruloplasmin, free copper, Coomb's test)
Urine (24 h copper excretion)
Liver biopsy (copper content)
Ophthalmologist (Kayser--Fleischer rings)
Genetic testing (ATP7B variants)
 Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin in serum
Alpha-1-antitrypsin phenotyping
Genetic testing (SERPINA1 variants)

Immune-related liver disease

Autoimmune hepatitis is a chronic inflammatory liver disease characterized by elevated transaminases, hypergammaglobulinaemia and presence of autoantibodies. The disease generally responds well to immunosuppressants [23]. ‘Watchful waiting’ without medication is, therefore, not an option. The goal is to strive for disease remission, which is defined as absence of symptoms; normalization of transaminases; and normalization of the immunoglobulin G level. The disappearance of autoantibodies is not a treatment goal in itself but is associated with long-term remission [24]. The long-term prognosis is good for those who achieve and maintain remission. In the paediatric age group, end-stage liver disease is only seen in less than 10% of the affected children, with liver transplantation being the only therapeutic option left.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease. In a prospective Canadian registry of children diagnosed with ulcerative colitis or IBD-unclassified, the risk of developing PSC before the age of 18 was around 9% [25▪]. Children with serum GGT greater than 50 U/l at the time of IBD diagnosis were more likely to develop PSC than those with normal GGT levels at baseline. Patients with the PSC--IBD combination often have a unique distribution of intestinal inflammation that can be characterized as pancolitis with rectal sparing and backwash ileitis [26]. PSC is characterized by inflammation and fibrosis of the entire bile tree, which leads to multifocal bile duct strictures and dilations. Patients with histologically confirmed bile duct disease and a normal MR cholangiopancreatography have small duct PSC (sdPSC). There is no agreement among experts whether patients with sdPSC have a more favourable prognosis than patients with large duct (ld)PSC [27]. More than half of the patients who initially presented with sdPSC eventually develop visible abnormalities on cholangiography, which suggests that sdPSC is rather a preliminary stage of ldPSC then being its own entity [28]. An estimated 25–33% of patients with childhood-onset PSC develop biliary complications, portal hypertension or chronic liver failure prior to transfer to adult-oriented care [29]. Fourteen per cent of this group require liver transplantation before the age of 18. Patients with PSC have a greater lifetime risk of developing malignancies than the general population, especially cholangiocarcinoma [odds ratio (OR) 400–1500], gallbladder carcinoma (OR 10) and colorectal carcinoma (OR 10) [30].

The overlap syndrome between AIH and PSC (aka autoimmune sclerosing cholangitis, ASC) is recognized more often in children than in adults. Perhaps the immune-mediated inflammation of the liver parenchyma gradually fades out into adulthood, and as a consequence, only the bile duct damage is still identifiable.

Viral hepatitis

Immunosuppressants, in particular, corticosteroids and anti-TNF drugs, can cause reactivation of hepatitis B. To prevent this potentially life-threatening condition, it is advised to evaluate hepatitis B serology immediately after the diagnosis of IBD [31]. Any new patient with a negative serology should receive a hepatitis B vaccination. Chronic hepatitis B carriers should start antiviral therapy irrespective of the level of viraemia, preferably at least 2 weeks prior to treatment with corticosteroids, azathioprine, or anti-TNF agents [31].

In case of an acute cytomegalovirus or Epstein--Bar virus hepatitis, it is recommended to temporarily stop immunosuppressive medication [31]. During the drug holiday, faecal calprotectin could be monitored on a monthly basis to recognize a flare at an early stage and adjust the treatment plan before symptoms appear [32].

Thiopurine-induced hepatotoxicity

Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)] should be measured in patients on thiopurines who have liver test abnormalities.

Thiopurine hypermethylation, which occurs in up to 20% of the population and leads to higher levels of 6-MMP and lower levels of 6-TGN, may resolve when the thiopurine is reduced to 25–33% of the original dose and allopurinol co-administration is initiated [33,34▪▪].

Hepatic steatosis

After an extended period of nutrition deprivation, re-introduction of calories may lead to refeeding syndrome and hepatic steatosis [35]. Although calorie restriction is considered an effective tool to induce NAFLD resolution in obese patients, chronic undernutrition is also detrimental to the liver but the underlying pathophysiology is far from being well understood [36].

Biliary obstruction

Elevated levels of GGT and conjugated bilirubin imply biliary obstruction. Cholelithiasis in Crohn's disease reflects malabsorption of bile acids with impaired enterohepatic circulation, depletion of bile salts, and consequently formation of cholesterol gallstones [37]. Choledochal cyst is a rare and benign congenital cystic dilation of the biliary tree, and is mostly diagnosed during childhood. Clinical presentation varies and most often consists of nonspecific abdominal pain. The classic triad of jaundice, abdominal pain, and right upper quadrant mass is rarely seen [38].

Vascular liver disease

During acute flares and infectious complications, the thrombotic tendency is at its greatest, which can result in splanchnic vein thrombosis [39]. Portal and hepatic vein thrombosis usually present with nonspecific symptoms (such as abdominal pain), which explains that the diagnosis is often made incidentally during abdominal imaging [40▪].

STEP 6: WHEN TO REFER TO A PAEDIATRIC HEPATOLOGY CENTER

A referral to an expert paediatric hepatologist is warranted when there is evidence of advanced liver disease. This includes portal hypertension (defined as the presence of ascites, oesophageal or gastric varices, splenomegaly, and thrombocytopaenia), advanced synthetic dysfunction (defined as a prolonged INR and hypoalbuminaemia) or the presence of bile duct irregularities on cholangiography matching the diagnosis of PSC. Persistent liver test elevation of unknown origin is another reason for referral to a paediatric hepatology centre [41].

CONCLUSION

The purpose of this review was to provide guidance for the situation that a child with IBD has an asymptomatic elevation of liver biochemistry. Prompt identification of the aetiology permits instituting specific interventions to ameliorate hepatic injury or, in the case of PSC, to establish a surveillance program for the early recognition of complications.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Keywords:

autoimmune hepatitis; autoimmune sclerosing cholangitis; drug-induced liver injury; paediatric; primary sclerosing cholangitis

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.