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Khat induced liver injury

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 Arab Journal of Gastroenterology 17 (2016) 45–48

Contents lists available at ScienceDirect

Arab Journal of Gastroenterology

journal homepage: www.elsevier.com/locate/ajg

Case Report

Khat-induced liver injuries: A report of two cases

Omkolsoum M. Alhaddad a,⇑, Maha M. Elsabaawy a,1, Eman A. Rewisha a,2, Tary A. Salman a,3,
Mohamed A.S. Kohla a,4, Nermine A. Ehsan b,5, Imam A. Waked a,6
a
Department of Hepatology, National Liver Institute, Menoufiya University, Shebeen El Kom 234511, Egypt
b
Department of Pathology, National Liver Institute, Menoufiya University, Shebeen El Kom 234511, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Khat is consumed for recreational purposes in many countries, including Yemen, where >50% of adults
Received 4 June 2015 chew khat leaves regularly. A wide spectrum of khat-induced liver injuries has been reported in the lit-
Accepted 29 February 2016 erature.
Herein, we report two patients with khat-induced liver injury. Both patients clinically presented with
acute hepatitis, one of whom showed radiological evidence of hepatic outflow obstruction. Based on the
Keywords: histological tests, both patients had acute hepatitis, which indicated drug-induced liver injury (DILI) on a
Khat
background of chronic hepatitis and portal fibrosis; of the two, one presented with symptoms of
Induced
Liver
immune-mediated liver injury.
Injury Ó 2016 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction hypertension, coronary vasospasm, myocardial infarction, delayed

More than 90% of Yemeni men and 50% of Yemeni women chew
khat leaves habitually [1]. The leaves of khat contain the following
pyrrolizidine alkaloids: cathine, cathidine, and cathinone [2].
Cathinone, a sympathomimetic amine with similar properties to
amphetamine, is responsible for the sense of delight associated
with khat consumption [3]. The Yemenis believe that khat chewing
can cure impotence and improve stamina [4]. However, this depen-
dence has a wide range of potential adverse effects [5], including
intestinal absorption, and mood disorders [6].
Several case reports have described liver diseases among khat
users in several countries [4]. The full spectrum of khat-related
liver injury is not fully known, which continues to evolve and
increase in incidence. We describe two cases of liver injury in khat
users referred to our hospital, and we discuss their clinical and
histological features.
Case 1

A 32-year-old man living in Yemen from birth was referred to

Abbreviations: DILI, drug-induced liver injury; EBV, Epstein–Barr virus; CMV, the National Liver Institute, a tertiary referral centre for liver
cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus;
disease in Egypt, for the management of an acute liver injury. He
HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core
antibody; HCV, hepatitis C virus; HEV, hepatitis E virus; PCR, polymerase chain had no medical history of chronic illness. He reported acute onset
reaction; RUCAM, Roussel Uclaf Causality Assessment Method; TIPS, transjugular of malaise and anorexia for 5 weeks, which was associated with
intrahepatic portosystemic shunt. jaundice, dark urine, and pruritus.
⇑ Corresponding author. Tel.: +20 1001779069; fax: +20 (048)2222743/2224586.
He has been chewing khat leaves regularly for 25 years, con-
E-mail addresses: dromkolsoum@yahoo.com (O.M. Alhaddad), maha.ahmed@
suming approximately 100 g daily. He did not report using other
liver.menofia.edu.eg (M.M. Elsabaawy), emanrewisha@yahoo.com (E.A. Rewisha),
tarysalman@yahoo.com (T.A. Salman), dr_mohamedsamy@yahoo.com herbal products or recreational drugs in the preceding 6 months.
(M.A.S. Kohla), nermine_ehsan@yahoo.com (N.A. Ehsan), iwaked@liver-eg.org On examination, the patient was found to be underweight
(I.A. Waked). (47 kg) and deeply jaundiced with mild right upper abdominal ten-
1
Fax: +20 (048)2222743/2224586. derness. The laboratory data are shown in Table 1. The results of the
2
Tel.: +20 1023473131; fax: +20 (048)2222743/2224586.
3 serological assays for the hepatitis viruses (A, B, C, and E), Epstein–
Tel.: +20 1003569090; fax: +20 (048)2222743/2224586.
4
Tel.: +20 1111047684; fax: +20 (048)2222743/2224586. Barr virus (EBV), cytomegalovirus (CMV), human immunodefi-
5
Tel.: +20 1115567334; fax: +20 (048)2222743/2224586. ciency virus (HIV), and herpes simplex virus (HSV) were negative
6
Tel.: +20 1222157256; fax: +20 (048)2222743/2224586. (anti-hepatitis A virus (HAV)-IgM, hepatitis B surface antigen

http://dx.doi.org/10.1016/j.ajg.2016.02.002
1687-1979/Ó 2016 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
46 O.M. Alhaddad et al. / Arab Journal of Gastroenterology 17 (2016) 45–48

Table 1
Laboratory data of case 1.

1 week before admission Admission labs Discharge labs

Total bilirubin 5.4 10.2 5.9
Direct bilirubin 2.7 7.06 5.2
Albumin 3.3 2.8 3.2
AST 67 1574 430
ALT 400 723 240
ALP 273 238
GGT 380 277
INR 1.09 1.04 1.04
HG 12.1 11.7 11
WBCs 5.3 7.2 6.1
Differential count NAD
Platelets 257 169 165

GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; INR, international normalised ratio; PC, prothrombin concentration; NAD, no
abnormality detected; WBCs, white blood cells; HG, haemoglobin.

Case 2

A 31-year-old man living in Yemen from birth with no history of

Fig. 1. Liver section from case 1 stained with H&E showing portal tract inflamma-
tion, bile duct injury (short arrow), apoptotic bodies (long arrow), and microvesic-
ular steatosis (arrowhead). Original magnification 200.
(HbsAg), anti-hepatitis B core (HBc)-IgG, anti-HBc-IgM,
anti-hepatitis C virus (HCV)-antibody, anti-hepatitis E virus
(HEV)-IgM, anti-EBV-IgM, anti-CMV-IgM, anti-HIV-Ab, and anti-
HSV-IgM). The results of the polymerase chain reaction (PCR) for
HCV-RNA were negative. Hypergammaglobulinaemia was detected
(IgG: 3147 mg/dl (normal 700–1600)). However, the results of tests
for autoantibodies (antinuclear antibody (ANAs), anti-smooth mus-
cle antibody (ASMA), and anti-liver/kidney microsomal antibody
(LKM)) were negative.
The findings on imaging the liver, biliary tree, and hepatic vas-
culature by ultrasonography and computed tomography were
unremarkable. Examination by upper endoscopy revealed severe
monilial oesophagitis, for which fluconazole was prescribed for
10 days.
A percutaneous liver biopsy (performed on the fifth day of
admission) showed interface hepatitis, cytoplasmic cholestasis,
and feathery degeneration with mixed inflammatory infiltrate high
in eosinophilic load, indicative of drug-induced liver injury (DILI),
as well as portal fibrosis (score of 3/6) with necroinflammation
rated 8/18 according to the Ishak score (Fig. 1) [10].
Calculation of the Roussel Uclaf Causality Assessment Method
(RUCAM) score of DILI was probable, whereas that of the autoim-
mune hepatitis score was unlikely [11–13].
The serum levels of bilirubin, alanine transaminase (ALT), and
aspartate transaminase (AST) decreased in a stepwise pattern,
which reflect the slow regression of the condition after khat with-
drawal. The patient was discharged and was recommended
monthly follow-ups.
chronic illness was referred to our hospital due to acute onset of
jaundice, dark urine, pain in the right upper quadrant, and pruritus
for 8 weeks. He has been chewing fresh khat leaves regularly for
25 years, consuming approximately 100 g daily. He has abstained
from khat since the onset of his illness, except one instance a week
before admission. The patient had been an alcoholic for several
years before abstaining from alcohol 7 years ago.
On examination, the patient was found to have jaundice with
mild right upper abdominal tenderness and mild hepatomegaly.
The laboratory data are shown in Table 2. The results of the sero-
logical assays for HAV, HBV, HCV, HEV, EBV, CMV, HIV, and HSV
were negative (anti-HAV-IgM, HBsAg, anti-HBc-IgG, anti-HBc-
IgM, anti-HCV-antibody, anti-HEV-IgM, anti-EBV-IgM, anti-CMV-
IgM, anti-HIV-Ab, and anti-HSV-IgM), and that of the PCR for
HCV-RNA was negative. The patient showed hypergammaglobuli-
naemia with a serum gammaglobulin level of 2408 mg/dl (normal
700–1600 mg/dl). The patient tested positive for ASMA with a titre
of 1/40, but negative for ANA, anti-LKM, and AMA.
Ultrasonographic examination revealed hepatomegaly with an
enlarged caudate lobe, completely thrombosed hepatic veins
(right, middle, and left), and an enlarged spleen, with no evidence
of ascites. Computed tomography and magnetic resonance imaging
(MRI) venography confirmed the diagnosis of hepatic vein occlu-
sion, showing the slit-like appearance of the retrohepatic portion
of the inferior vena cava.
Coagulation studies revealed normal levels of anti-thrombin III
(82%), as well as negative results for anti-cardiolipin IgM and lupus
anticoagulant. Negative results were obtained in tests for factor V
Leiden, prothrombin gene, and Janus kinase 2 (JAK 2) mutations.
A heterozygous mutation of the methylene-tetra-hydro-folate
reductase (MTHFR) gene was detected.
A transjugular intrahepatic portosystemic shunt (TIPS) was
placed 2 days after admission. One day later, percutaneous liver
biopsy was performed. Histopathological examination revealed
no evidence of centrilobular congestion or data indicative of
veno-occlusive disease. The patient presented with moderate
interface hepatitis, spotty and focal confluent necrosis with mixed
inflammatory infiltrate rich in plasma cells and eosinophils, which
is indicative of an autoimmune-related liver injury associated with
a new insult. The histopathological examination also revealed the
presence of some microvesicular steatosis, implicating khat in
the new acute insult and possibly the chronic features. The fibrosis
score was 4/6, and the necroinflammatory activity score was 9/18
according to the Ishak score (Fig. 2) [7].
 O.M. Alhaddad et al. / Arab Journal of Gastroenterology 17 (2016) 45–48
Table 2
Laboratory data of case 2.
1 week before admission
Total bilirubin 6.1
Direct bilirubin 4.3
Albumin 3.9
AST 390
ALT 275
ALP
GGT
INR 1.4
HG 12.1
WBCs 5.3
Differential count Mild eosinophilia:14% in Yemen and 8% in NLI
Platelets 235
GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; INR, international normalised ratio; PC, prothrombin concentration.
Fig. 2. Liver section from case 2 stained with H&E showing portal tract inflamma-
tion containing eosinophils (long arrow), bile duct injury (short arrow), and
microvesicular steatosis (arrowhead). Original magnification 200.
The calculated RUCAM score of DILI was found to be probable
and the autoimmune hepatitis score was 6 [8,9]. The laboratory
and histological findings implicate khat in both the acute injury
and the chronic condition via an autoimmune mechanism.
The patient received subcutaneous enoxaparin 80 IU twice
daily, which was withheld prior to the placement of TIPS and liver
biopsy, warfarin was added, and no corticosteroids were given. The
patient gradually improved, and he was discharged after being
prescribed oral warfarin.
Discussion
The histopathological examination of liver tissue from khat-
treated laboratory animals showed strong evidence of khat-
induced liver injury [13]. The vasoconstrictor action of cathinone
is suggested to be a contributing factor to these liver insults [14].
Several case reports have highlighted the role of khat chewing
in liver injury in humans [4]. In particular, the toxic effects of khat
can potentiate chronic injury and manifest as drug-induced
autoimmune hepatitis (AIH) [11]. This explains the hypergamma-
globulinaemia and interface hepatitis with eosinophilic infiltration
observed in the liver biopsies of these patients, along with the
unlikely autoimmune hepatitis score and the probable RUCAM
score. Differentiating drug-induced AIH from DILI has posed a
challenge. Various causality methods have been used to treat
herbal-induced liver injury and AIH, although none of these meth-
ods has become popular [8]. It is difficult to establish the diagnosis
of drug-induced liver disease. Histopathological examination of
47
Admission labs Discharge labs
3.9 0.9
2.1 0.4
3.8 4.1
321 104
375 142
245 238
522 206
1.6 1.9
11.7 11
7.2 6.1
234 238
liver biopsies would be unjustifiable, as it mainly describes the
type and degree of liver injury rather than the underlying aetiol-
ogy. This issue was also encountered in both patients in our study;
moreover, their calculated RUCAM score and AIH score were equiv-
ocal. However, both patients satisfied more clinical criteria of
immune-mediated DILI than of drug-induced AIH, as their bio-
chemical abnormalities gradually reduced after khat withdrawal
without the introduction of steroids. However, the natural history
of khat-associated hepatotoxicity remains to be elucidated. In our
two patients, the liver biopsy provided evidence of preexisting
chronic liver disease (fibrosis score of 3/6 and an Ishak score of
4/6, respectively).
In the second case, the thrombosed hepatic veins could not be
easily identified without any histological evidence of ascites or
centrilobular congestion. This is the first report of Budd–Chiari
syndrome among khat chewers. Biopsy was performed 24 h after
the placement of TIPS, which might have relieved the centrilobular
congestion. The patchy nature of Budd–Chiari syndrome may also
account for its nontypical histological features. Haematological
studies did not reveal any of the known predisposing conditions
for the development of Budd–Chiari syndrome, apart from MTHFR
heterozygosity, a clinically irrelevant condition without any risk of
thrombogenic activity [12]. In a case report of a male khat chewer
with myocardial infarction (MI), stenosis was described in the left
anterior descending coronary artery as well as filling defects con-
sistent with thrombus formation [12]. In another case report of a
28-year-old male khat chewer, both acute MI and cerebral infarc-
tion were described, having been caused by thrombus occlusion
of the proximal right coronary and cerebral arteries, respectively
[13]. Vascular thrombosis among khat chewers can be attributed
to khat itself. Khat chewing was found to be associated with
reduced bleeding time in patients with MI receiving long-term
aspirin therapy [14], which indicates the role of khat in extenuat-
ing aspirin-induced antiplatelet aggregation [14]. Catecholamines
released by cathinone may be responsible for this pro-
aggregatory action [7]. This hypothesis should be investigated in
further studies evaluating the potential thrombogenicity of khat
[7]. Budd–Chiari syndrome was recently reported in a 10-month-
old boy after consuming a pyrrolizidine-containing herbal drink
for 3 months [15]. Accordingly, the pyrrolizidine present in khat
leaves may have been a major contributing factor to Budd–Chiari
syndrome in case 2.
In brief, our two cases demonstrated khat-induced hepatotoxi-
city in the form of immune-mediated acute and chronic liver inju-
ries that will eventually progress to fibrosis and even cirrhosis.
Furthermore, this is the first report of hepatic vein thrombosis in
case 2. The harmful effects of khat on the liver must also be the
focus of future studies.
48 O.M. Alhaddad et al. / Arab Journal of Gastroenterology 17 (2016) 45–48

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