An Unusual Case of Dietary-Induced Liver Injury during Pregnancy: A Case Report of Probable Liver Injury due to High-Dose Turmeric Intake and Literature Review

Turmeric-induced liver injury is a controversial topic, and turmeric is safe to consume during pregnancy in small amounts; however, it might be an uncommon cause of liver injury if consumed in large amounts. We hereby report a case of a pregnant patient who demonstrated atypical signs and symptoms of dietary-induced liver injury during pregnancy. She presented with itching at 23 weeks 4 days of pregnancy and had deranged liver function tests and was diagnosed with dietary-induced liver injury. The patient was managed with a strict diet during the pregnancy which resulted in a significant improvement in the clinical and biochemical findings during the pregnancy.


Background
Turmeric is an herb that people have used for thousands of years for both favour and medicinal properties.Turmeric root has anti-infammatory efects and is rich in antioxidants.Studies on pregnant rodents, as well as in vitro studies, emphasized the numerous biological activities of curcumin [1].Curcumin appeared to ameliorate diabetes in a GDM mouse model, as well as a rat model, and was found to be neuroprotective against environmental toxic agents [1], and researchers have not carried out studies on the safety of turmeric consumption during pregnancy in humans [2].

Case Presentation
A pregnant patient, Gravida 3, Para 1, presented at 23 weeks and 4 days of gestation with a history of one week of generalized itching all over her body.Te patient had a previous uncomplicated pregnancy and denied any personal or family history of liver disease.She also denied any history of headache, blurred vision, jaundice, change in urine or stool colour, chills, rigors, nausea, vomiting, or abdominal pain.Te patient did not consume alcohol during pregnancy or use medication; however, she consumed turmeric 3-4 times per day (5-10 grams) for the frst time due to sore throat.Laboratory investigations revealed elevated liver enzymes: alanine aminotransferase 734 U/L, alkaline phosphatase 175 U/L, gamma-glutamyl transferase 40 U/L, and high nonfasting serum bile acid levels 73 μmol/L.She was admitted to the hospital for further workup and management.Viral serologies including EBV, toxoplasmosis, herpes simplex virus, cytomegalovirus, HIV, parvovirus, and hepatitis profle (A, B, C, D, and E) were negative, blood count and coagulation profle were within normal range, preeclampsia workup was negative, and autoimmune antibodies for liver and kidney diseases were negative.Imaging modalities including abdominal ultrasound and MRCP could not identify any signifcant abnormality that might be related to the clinical fndings (all the investigations are summarized in Table 1).Ursodeoxycholic acid 250 mg QID commenced as atypical presentation of early-onset intrahepatic cholestasis of pregnancy could not be fully excluded.However, this was unlikely due to early gestational age and signifcantly high transaminase levels.Te patient was also asked to commence a restricted diet-Mediterranean diet, no  Case Reports in Hepatology spices/turmeric (and no any kind of food that might be related to liver injury)-as there was a presumption that the clinical presentation might be related to diet-induced liver injury.She was discharged home at 24 weeks and 6 days of gestation.Te patient continued to have weekly outpatient follow-up in our maternal-fetal medicine and gastroenterology clinics to monitor her symptoms and liver function tests and for fetal growth surveillance.Over the course of the pregnancy, her symptoms resolved and her liver enzymes including bile acid levels stabilised and reached almost normal levels around 32 weeks of gestation, and this made the presumed diagnosis of diet-induced liver injury probable.At 35 weeks of pregnancy, the patient presented with hands and palms itching, she stated she was following the medical advice regarding strict Mediterranean diet and has not been having turmeric or any other spices as advised, the liver function tests started to be deranged again, and the serum bile acids increased, which raised the probability of a new diagnosis of intrahepatic cholestasis of pregnancy which is not related to her previous medical history as shown in Table 2. Given her fasting serum bile acids were elevated to 64 μmol/L despite being on ursodeoxycholic acid and restricted diet, the patient delivered vaginally at 37 weeks following an induction of labour and a 2916 grams healthy female was born.

Diferential Diagnosis If
Relevant.Te diferential diagnosis included early-onset intrahepatic cholestasis of pregnancy, which is still considered as an uncommon presentation, and dietary-induced liver injury with unclear etiology, the patient was on restricted diet with no herbs including turmeric, and a marked improvement in LFTs and serum bile acids was noticed.

Outcome and Follow-Up.
Te patient was monitored for 2 days after giving birth, and a marked improvement in the liver function was noticed; the plan was for a follow-up in 4 weeks in the gastroenterology department to repeat serum biochemistry and commence turmeric intake as a trial to monitor the liver function test; liver function test was repeated, normal results revealed, and all the investigations and the imagining modalities were reviewed before recommencing turmeric intake.Te patient stated that she commenced turmeric in small amounts added to food but not similar amount to what she ate before (less than 1 small tablespoon), and the follow-up of liver function tests was within normal range; when she was asked to have similar amount, she declined as she was stressed and anxious it might afect her liver.

Discussion Include a Very Brief Review of Similar Published Cases
Approximately 3 percent of all pregnancies are complicated by liver function test abnormalities.A database from the USA that included over 40 million pregnancy hospitalizations from 2002 to 2010 found that the liver disease diagnoses that can afect the pregnancy can vary such as diseases bundled together as liver disorders of pregnancy (i.e., acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy, and postpartum hepatorenal syndrome, HELLP) or can be presented during the pregnancy (i.e., gallbladder disease, cholelithiasis, hepatitis C virus infection, biliary tract disease (biliary obstruction, cholangitis), hepatitis B virus infection, haemolysis, and alcohol-related liver disease); however, the prevalence data for liver disease in pregnant patients who do not require hospitalization are lacking [4].Elevated liver biochemical and function tests in pregnant patients may pose a challenge for the clinicians as it might be related or unrelated to the pregnancy itself; thus, it requires a diagnostic evaluation similar to the evaluation of the nonpregnant patients while also taking into consideration the expected physiological changes of the pregnancy as well as pregnancy-related liver disorders such as intrahepatic cholestasis, HELLP, and acute fatty liver.During the last few decades, there has seen a rise in the use of herbal supplements, natural products, and traditional medicines; however, there are growing concerns related to the safety, toxicities, and the amount of these medicines.Clinical manifestations range from asymptomatic cases with abnormal liver function tests to a sudden and severe liver failure necessitating liver transplantation [5].Tere are no precise estimates of the frequency of hepatotoxicity attributable to herbal and dietary supplements.Patients often do not report the use of herbal products to their clinicians.Tey self-medicate with large amounts [6], and the untoward efects of using herbs in pregnancy can vary from heartburn and allergic reaction to miscarriage, premature labour, and even theoretical concerns regarding birth defects (green tea might interfere with serum folate metabolism) [7].
Te United States Drug-Induced Liver Injury Network (DILIN) found that approximately 15 to 20 percent of cases of drug-induced liver injury (DILI) could be attributed to herbal and dietary supplements [8].Herb-induced liver injury typically presents as acute hepatocellular injury with elevated aminotransferases, bilirubin, and jaundice [9].However, it may also present as asymptomatic liver enzyme elevations, acute or chronic hepatitis (symptomatic malaise, nausea, vomiting, abdominal pain, etc.), acute liver failure with coagulopathy and encephalopathy, or signs and symptoms of cirrhosis.Te list of herbal medications and dietary supplements associated with hepatic injury is long (i.e., Pyrrolizidine alkaloids, Ayurvedic herbs, Germander Greater celandine, Chaparral, and green tea extracts), and a more complete listing can be found in the searchable database of drugs, herbal medications, and dietary supplements developed by the National Institutes of Health [10].
Turmeric is an herb that has long been recognized for its medicinal properties and has received interest from both the medical and scientifc world and from culinary enthusiasts as it is the major source of polyphenol curcumin.It aids in the management of oxidative and infammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia [3].Current evidence suggests that curcumin is a highly pleiotropic molecule with numerous targets and mechanisms of action.It has properties that alter the activity of enzymes (the activity of COX-2 activity, lipoxygenase, and Case Reports in Hepatology the iNOS enzyme), growth factor receptors (DR5 expression, p38-dependent upregulation, and TNF-α), cofactors, and other molecules [11].
Curcumin has the potential to prevent and/or manage various diseases due to its anti-infammatory, antioxidant, and antiapoptotic properties with an excellent safety profle [12].It has been extensively studied in various felds, showing a wide range of action which was demonstrated by in vitro studies and animal models suggesting the use of this compound as a therapeutic agent in counteracting several pregnancy complications, and for this reason, curcumin could play a key role in improving pregnancy outcome in these complications [13].Turmeric has years of traditional use, and there are some preliminary convincing research studies, but there is no standard dosage recommended, and it is suggested that 500−2,000 mg of turmeric extract per day is generally considered safe for pregnant women [14,15].
A wide variety of preclinical studies support the efectiveness of dietary curcumin in the management of oxidative associated liver diseases; however, there are only few RCTs assessing the efcacy of curcumin in liver disorders.Further well-designed RCTs are required to confrm the dietary and adjunctive role of curcumin as a promising protective or curative agent in the management of oxidative associated liver disease [16].Products containing turmeric are generally listed by the curcuminoid content, commonly making up only 3-5% of turmeric rhizome and giving turmeric its yellow appearance [17].It is widely used due to its therapeutic efectiveness and acceptable safety specifcation [18,19].On the contrary, turmeric causes potentially severe liver injury that is typically hepatocellular with a latency of 1 to 4 months either to usage or in combination with black pepper, and there is a strong linkage to HLAB * 35 : 01 [20].Gianmarco reported that no solid evidence exists that the combination of curcumin and piperine could be the cause of hepatotoxicity.Also, for the specifc case of curcumin, the number of cases reported is still too limited for defnitive answer and only a more extensive clinical trial in the presence of bioavailability enhancers could defnitively settle this dispute [21].Furthermore, Niccolo in recent case series and systematic review of hepatotoxicity due to turmeric revealed an association between high bioavailability and high dosage of curcumin/curcuminoids and liver injury, and the causal relationship was also supported by the positive dechallenge observed in most cases.Te evaluation of Italian cases of Curcuma longa-induced acute hepatitis confrmed the association between Curcuma longa and liver injury [22].Few other case reports have concluded that pure turmeric might directly lead to liver injury but stated that unknown contaminants causing hepatic injury could not be excluded [23].
Lastly, the use of other diferent herbs in pregnancy such as garlic, sage, and ginger is also controversial.While these herbs can be safely used in pregnancy in amounts found in food, larger amount could potentially be harmful [12].

Summary
Te presented case is "probable" for turmeric-induced liver injury.Te timing with respect to onset and ofset of liver injury was compatible; the patient underwent extensive serological screening to exclude other causes of deranged liver function; all the investigations were within normal range.Tat is why a strict dietary modifcation commenced and showed signifcant improvement in the liver injury.

Learning Points/Take Home Messages
(i) Liver injury in pregnant patients may pose a challenge for clinicians as it includes a wide range of diferential diagnosis (ii) Curcumin/turmeric causes potentially severe liver injury in high doses (iii) Further high-quality studies are needed to establish the safety of using herbs and their efectiveness during pregnancy and the amount which can be considered safe echogenic lesion within segment VIII has sonographic appearances of a probable benign haemangioma.No cause found for patient's raised LFTs Gallbladder contains mobile debris, no sonographic evidence of cholelithiasis or cholecystitis MRI cholangiogram No biliary dilatation or choledocholithiasis.Cystic pancreatic lesions are compatible With side-branch IPMN, with no worrisome features on this study Obstetric ultrasound Normal growth and wellbeing EFW is on the 29 th percentile with normal fetal movements, AFI and Doppler 2

Table 1 :
Laboratory and imaging results.