Title: Presence of fatty liver disease leads to unusual rise of liver enzymes in patients with common bile duct colic.

doi:10.21203/rs.3.rs-2564037/v1

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Research Article

Title: Presence of fatty liver disease leads to unusual rise of liver enzymes in patients with common bile duct colic.

https://doi.org/10.21203/rs.3.rs-2564037/v1

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Background

Acute common bile duct (CBD) obstruction due to calculi leads to intra ductal hypertension and transient hepato-cellular injury. Fatty liver disease (FLD) has adverse impact on hepatic microcirculation. This study compares liver enzymes, inflammatory markers and bilirubin levels in patients with and without fatty liver disease (FLD) presenting with common bile duct (CBD) obstruction.

Methods

CBD colic was diagnosed based on clinical, radiological and biochemical criterion. Patients were divided in to two groups as presence or absence of FLD based on ultra sound scan and the macroscopic appearance of liver during surgery. AST, ALT, bilirubin level and inflammatory markers were prospectively assessed and the peak levels were compared between the two groups.

Results

Out of 42 individuals, there were 22 (52.3%) patients with FLD. Median body mass index was 26.9 (24.1 – 30.8) in fatty liver group compared to 25.7 (23.5 – 26.2) in others. Individuals with FLD showed high AST (558.5 vs. 247.0, p = 0.005), ALT (467 vs. 228.5, p = 0.005) and bilirubin (3.8 vs. 2.2, p = 0.015) levels compared to those without FLD. According to multiple linear regression models, high AST and ALT levels showed significant associations with FLD after adjusting for age, gender, BMI, amylase and CRP levels. The median enzyme level at two weeks did not show a difference.

Conclusions

Presence of FLD causes unusual rise of AST and ALT levels in patients with CBD stones. This rise is transient.

Gallstones

Fatty Liver

liver enzymes

Non-alcoholic Fatty Liver Disease

Common bile duct (CBD) stones are seen in 5–10% of the patients with symptomatic gallstone disease [1]. These are typically associated with mild to moderate elevation of liver enzymes including aspartate amino transferase (AST), alanine amino transferase (ALT) and bilirubin [2]. During the clinical practice we have observed an unusually high transaminitis and a hyper bilirubinemia in selected patients with CBD stones. These patients recovered rapidly after CBD clearance. Several authors have previously documented similar observations [3, 4]. This unusual rise can lead to confusions in diagnosis and clinical management eventually resulting in unnecessary investigations, hospital stay and follow up.

Fatty liver disease (FLD) is becoming a global health concern [5]. Particularly, Sri Lanka has one of the highest incidences of FLD [6]. We postulated that Non-alcoholic fatty liver disease (NAFLD) as the potential cause for the observed change of liver enzymes and planned this prospective study to compare the difference of liver enzymes in patients with and without FLD and having CBD stones.

Inclusion criteria

This prospective study was carried out over a period of 18 months. Appropriate consent was obtained from all research participants. Forty-two patients presenting with biliary colic were included in the study. Primary inclusion criterion was clear evidence of presence of CBD stones. CBD stones were diagnosed when all three criterions were fulfilled. These were, clinical evidence of having typical epigastric pain, imaging evidence of presence of common bile duct stone or dilatation [in ultra sound scan (USS), computerized tomography (CT) scan or magnetic resonance cholangiogram] and biochemical evidence of raised bilirubin or alkaline phosphatase level. Patients presenting after 48 hours of symptoms, patients with cirrhosis and other known chronic liver cell disease (excluding FLD) and patients who had sepsis were excluded from the study.

Diagnosis of FLD

Diagnosis of FLD was made according to ultra sound scan and intra operative appearance. A single experienced consultant radiologist performed USS in all patients. Ultrasonic diagnosis and grading of FLD was based on previously defined criteria. During the laparoscopic cholecystectomy macroscopic appearance of rounded edges and yellow color surface was considered as features of FLD. The group was divided in to two, as having fatty liver or not based on above criterion.

Biochemical assessment

Upon admission of the patient, the basic demographic data were documented using an interviewer-administered questionnaire. Patient underwent assessment of liver enzymes (AST, ALT, Gama glutamyl transferase and bilirubin levels) C reactive protein and serum amylase on initial contact. Interval of repeating investigations were not standardized and done according to clinical status. The peak value was taken for the analysis. Patients with evidence of cholangitis or cholecystitis were treated with antibiotics. Liver biochemistry was repeated at first follow-up visit at two weeks.

Management of common bile duct stones.

Endoscopic retrograde cholangio pancreatogram (ERCP) was offered based on the clinical status with therapeutic intention. Subsequently, patients underwent laparoscopic cholecystectomy during the same admission or after six weeks interval.

Data analysis

Between the two groups peak serum aspartate amino transferase (AST), alanine aminotransferase (ALT), bilirubin levels, and alkaline phosphatase levels, C reactive protein (CRP) levels and Serum amylase levels were compared. Distributions of study variables (i.e. AST, ALT and Bilirubin) were presented with medians and interquartile ranges. Normality of study variables was assessed using Shapiro-Wilk test of normality. Group comparisons between the fatty liver groups (i.e. presence and absence) were done using Student’s t test and Wilcoxon Rank Sum Test based on the presence and absence of normal distribution in the study variables, respectively. Multiple linear regression models were used to assess the effect of fatty liver on study variables after

adjusting for age, BMI (Body Mass Index), amylase and CRP levels. P value of 0.05 was taken as significant. Statistical analysis was performed with R programming language version 3.5.1.

Out of 42 individuals, 31 (73.8%) were females. Median (interquartile range -IQR) age of the study group was 46.0 (34.5–55.7). There were 22 (52.3%) patients with FLD. Median (IQR) body mass index was 26.9 (24.1–30.8) in fatty group compared to 25.7 (23.5–26.2) in others.

Individuals with FLD showed high AST, ALT and bilirubin levels compared to those without FLD (Table 1).

Table 1

Comparison of study variables between groups
	Fatty liver absent Median (Interquartile range) (units/L)	Fatty liver present Median (Interquartile range) (units/L)	P value
AST	247.0 (94.5–427.5)	558.5 (341.0–802.0)	0.005^*
ALT	228.5 (102.2–393.0)	467.0 (284.8–697.5)	0.005^**
Bilirubin	2.2 (1.9–3.2)	3.8 (2.5–4.7)	0.015^***

1 *,** -Wilcoxon-Rank Sum test ***- Student’s t test

Alkaline phosphatase levels, C reactive protein levels and Serum amylase levels were not different. Distribution of AST, ALT and bilirubin among the patients with and without FLD is shown in Fig. 1.

According to the fitted multiple linear regression models, high AST and ALT levels showed significant associations with presence of fatty liver after adjusting for age, gender, BMI, amylase and CRP levels. None of the other variables showed significant associations with AST or ALT. High bilirubin showed significant association with rising amylase levels but not with fatty liver (Table 2).

Table 2

Fitted linear regression models for AST, ALT and Bilirubin.
Dependent variable	Independent variable	Estimate (units/L)	Std. err (units/L)	t value	P
AST	Intercept	280.466	248.890	1.127	0.268
	Fatty liver	249.351	101.065	2.467	0.019
	Age	2.9247	3.296	0.887	0.382
	Gender	-43.925	102.088	-0.430	0.670
	BMI	-1.220	2.570	-0.475	0.638
	Amylase	0.162	0.097	1.662	0.107
	CRP	-0.772	0.640	-1.206	0.237
ALT	Intercept	354.630	218.848	1.620	0.115
	Fatty liver	210.346	88.866	2.367	0.024
	Age	0.843	2.898	0.291	0.773
	Gender	-68.031	89.766	-0.758	0.454
	BMI	0.155	2.260	0.069	0.946
	Amylase	0.114	0.086	1.330	0.193
	CRP	-0.580	0.564	-1.030	0.311
Bilirubin	Intercept	2.849	1.233	2.310	0.027
	Fatty liver	0.728	0.501	1.454	0.156
	Age	0.0113	0.016	0.694	0.493
	Gender	-0.392	0.506	-0.775	0.444
	BMI	-0.007	0.013	-0.584	0.563
	Amylase	0.002	0.001	3.147	0.004
	CRP	-0.002	0.003	-0.607	0.548

The median AST level at two weeks was 34 U/L (23–77) and 29 (26–89) U/L showing no difference in two groups (p = 0.11). The median ALT level at two weeks was 39 (32–72) U/L in fatty and 33 (26–67) U/L and non-fatty without a significant difference.

Results show that that there was a significant rise of AST and ALT levels with CBD colic in patients with fatty liver disease compared to normal livers. Median enzyme levels were almost doubled in patients with fatty liver. The enzyme levels at two weeks did not show a difference in two groups.

Biliary colic is known to cause a significant transaminitis [2]. Gallstones obstructing the common bile duct lead to intra ductal hypertension. Gamma glutamyl transferase and alkaline phosphatase are classically considered to rise in obstructive causes [7, 8]. Rise in AST and ALT is probably a result of high biliary pressures leading to impairment of bile secretion and retention with accompanying hepatocyte apoptosis and necrosis leading to leakage of enzymes [1]. This rise of enzymes is usually 2–3 fold.

During our clinical practice we noticed that there were patients with CBD colic who showed an unusual rise in liver enzymes. Most of these patients USS report concluded of having background FLD. Tetangco reported four patients of CBD colic with unusually high transaminitis. They had rapid and complete recovery after CBD clearance [9]. In a similar much larger study 6% (n = 45) of the patients had a transaminitis over 1000 units / L. Group reported that female age, normal size bile duct and previous cholecystectomy as possible predictors [4]. Similar observations of high transaminitis were made by other investigators as well. None of these previous publications evaluated FLD as a potential contributing factor. Previous authors described this observation as an unknown entity [10, 3, 11].

NAFLD has become a global epidemic. It is the leading cause of chronic liver cell disease [12]. In developing countries like Sri Lanka, due to rapid change in the diet and lifestyle influenced by genetics, NAFLD has become a major health concern [13]. In these patients, liver cell injury is thought to trigger by genetic predisposition, gut micro biogenesis or bile salt accumulation. Relative oxidative stress and parenchymal inflammation is thought to lead to subsequent hepatocyte injury [14]. One third of NAFLD patients have associated rise in ALT and AST levels. Though there is no consensus on the level, a broad values between 26–66 U/L is suggested by many studies [15, 16]. In the presence of common bile duct obstruction it is likely that already compromised parenchyma with FLD is further damaged by the additional biliary hypertension and stasis.

Importantly it was reported that this group of patients required additional imaging and investigations. Twenty-eight percent of these patients had additional imaging. Forty-five percent had extra serological workup and additional hospital stay [4]. Eventually these patients liver enzymes reverted back to normal. In our patients also assessment at two weeks did not show a difference. Hence in the presence of FLD unusual rise of liver enzymes is not unusual and this is reversible.

In our study, we did not do a serial assessment of liver enzymes as the patients presented to us at different time points since the onset of colic. Our sample size was relatively small with 42 cases. This was partly due to strict selection criterion.

In conclusion presence of FLD causes unusual rise of AST and ALT levels in patients with CBD stones. This is completely reversible at 2 weeks. Performing extensive investigations within this period seems unnecessary.

CBD- common bile duct
FLD- Fatty liver disease
AST- Aspartate amino transferase
ALT- Alanine amino transferase
CRP- C-reactive protein
BMI- Body mass index
NAFLD- Non alcoholic fatty liver disease
USS- Ultrasound scan
CT- Computed Tomography
ERCP- Endoscopic retrograde cholangiopancreatography
IQR- Interquartile range

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Informed consent was taken from all subjects or their legal guardians. All experiments were performed in accordance with relevant guidelines and regulations (such as the Declaration of Helsinki). This study was approved by the Ethics Committee of the Faculty of Medicine, University of Kelaniya, Sri Lanka.

Consent for publication - Not applicable
Availability of data and materials - The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
Competing interests - none
Funding - Not applicable
Authors' contributions

Conception and design: Siriwardana Rohan Chaminda
Administrative support: Chanaka Ekanayaka, Thilakarathne MSB
Provision of study materials or patients: Paranaheva Lakmali
Collection and assembly of data: Ediriweera Deleepa Senajith
Data analysis and interpretation: Ediriweera Deleepa Senajith
Manuscript writing: All authors
Final approval of manuscript: All authors

Acknowledgements - Not applicable

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Title: Presence of fatty liver disease leads to unusual rise of liver enzymes in patients with common bile duct colic.

Status:

Version 1

Abstract

Figures

Background

Methods

Inclusion criteria

Diagnosis of FLD

Biochemical assessment

Data analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1