2 Section of Gastroenterology and Department of Medicine, Aga Khan University, Pakistan
Submission:December 03, 2019; Published: December 10, 2019
*Corresponding author:Shahab Abid, Professor and Head Section of Gastroenterology, Department of Medicine, Aga Khan University, Stadium Road P.O Box 3500, Karachi, Pakistan
How to cite this article: Adeel A, Faryal S, Farhana K, Safia A, Shahab A. Drug Induce Liver Injury is Associated with High Mortality - A Study from a
Tertiary Care Hospital in Pakistan. Adv Res Gastroentero Hepatol, 2019;14(3): 555886. DOI:10.19080/ARGH.2019.14.555886.
Background and Aim: In light of the paucity of data on drug induced liver injury DILI especially from South Asia, this study aims to evaluate the clinical spectrum and predictors of mortality and morbidity of hospitalized patients with suspected DILI.
Patients and Methods: DILI cases were identified and categorized on basis of COIMS/RUCAM score and the exclusion of other liver diseases. Clinical and laboratory parameters were analyzed to identify the predictors of morbidity (prolonged hospital stay. > 5 days) and mortality.
Results: Out of 462 patients, there were 264 (57.6%) males and the mean of the cohort was 50.83 years (range, 20-94 years). DILI was classified as definite or highly probable in (31.1%, probable in 62.5% and possible in 7.4% of cases. Pattern of liver injury was hepatocellular in 25.1%, cholestatic in 56.17% and mixed in 18.72% of patients. Anti-tuberculous drugs (ATDs) were found to be the most common cause of DILI in 295 (63.9%) encephalopathy was present in 21.6% patients other presenting symptoms were abdominal pain (57.1%), vomiting (57.1%,), jaundice (54.1%,) and pruritus (42.3%). In-hospital mortality was 26.5% and prolonged hospital stay was observed in 35.93% of patients. Mortality was significantly greater in patients with encephalopathy, male gender, hepatocellular pattern of DILI, increased INR and use of ventilator support.
Conclusion: The most frequent cause of DILI was ATDs in hospitalized patients in our study. More than a quarter of patients died during hospital stay. A close control of clinical and biochemical parameters is required especially ATDs in our region.
Keywords: Drug induced liver injury; Spectrum and predictors of outcome; Liver dysfunction; Liver tests; Liver injury; Acute liver failures; Autoimmune hepatitis; Anti-inflammatory drugs; Hepatotoxicity; Hepatitis B virus
Abbreviations: DILI: Drug Induced Liver Injury; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; ALP: Alkaline Phosphatase; ULN: Upper Limit Of Normal; FDA: Food and Drug Administration; LFTs: Liver Function Tests; RUCAM: Roussel Uclaf Causality Assessment Method; NSAIDs: non-Steroidal Anti-Inflammatory Drugs; HDS: Herbal And Dietary Supplements; MTAs: Molecular Targeted Agents; TKI: Tyrosine Kinase Inhibitor; EGFR: Epidermal Growth Factor Receptor; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; ATDs: Anti-Tuberculous Drugs
Drug induced liver injury (DILI) is defined as hepatotoxicity caused by various medications, herbs, or other xenobiotics, subsequently leading to abnormalities in liver tests or liver dysfunction with the reasonable exclusion of other etiologies . Specific laboratory criteria are utilized to identify DILI: typically, a 3-5 times elevation of liver enzymes, namely transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase
[AST]), alkaline phosphatase (ALP), or bilirubin, above their
upper limit of normal (ULN) is required . Altogether, in excess of a thousand medicines and chemicals have been implicated in drug induced liver injury [3,4].
In the United States, DILI accounts for nearly 10% of the total cases of acute hepatitis, 5% of all hospital admissions, 50% of all cases of acute liver failures . DILI carries a mortality rate
of approximately 10% [3-5]. It is the premier reason for drug
withdrawal by the Food and Drug Administration (FDA) in the
United States [5,6].
The wide spectrum of clinical symptomatology, nonavailability
of specific diagnostic markers and lack of
standardization between studies performed to date make it
difficult to establish causality to a particular drug. Moreover,
causal association to a specific drug is heterogeneous. It depends
on the exclusion of other causes notably viral and autoimmune
hepatitis. Causality is dependent on the temporal relationship
of the drug to the derangement in patient’s liver function tests
(LFTs). As a result, sometimes certain scoring system such as
Roussel Uclaf Causality Assessment Method (RUCAM)  is used
to assess the probability of association. The RUCAM system is
a means of assigning points for clinical, biochemical, serologic
and radiologic features of liver injury which gives an overall
assessment score which reflects the likelihood that the hepatic
injury is due to a specific medication .
Annual incidence of DILI ranges from 1.3 to 19 per 100,000
in various databases, depending on the country of origin, type
of data and method of obtaining information [9-11] .The largest
drug category responsible for DILI is antimicrobials, lead by
amoxicillin-clavulanate [12,13]. Amongst antibiotics, ATDs
are another major group associated with DILI especially in the
developing world. Approximately 5.3% of all the cases in the
United States DILI Network (US DILIN) were reported due to
isoniazid (second only to amoxicillin-clavulanate) likewise 7%
of the cases in the Spanish DILI Registry were due to isoniazid
alone or in combination with other drugs [12,13].Other common
drug groups include non-steroidal anti-inflammatory drugs
(NSAIDs) [9,13], herbal and dietary supplements (HDS)  and
rarely statins [12,15,16].
A growing concern for pharmaceutical industry regarding
drug development is hepatotoxicity induced by the newer
molecular targeted agents (MTAs) which are increasingly being
used in oncology. A third of patients treated with a protein kinase
inhibitor experience liver injury, with pazopanib, sunitinib
and regorafenib identified as the potentially lethal agents .
Similarly, 10% of patients treated with immune checkpoint
inhibitors, such as ipilimumab, are susceptible to DILI .
Additionally, the epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor (TKI) gefitinib is associated with
18.5% frequency of hepatotoxicity. It has resulted in casualties
as well .
In many countries, DILI registries have been set up which
record every DILI case with a formal causality determination
process, providing in-depth information about the types of drugs
that cause DILI, the pattern of injury and the risk of mortality and
morbidity. There is paucity of data from South Asia with no such
DILI registries in place. This study aims to provide an analysis of
clinical presentation and outcome of patients admitted with the
discharge diagnosis of DILI from Pakistan.
Patients admitted at Aga Khan University Hospital Karachi
Pakistan, from January 2010 through December 2016, and
discharged with a diagnosis of DILI, were recruited. The course
of their hospital stay was reviewed through the medical record
Patients with known or suspected acetaminophen toxicity,
history of bone marrow or liver transplantation before the liver
injury event, history of malignancy of liver and metastasis to
liver, underlying hepatitis C virus (HCV), hepatitis B virus (HBV),
or nonalcoholic fatty liver disease were all excluded alongside
cases with other types of underlying chronic liver disease.
The diagnosis of DILI and the causal relationship between
liver injury event and implicated drugs were evaluated in a
formal and standardized fashion by using a causality instrument:
Roussel Uclaf Causality Assessment Method (RUCAM) .
Points were awarded for seven components comprising of
the following: time to onset of the injury following start of the
drug, subsequent course of the injury after stopping the drug,
specific risk factors (age, alcohol use, pregnancy), use of other
medications with a potential for liver injury, exclusion of other
causes of liver disease, known potential for hepatotoxicity of
the implicated drug and response to re-challenge. The RUCAM
provides a semi-quantitative evaluation of causality by assigning
−3 to +3 points to each of the aforementioned seven components.
Based on the final score, a causal relationship between the
implicated agent and the liver injury event was categorized as
highly probable (>8), probable (6–8), possible (3–5), unlikely (1
or 2), or excluded (<0).
According to the Council for International Organizations
of Medical Sciences (CIOMS) criteria, DILI is classified as
hepatocellular, cholestatic or mixed based on its R-value . The
R-value is defined as the serum ALT/ULN divided by the serum
ALP/ULN ratio. R-values > 5 were classified as hepatocellular, <
2 as cholestatic and 2–5 as mixed injury.
In-hospital morbidity was quantified in terms of prolonged
hospital stay, defined as hospital stay for more than 5 days.
Predictors of mortality and morbidity were assessed by
considering patients’ clinical and laboratory parameters
including liver synthetic functions (prothrombin time and serum
A total of 462 DILI cases were identified (Figure 1), out of
which 264 (57.6%) patients were male with a mean age of 50.83
(range: 20-94). By using the RUCAM model for drug causality
assessment, DILI was classified as definite or highly probable in
141 (31.1%), probable in 289 (62.5%) and possible in 34 (7.4%)
The severity of liver injury was found to be mild in 204
(44%), moderate in 78 (16.8%), and severe in 54 (13.8%)
patients while 116 (25.1%) cases were seen to have had liver
failure due to drug intake. Mortality was significantly high in
patients with liver failure (p value=0.006) (Table 1).
Encephalopathy (encephalopathy) was present in 98
(21.6%) patients on the day of hospital admission while patients
who presented with abdominal pain, vomiting, jaundice and
pruritus were in the following order: 57.1%, 57.1%, 54.1%, and
42.3% (Figure 3). Furthermore, mean total bilirubin levels, ALT
and AP levels were 5.37mg/dl (range: 0.20-79.1), 358.65 (range:
7-8938) IU/L and 168.68 (range: 32-1040) IU/L respectively.
In-hospital mortality was 122 out of 462 (26.5%) and
morbidity (quantified as prolonged hospital stay more than
5 days) was observed in 214 out of 462 (35.93%) patients.
None of the patients underwent a liver transplant due to nonavailability
of the facility at our institution and in the city
during that time period. On multivariate analysis, mortality
was significantly greater in patients with encephalopathy, male
gender, hepatocellular pattern of DILI, increased INR (>1.5),
acute liver failure and patients who were on ventilator support
in ICU (Table 2). Likewise, prolonged hospital stay (duration of
>5 days) was associated with female gender, increased ALT, AST
aspartate aminotransferase levels, use of ventilator support and
mixed pattern of DILI, (Table 3).
Drug induced liver injury is the most under-recognized
and under-reported cause of liver injury, ultimately leading
to underestimation of its burden. The present study analyzes
hospitalized patients suffering from drug induced liver injury
who were admitted in a tertiary care center in Pakistan, over a
seven-year period. This is a large data set related to DILI from a
developing country from where there is paucity of such kind of
One important information that was revealed from this study
is that the order and frequency of drugs associated with DILI
is different from the list provided in the report from the Drug
Induced Liver Injury Network (DILIN) and the Spanish Registry
[12,13]. These studies showed that amoxicillin-clavulanate was
the most common causative agent amongst the antimicrobials.
A recently published review found 9 of the top 10 causes of DILI
to be antimicrobial agents, majority of them antibiotics; this is a measure of their hepatotoxic potential, as well as the common
use and duration of treatment with these drugs .
We found ATDs to be the most commonly implicated drug
with approximately 64 % of cases that were reviewed having
received ATT. This reflects the differences in the epidemiology
of infectious diseases and corresponded to numbers observed
by other studies from this region . ATDs was followed by
homeopathic and herbal medications with 9% of cases having
received it, similar to other prior studies . After ATD, the
category of drugs most frequently implicated in DILI were the
homeopathic and herbal medications, with a frequency within
a range provided in prior studies from regions with a history
of common consumption . More than 20% of patients in
our series had encephalopathy accounting for fulminant or
acute liver failure at the time of presentation in the hospital.
Conversely, the Spanish registry reported very low number
of patients with fulminant hepatic failure with 11 out of 439
cases being classified as such [13,23]. The high prevalence
of encephalopathy in our study can be attributed to a delay in
presentation to the hospital with very little knowledge about the
drug being a cause of liver injury. Additionally, our center is one
of the main tertiary care hospitals in Pakistan that receives an
increasing number of complicated referrals.
Another noteworthy observation deduced from our study is
the fact that more than a quarter of hospitalized patients with
DILI died while in the hospital. The mortality rate in our study
appeared significantly high compared to that observed in several
other studies, which ranges from 10 to 17.3% [9,12,24,25].
This difference in mortality is perhaps due to the fact that our
series of DILI is for hospitalized patients which are expected to
be more severely ill. Another factor for high mortality in our
study could be the fact that ATDs was the leading cause of DILI
as it has been observed in an Indian study that mortality in DILI
patients with ATDs was significantly high compared to those
without ATDs; 21.5 % vs. 11.4 % respectively p = 0.02 . Lack
of facilities for liver transplantation could be another reason
for high mortality in our series. Very few studies have reported
predictors of outcome for DILI the include hepatocellular
damage, high bilirubin, female sex, as described by the US DILI
network . The Spanish registry and a Swedish study have
described the hepatocellular pattern of damage as the most
common form of liver injury associated with high incidence of
liver transplantation or death if patient presented with jaundice
[13,25]. In a Chinese study, ATDs were found to be the primary
etiological factor for fatal DILI. Additionally, the same study
also identified that hepatic encephalopathy, ascites, jaundice,
alcohol abuse and direct bilirubin levels were associated with
the death of DILI patients . Likewise, in an Indian study,
high-MELD score or a combination of ascites, encephalopathy,
high bilirubin, prothrombin time, and leukocyte count were
identified as predictors of mortality . In our study, we also
observed that mortality was significantly greater in patients
with encephalopathy, male gender, hepatocellular pattern of
DILI, increased INR (>1.5) and patients on ventilatory support
Limitations of the present study include a retrospective
study design and a sample population based in a single tertiary
care center setting. Non-availability of transplantation facility
for ultimate treatment of patients restricted us from reviewing
the outcomes in such patients in detail.
In the present study the most frequent cause of DILI in
hospitalized patients was seen to be ATD. More than a quarter
of patients died during hospital stay. As a result, care among
physicians is required while prescribing potentially hepatotoxic
agents. A close control of clinical and biochemical parameters
are required while prescribing potentially hepatotoxic agents
especially ATDs in our region. Additionally, efforts at the national
level should be undertaken to make the public more aware about
DILI especially while using ATDs.