A challenging case of drug-induced cholestatic liver injury: How to approach?

doi:10.21203/rs.3.rs-4831502/v1

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Case Report

A challenging case of drug-induced cholestatic liver injury: How to approach?

https://doi.org/10.21203/rs.3.rs-4831502/v1

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Background

Drug-induced liver injury (DILI) of cholestatic pattern presents a significant burden to the health care system. It is one of the most challenging liver disorders faced by hepatologists. It can have several histological features of different prognoses. The diagnosis depends on the exclusion of other related differential diagnoses. However, there is insufficient data on effective therapeutic strategies for such disorders.

Case presentation:

A female patient presenting with jaundice and pruritis that was eventually diagnosed as DILI of cholestatic pattern after exclusion of various related D.D.

Conclusion

we aimed to summarize the issues related to pathophysiology, clinical approach and management of such a challenging liver disorder.

Gastroenterology & Hepatology

drug-induced liver injury

cholestatic pattern

case report

diagnostic approach

Cholestasis of DILI is considered a challenging form that can result in serious hepatic impairment. Owing to the absence of universal diagnostic criteria, the unpredictable nature of the clinical presentation and even the prognosis of such disorder, moreover, the delay in reaching the appropriate diagnosis, which necessitates the exclusion of other differential diagnoses, may eventually lead to a potentially life-threatening course. It can be considered as a rise in alkaline phosphatase (ALP) levels beyond two times the upper limit normal (ULN) and/or ALT/ALP ratio of lower than two after excluding other related differential diagnoses. In addition, to confirm and differentiate it from other patterns by considering the R-value, to be less than two ^(1–3). Drug-induced cholestasis has been found in around 20–40% of cases among those presenting with various patterns of DILI, particularly in the elderly. Several studies observed various medications associated with cholestatic side effects; In North America and Europe, non-steroidal anti-inflammatory drugs, antibiotics, and herbal/dietary supplements are considered the most common cause of DILI, especially amoxicillin/clavulanate which represents a chief cause of DILI of cholestasis. Various histologic presentations have been identified; The common form is cholestatic hepatitis, also bland cholestasis has been reported with hormonal drugs. On the other hand, the patterns of acute onset are characterized by a favourable prognosis, on the contrary, the chronic forms of ductal injury including vanishing bile duct syndrome have the worst outcome. Lastly, abnormalities in liver tests are usually restored in most cases by cessation of the offending agent, however at a slower rate compared to other DILI patterns. All these issues will be discussed in our case report ^(3–5).

A 40-year-old housewife was seen for evaluation of abnormal liver enzymes of cholestatic pattern, jaundice, and pruritus. She was taking Augmentin for Right mastitis 2 weeks before the presentation at OPC, she was also taking multiple vitamin supplements. Viral and autoimmune hepatitis serologies were negative. Her hepatic/biliary imaging was normal. Lastly, a liver biopsy was performed, a picture suggestive of cholestatic hepatitis (Fig. 1.). The patient was managed with supportive care/symptomatic treatment, with the withdrawal of the suspected hepatotoxic drugs. Two weeks later, there was significant clinical and laboratory improvement, with complete recovery within a month.

Various hypotheses have been proposed in several studies regarding the pathophysiology associated with drug-induced cholestasis; First, the inhibition of hepatic transporters by various drugs including the organic anion apical transporting polypeptides, and the canalicular bile transporters which involves the (MDR) protein (MRP) family, and (BSEP) can eventually lead to cholestasis. Hence, mutations in genes encoding these transporters have an increased risk of cholestatic DILI. Second, there are molecular mechanisms that have been also reported, in the form of cytoskeleton destruction, and tight junction network disruption, with inhibition of ATP-dependent transporters. Lastly, alterations in the dynamics of bile canaliculi flow by inducing either constriction or dilatation can contribute to DILI cholestasis ^(6–8). As regards the triggering factors which may be associated with such a pattern of DILI; It has been found that it occurs mainly among the elderly, the exact cause is not evident yet, it may be attributed to lower hepatocellular transporters. Moreover, cholestatic liver diseases including intrahepatic cholestasis of pregnancy and primary biliary cholangitis have been reported in studies to be considered as precipitating factors, however, this issue is still questionable and has not been confirmed yet. On the other hand, genetic determinants have been considered one of the most serious precipitating factors as observed in various studies, which was found to be associated with Amoxicillin/Clavulanate (Augmentin) intake in those with (HLA) haplotypes, HLADRR1*15:01, also those with HLA-B*5701 have an increased risk of Flucloxacillin-induced DILI. In addition, the lipophilic nature of different medications and the dosage administration over 50–100 mg daily with extensive hepatic metabolism of ⩾50% were found to be strongly correlated with DILI risk ^(9–11).

The clinical presentation is variable, ranging from an asymptomatic rise in liver enzymes to symptoms of jaundice, pruritus, and fever. Unfortunately, no reliable serologic markers can diagnose DILI. Therefore, a thorough history is warranted regarding the prescription and OTC medications intake, as well as vitamins and herbal supplements, with a focus on the exact timing of their intake; A commonly used tool to assess a possible causal association between liver injury and the drug is the Roussel Uclaf assessment model (RUCAM), which can be useful in clinical practice, focusing on exact onset of hepatotoxicity, risk factors, liver tests follow-up after withdrawal, exclusion of other D.D., known hepatotoxicity side effect of the used drug. Hence, the diagnosis should be considered based on these criteria, together with the clinical sense to exclude other related D.D. Moreover, HLA genotyping may be used to support the diagnosis of DILI in specific drugs or exclude AIH, however further evaluation is needed before routine use can be validated. On the other hand, there is no clear consensus regarding liver biopsy indication. However, it can be considered in progressively worsening liver enzymes with diagnostic uncertainty and predictive value ^{(2, 3, 12)}. As regards the histological variants of DILI cholestasis, different patterns have been reported; Vanishing bile duct syndrome has been observed in those with prolonged cholestasis, commonly associated with chlorpromazine use, and secondary sclerosing cholangitis occurrence has been reported with chemotherapeutic agents. On the other hand, bland cholestasis is commonly seen in hormonal drugs such as anabolic steroids and OCPs, and together with cholestatic hepatitis are categorized as acute forms with good prognosis. Lastly, prolonged cholestasis even without inflammation can lead to ductal sclerosis and periportal fibrosis, which subsequently ends up with liver damage ^{(4, 13)}. Lastly, treatment involves immediate withdrawal of the suspected drug while avoiding rechallenge, particularly when the patient develops severe injury as evidenced by what's known as Hy’s or modified Hy’s law; UDCA may be given, although the data are insufficient; It has several merits including protection against cytotoxicity caused by toxic bile salts, choleretic effect, antioxidant as well as anti-apoptosis activity, along with glutathione levels enhancement. while the treatment of symptoms as pruritus includes cholestyramine use, antihistamines, rifampin, phenobarbital, and opioid analogues, also, Ultraviolet B phototherapy and plasmapheresis can be alternative options for those who have failed medical therapy ^{(3, 13)}.

In summary, recognition of drug-induced cholestasis is challenging as it’s the diagnosis of exclusion. It can result in acute/chronic liver injury; However, most cases resolve after drug withdrawal, with a minority progressing to advanced stages. The mainstay of management relies on earlier recognition and avoidance of the offending drug and is tailored according to each case scenario.

DILI

drug-induced liver injury

D.D.

differential diagnosis

ALP

Alkaline phosphatase

ULN

upper limit normal

MDR

multi-drug resistance

MRP

multidrug resistance-associated protein

BSEP

bile salt export pump

HLA

human leucocytic antigen

OTC

over the counter

RUCAM

Roussel Uclaf assessment model

UDCA

Ursodeoxycholic acid.

A Complete written informed consent was obtained from the patient for the publication of this study and accompanying images.

Yang K, Köck K, Sedykh A, Tropsha A, Brouwer KL (2013) An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. J Pharm Sci 102:3037–3057. 10.1002/jps.23584
Siddique A, Kowdley KV (2012) Approach to a patient with elevated serum alkaline phosphatase. Clin Liv Dis 16:199–229
Andrade RJ, Aithal GP, Björnsson ES et al (2019) EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 70:1222–1261
Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB et al (2014) Drug-Induced Liver Injury Network (DILIN). Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology 59:661–670
Fontana RJ, Hayashi PH, Barnhart H, Kleiner DE, Reddy KR, Chalasani N et al (2015) DILIN Investigators. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury. Am J Gastroenterol 110:1450–1459
Gijbels E, Vilas-Boas V, Deferm N et al (2019) Mechanisms and in vitro models of drug-induced cholestasis. Arch Toxicol 93:1169–1186
Pauli-Magnus C, Meier PJ (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44:778–787
Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R et al (2007) Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 17:47–60
Lucena MI, Molokhia M, Shen Y et al (2011) Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 141:338–347
Monshi MM, Faulkner L, Gibson A et al (2013) Human leukocyte antigen (HLA)-B*57:01- restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 57:727–739
Chen M, Borlak J, Tong W (2013) High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 58:388–396
Danan G, Teschke R (2015) RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci 17:14
Bjornsson ES, Jonasson JG (2013) Drug-induced cholestasis. Clin Liver Dis 17:191–209

The authors declare no competing interests.

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A challenging case of drug-induced cholestatic liver injury: How to approach?

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Abstract

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Background

Case presentation

Discussion

Conclusion

Abbreviations

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