Hepatology Research 23 (2002) 55–61

Clinical spectrum of acute sporadic hepatitis E and possiblebenefit of glycyrrhizin therapy

Anurag Tandon, B.N. Tandon *, R.A. BhujwalaPushpawati Singhania Research Institute, Digesti�e Diseases Foundation, DDA SFS Flats, 3 C Vijay Mandal Encla�e,

New Delhi 110 016, India

Received 17 November 2000; received in revised form 19 July 2001; accepted 21 August 2001

Abstract

The aim of the present study was to record the spectrum of sporadic hepatitis due to hepatitis E virus infection withspecial reference to moderate and severe liver disease, described as sub-acute hepatitis. Further, efficacy ofglycyrrhizin therapy was studied as an open trial. Sixty-two consecutive patients were registered for the study. Theclinical and laboratory profile of the patients was recorded on a preplanned proforma. Moderate and severe hepatitiswas arbitrarily defined on the basis of clinical symptoms and serum bilirubin (total) of 10–15 mg% and 16 mg% orhigher, respectively, at the time of presentation. It was noted that 22 (36.1%) of acute sporadic hepatitis E patientshad moderate or severe liver disease. Glycyrrhizin was administered to these 22 patients by intravenous (IV) route inthe dose of 60 ml daily. Therapy was tapered and stopped once significant clinical and biochemical improvement wasnoted. All patients showed clinical improvement by the seventh day of therapy. Total bilirubin was reduced by 68.9%by the end of 2 weeks of treatment and at this time, reduction in AST and ALT levels was to the tune of 94 and 97%,respectively. Normalization of AST and ALT levels was recorded in 19 patients (86.4%) and total bilirubin in 13(59.1%) patients within 30 days of commencement of therapy. There were no side effects of IV glycyrrhizin therapy.It is concluded from the results of the present study that over one-third patients with acute sporadic hepatitis E inIndia have either moderate or severe liver injury. IV glycerrhizin therapy in this group of patients is well tolerated andeffective. © 2002 Elsevier Science B.V. All rights reserved.

Keywords: Bilirubin; Glycyrrhizin therapy; Hepatitis E; Substrate; Hepatitis; Subacute hepatitis

www.elsevier.com/locate/ihepcom

1. Introduction

Viral hepatitis is a common liver disease world-wide. However, its presentation varies geographi-cally and this aspect of the disease has received farless attention than it deserves. Hepatologists from

India have attempted to highlight this issue foracute and sub-acute liver failure [1,2]. In thispaper, we present the data on acute sporadichepatitis E, a major public health problem inIndia. The importance of sporadic hepatitis E isinadequately perceived by most international hep-atologists as it is an uncommon clinical problemin the economically advanced countries of theworld. While a number of publications have de-

* Corresponding author.E-mail address: drvivektandon@vsnl.com (B.N. Tandon).

1386-6346/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.

PII: S1 386 -6346 (01 )00155 -3

A. Tandon et al. / Hepatology Research 23 (2002) 55–6156

scribed the epidemic form of hepatitis E [3–7],reports pertaining to the different issues of spo-radic hepatitis E are few, in spite of the fact thatthe disease is a major clinical problem in hepatitisE endemic regions.

The present study was carried out to validatethe experience of Indian hepatologists that hepati-tis E virus (HEV) is the cause of severe liverdisease in a significant proportion of sporadichepatitis patients. Since liver injury in HEV infec-tion is primarily immunological and not cyto-pathic an open trial of an immunomodulatordrug, glycyrrhizin has also been carried out in asub-group of patients who had moderate or severehepatitis.

Glycyrrhizin therapy has been extensively stud-ied in the treatment of chronic hepatitis [8–10]and has been rarely evaluated in acute and sub-acute hepatitis. It is a drug derived from a herbalplant Glycyrrhiza glabara, the active principle be-ing glycyrrhizin. The pharmacological actions ofthis drug include,1. anti-viral [11],2. natural interferon stimulation [12],3. immunomodulation [13],4. anti-inflammatory [14], and5. hepatoprotective [15].

In vitro efficacy and safety and in vivo trials inchronic hepatitis have stimulated the present pilotstudy as an open trial in moderate and severeacute hepatitis E with an aim to reduce the mor-bidity period and to prevent the complication ofsub-acute liver failure.

2. Methods and materials

Patients presenting with an acute illness with aprodrome constituting the characteristic featuresof anorexia, nausea, vomiting and fever followedby jaundice were examined and investigated. Thetests included standard blood tests for liver func-tion (serum bilirubin, AST, ALT, alkaline phos-phatase), an abdominal ultrasound and viralmarkers for hepatitis [16]. Patients with chronicliver disease and surgical obstructive jaundicewere excluded on the basis of standard clinicalcriteria, liver functions, ultrasonography, a his-

tory of past illness suggestive of liver disease andendoscopic examination for varices. Acute viralhepatitis was labeled on the basis of clinical fea-tures and abnormal liver functions. HEV IgMpositivity was considered diagnostic of sporadicacute hepatitis E [17]. HBsAg positive and IgMcore negative patient in this group were consid-ered to have superinfection with the E virus in aHBV carrier. Co-infection of hepatitis A and Evirus was confirmed if IgM antibodies to both Aand E virus were positive. Patients with jaundiceof more than 4 weeks duration, low serum albu-min and ascites on ultrasound were labeled assub-acute liver failure. The presence of chronicliver disease was excluded by the absence ofvarices on gastrointestinal endoscopy and collat-erals, splenomegaly, a shrunken liver and a di-lated portal vein on ultrasonography [18]. Patientsof acute hepatitis presenting with encephalopathywithin 4 weeks of illness and without any historyof previous liver disease were labeled as acuteliver failure [19].

The general supportive treatment for acute spo-radic hepatitis E included vitamins, antacids,domperidone, a soft bland diet and intravenous(IV) 10% glucose if oral diet intake provided lessthan 1800 cal. Most of the patients were onursodeoxycholic acid 150 mg three times a day atthe time of registration so this drug was given toall the patients [20]. Moderate and severe acutehepatitis was arbitrarily defined on the basis ofseverity of symptoms of anorexia, itching andpersistence or increasing jaundice 4 weeks afterthe onset of the icteric phase. Their serum biliru-bin levels were 10–15 mg%, and more than 16mg%, respectively.

All the patients who had moderate or severehepatitis were administered IV glycyrrhizin 60 mldaily. The dose was reduced to 40 ml daily andfinally, to thrice weekly when progressive clinicaland biochemical recovery was recorded. Adminis-tration of IV glycyrrhizin was stopped whenserum bilirubin reached a level 5 mg% and ALTlevels decreased to 150 IU (less than three timesupper limit of normal). Patients were followed at6–12 weeks interval till normalization of serumbilirubin and ALT levels and 3 months after thispoint of recovery.

A. Tandon et al. / Hepatology Research 23 (2002) 55–61 57

Side effects of IV glycyrrhizin on clinical, he-matological and renal parameters were recorded.Glycyrrhizin was obtained from Curewell India,the company that imports this drug fromMenophagen Pharmaceutical Co, Japan.

3. Results

A total of 62 patients with sporadic hepatitisE infection were registered for the study over aperiod of 2 years. This included 52 patients withuncomplicated infection, four with sub-acuteliver failure and six patients with acute liver fail-ure. The group with acute liver failure andgrade IV encephalopathy was not included inthe study and data analysis as they received ad-ditional treatment in the intensive care unit.Three patients in this group were pregnant andthey had a fatal end. The fourth patient withacute liver failure who expired had associatedGullian Barre Syndrome.

Demographic data of the 56 patients are pre-sented in Fig. 1. Males predominated in a ratioof 4:1. 78.5% patients were adults between 20and 50 years of age. Only 14.2% were childrenand 7.1% were above 60 years of age. The dura-tion of the icteric phase at registration was be-tween 14–21 days in 28.8%, 21–29 days in46.2% and more than 30 days in 25% patients.Fever and anorexia were the commonest symp-

toms in 38.8 and 48.1% patients, respectively.Itching was the major complaint in 29.6% pa-tients, followed by nausea and vomiting in 27.8and 20.3%, respectively. Weakness and fatiguewere troublesome in 20.4% patients.

8.9% of the male patients but none of thefemale patients consumed alcohol occasionally.However, none had alcoholic liver disease.13.3% of the male patients were on oral hypo-glycemic medication for diabetes.

Based on the clinical features and serumbilirubin levels, 22 had moderate or severe dis-ease while 34 had mild disease. Only patientswith moderate or severe disease (22 patients)were treated with IV glycerrhizin in addition tosupportive care. Distribution of patients accord-ing to severity of hyperbilirubinemia in this gly-cyrrhizin treated group and decrease in totalbilirubin levels at 7, 14, 30 and after 30 days oftherapy is presented in Fig. 2. The fall in serumbilirubin at the end of the first week of therapyranged from 41.4 to 57.5% from the pretreat-ment value, with a mean percentage drop of43.5%. There was a trend for a greater declinein the serum bilirubin in patients with higherbaseline values. The decline in the bilirubin levelcontinued with therapy (mean decline of 68.9%by 15–30 days and 87.5% by the end of 30days). Only 10% patients required more than 30days treatment for further improvement.

Fig. 1. Age and sex distribution of patients with acute hepatitis E.

A. Tandon et al. / Hepatology Research 23 (2002) 55–6158

Fig. 2. Mean percentage drop in total S.bil at different periods of treatment with IV glycyrrhizin.

Fig. 3 presents the time taken for normalizationof total bilirubin levels, 59.1% in less than 30days, 22.7% between 31 and 45 days while fourpatients (15.2%) took 46–90 days for completerecovery. The dynamics of the recovery of serumAST/ALT levels is presented in Fig. 4. By theseventh day of IV glycyrrhizin therapy there was amean drop of 75.8% and it reached 94% by the14th day of therapy. Only three patients requireda longer period (up to 45 days).

Normalization of AST and ALT was quickerand occurred in a shorter period compared to theserum bilirubin levels. Improvement in clinicalsymptoms was parallel to the decline in serumALT and AST but all patients and relatives werepersistently concerned regarding the yellow discol-oration of urine and eyes till normalization ofserum bilirubin levels.

There was no febrile or allergic response toglycyrrhizin. Hemoglobin levels, total leucocytecounts, blood urea and serum creatinine remainednormal. No albuminurea was recorded duringtherapy in any of the patients.

4. Discussion

The present report highlights pertinent pointsabout acute sporadic hepatitis E that should helpimprove the management of this disease in coun-tries where the disease is endemic and hyperen-demic. In addition, hepatologists from countrieswhere the disease is rare would appreciate itsmagnitude and seriousness. Firstly, it should benoted that acute sporadic hepatitis E is as com-mon as acute hepatitis B and in the monsoon and

A. Tandon et al. / Hepatology Research 23 (2002) 55–61 59

post-monsoon months (i.e. the rainy season) itbecomes more common than the acute hepatitis B[21]. The present data show that over 45% ofpatients have moderate or severe hepatitis and10% presented with fulminant hepatitis and acuteliver failure. Previous reports from India [1,22]have recognized the importance of hepatitis E inacute and sub-acute liver failure, both potentiallyfatal complications of acute hepatitis. The diseasemost commonly afflicts adult males in their mostproductive age (20–50 years in the present study)thus having a significant impact on economiccondition of the predominantly middle and lowincome population of a developing country likeIndia. It leads to loss of 45–60 working daysbefore the patient feels confident to resume hisactivities.

Not much has been reported about acute spo-radic hepatitis E in western literature. A fewpublications from India support the findings ofthe present study [22,23]. Hepatologists fromAfrica [24] and China [25] have also noted acutesporadic hepatitis E to be a severe form of liverdisease. However, the experience from the westhas been different and at the IASL post-graduate

course in Chicago in November 1998 Krawczyn-ski commented that sporadic hepatitis E is a milddisease like hepatitis A [26]. Reports from Spain[27], Hong Kong [28] and Australia [29] alsosupport this view. It is possible that the clinicalspectrum of this disease in endemic and hyperen-demic countries is severe and while it is mild andself-limiting in populations with low endemicity.The possibility of genomic differences of HEV indifferent regions in the world and its relationshipwith severity of hepatitis has not been studied.Populations in endemic and hyperendemic coun-tries repeatedly get exposed to hepatitis E due tounhygienic conditions and possibly the infectiveload is also higher due to heavy fecal contamina-tion of drinking water. In Delhi, in the epidemicof 1955–1956, the severity of liver disease wasfound to be related to the latter factor [3]. Themechanism of severe liver disease, its higher fre-quency in adult males and its bringing greatermortality in pregnant women, remains unknown.

There is no reason to accept an approach ofonly supportive treatment in moderate and severeliver disease due to sporadic HEV infection. Rela-tives and patients are keen for an effective treat-ment by specialists when jaundice is persistent andappears deep. IV Glycyrrhizin is a safe drug de-veloped from the Glycyrrhiza glabora plant. It hasantiviral, cytoprotective, immunomodulatory andanti-flammatory properties [11–15]. It is beingextensively used in chronic hepatitis B and C[8–10] and has been successfully used in sub-acuteliver failure in India [25–27,30]. The present re-port demonstrates its efficacy in moderate andsevere types of acute sporadic hepatitis E. Thedata suggest good clinical and enzymatic responsein nearly 85–94% of patients within 2 weeks oftherapy. Complete normalization of bilirubin wasnoted in 59% (13 out of 22 cases) with a 87%decrease in bilirubin levels from the baseline valuewithin 30 days of therapy. These patients had amedian total bilirubin of 15.9 mg% with a rangeof 10–40 mg% prior to commencement of ther-apy. No side effects were noted during therapywith IV glycyrrhizin.

Moderate and severe acute hepatitis E leads toseveral weeks of morbidity. Further, it carries therisk of the serious complication of sub-acute hep-

Fig. 3. Normalization period after onset of icterc phase fortotal bilirubin, AST and ALT levels after IV glycyrrhizin in 22patients with acute severe hepatitis E.

A. Tandon et al. / Hepatology Research 23 (2002) 55–6160

Fig. 4. Percentage drop in ALT levels after commencement of IV glycyrrhizin.

atic failure. It is suggested that IV glycyrrhizintherapy may reduce the duration of illness and thefatal complication of sub-acute liver failure due toHEV infection. Pocok et al. have recently sug-gested that observational data should prompt ran-domized control trials [31]. The present reportshould stimulate a randomized trial to confirm theobserved data of this study and formulate recom-mendations for the effective treatment of moder-ate and severe acute sporadic hepatitis E inhyperendemic countries of the world.

References

[1] Acharya SK, Dasrathy S, Kumar TL, et al. Fulminanthepatitis in tropical population: clinical course, cause andearly predictors of outcome. Hepatology 1996;23:1448–55.

[2] Tandon BN, Joshi YK, Krishnamurthy L, et al. Subacutehepatic failure: is it a distinct entity? J Clin Gastroenterol1982;4:343–6.

[3] Vishwanathan R. Infectious hepatitis in Delhi (1955–56):

a critical study: epidemiology. Ind J Med Res1957;45(Suppl.):49–58.

[4] Tandon BN, Joshi YK, Jawan SJ, et al. An epidemic ofnon-A, non-B hepatitis in North India. Ind J Med Res1982;75:739–44.

[5] Khuroo MS. Study of an epidemic of non-A, non-Bhepatitis: possibility of another human hepatitis virusdistinct from post-transfusion non-A, non-B type. Am JMed 1980;68:818–23.

[6] Kane MA, Bradley DW, Shrestha SM, et al. Epidemicnon-A, non-B hepatitis in Nepal. Recovery of a possibleetiologic agent and transmission studies in marmosets. JAm Med Assoc 1984;252:3140–5.

[7] Naik SR, Agarwal R, Salunke PN, et al. A large waterborne viral hepatitis E epidemic in Kanpur, India. BullWHO 1992;70:597–604.

[8] Takahara T, Watanabe A, Shiraki K. Effects of gly-cyrrhizin on hepatitis B surface antigen: a biochemical andmorphological study. J Hepatol 1994;21:601–9.

[9] Arase Y, Iked K, Murashima N, et al. The long termefficacy of glycyrrhizin in chronic hepatitis C patients.Cancer 1997;79:1494–500.

[10] Zhang L, Cui Z, Wang B. Therapeutic effect of strongerneo-minophagen C in patients with chronic liver disease.Hepatol Res 2000;16:145–54.

A. Tandon et al. / Hepatology Research 23 (2002) 55–61 61

[11] Pompei R, Flore O, Marccialis MA, et al. Glycyrrhizicacid inhibit virus growth and inactive virus particles.Nature 1979;281:689–90.

[12] Abe N, Ebina T, Ishida N. Interferon induction by gly-cyrrhizin and glycyrrhetinic acid in mice. Microbiol Im-munol 1982;26:535–9.

[13] Kimura M, Watanabe H, Abo TR. Selective activation ofextrathymic T cells in the liver by glycyrrhizin. Biotherapy1992;5:167–76.

[14] Ohhuchi K, Tsurufuji A. A study of the anti-inflamma-tory mechanism of glycyrrhizin. Mino Med Rev1982;27:188–93.

[15] Finney RSH, Somers GF. The anti inflammatory activityof glycerrhetenic acid and derivations. J Pharm Pharma-col 1958;10:613–20.

[16] Sgerlock S. In: Zuckerman AJ, Thomas HC, editors.Clinical features of hepatitis in viral hepatitis, 2nd ed.London: Churchill Livingstone, 1998.

[17] Khurro MS, Kamil S, Dar MR, et al. Hepatitis E andlong term a status. Lancet 1993;341:1335.

[18] Tandon BN, Bernauau J, O’Grady J, et al. Recommenda-tions of the IASL subcommittee on the nomenclature ofacute and subacute liver failure. J Gastroenterol Hepatol1999;14:403–4.

[19] Tandon BN, Acharya SK. Fulminant hepatic failure:clinical syndrome and progress on management. FrontierHepatol 1993:11–7.

[20] Galsky J, Bansky G, Holubova T, et al. Effect ofursodeoxycholic acid in acute viral hepatitis. J Clin Gas-troenterol 1999;28:249–53.

[21] Tandon BN, Gandhi BM, Joshi TK. Aetiological spec-trum of viral hepatitis and prevalence of markers of

hepatitis A and B virus infection in North India Bull. BullWorld Health Organ 1984;62:67–73.

[22] Khuroo MS, Rustagi VK, Dawson GJ, et al. Spectrum ofhepatitis E virus in India. J Med Vir 1994;43:281–6.

[23] John R, Abraham P, Kurien G, et al. Sporadic hepatitisE in southern India. Trans Roy Soc Trop Med Hyg1997;91:392.

[24] Coursaget P, Buisson Y, N’gawara MN, et al. Role ofhepatitis E virus in sporadic cases of acute and fulminanthepatitis in an endemic area. Am J Trop Med Hyg1998;58(3):330–4.

[25] Tan De, Stanley WKI, Yao JL, et al. Acute sporadichepatitis E virus infection in southern China. J Hep1995;23:239–45.

[26] Krawczynsk K. Hepatitis E: current status in Roc IASLPostgraduate course. Adv. Therapeut. Hepatol. A WorldView. 1998;23–32.

[27] Jardi R, Buti M, Frias F, et al. Hepatitis E infection inacute sporadic hepatitis in Spain. Lancet 1993;341:1355.

[28] Lok ASF, Kwan WK, Moeckli R, et al. Seroepidemiolog-ical survey of hepatitis E in Hong Kong by recombinant-based enzyme immunoassays. Lancet 1992;340:1205–8.

[29] Moaven L, Asten MV, Crofts N, et al. Seroepidemiologyof hepatitis E in selected Australian populations. J MedVirol 1995;45:326–30.

[30] Acharya SK, Panda SK, Tandon BN, et al. A preliminaryopen trial on interferon stimulator SNMC derived fromGlyerrhiza glabra in the treatment of subacute hepaticfailure. Ind J Med Res (B) 1993;98:69–74.

[31] Pocok ST, Elbourre DR. Radomized trials of observa-tional tribulations. New Engl J Med 2000;342:1907–9.