Typhoid Hepatitis in Children

by Avinash K. Shettya MD, Seema R. Mitalb MD, Abdul Husein T. Bahrainwalab MD, Raju P. Khubchandanib MD,
and Narsing B. Kumtab MD
a
Departments of Pediatrics, Louisiana State University Medical Centre, New Orleans, LA, USA
b
Kasturba Hospital for Infectious Diseases, Bombay, India

Summary
Liver involvement is commonly observed in patients with typhoid fever. However, a hepatitis-like
picture with fever and jaundice is unusual and infrequently reported in the paediatric literature. Our
aim was to characterize the clinical picture, biochemical features, and prognosis of typhoid hepatitis.
One hundred cases of typhoid fever (age 0 to 12 years), proven by positive blood cultures to
Salmonella typhi, were studied with special reference to hepatic dysfunction. Of these, eight patients
were found to have hepatitis during the course of their illness. All had high fever, tender
hepatomegaly, elevated serum bilirubin (in the range of 2.5–5.8 mg/dl), and elevated serum alanine
transaminase levels (in the range 100–620 IU/l). All the eight patients showed complete clinical and
biochemical recovery in response to appropriate antibiotics. The clinical picture of typhoid hepatitis
frequently mimics acute viral hepatitis. In tropical areas, the differential diagnosis of a child
presenting with fever and jaundice should include typhoid hepatitis.

Introduction serological markers for viral hepatitis. One hundred

Although typhoid fever is a very common disease in the
Third World, sporadic cases and limited outbreaks could
always occur in industrialized countries as a result of
increasing air travel.1;2 Various organs including the
liver have been involved in the course of typhoid fever,
resulting in a wide spectrum of presentations.3;4
Biochemical abnormalities of liver function tests are
commonly found in patients with typhoid fever.5
However, a hepatitis-like picture with fever and frank
jaundice in typhoid fever, also called ‘hepatitis typhosa’
is uncommon.6 Although well recognized in adult
cases,6¹9 reports of typhoid hepatitis in children are
very few and limited only to case reports.10;11 The
purpose of this study was to examine the clinical picture,
biochemical features, and prognosis of typhoid hepatitis
in children.
Patients and Methods
Study population
The study was conducted at Kasturba Hospital for
Infectious Diseases in Bombay, India. The diagnosis of
typhoid hepatitis was established when a clinical profile
of acute hepatitis was found in association with positive
blood cultures for Salmonella typhi and negative
Acknowledgements
We thank Dr Russell W. Steele, MD for his critical review of the
manuscript.
Correspondence: Avinash K. Shetty MD, Paediatric Infectious
Diseases, Room G312, Stanford University School of Medicine,
300 Pasteur Drive, Palo Alto, CA 94305-5208, USA.
cases of typhoid fever in children (age 0 to 12 years)
were identified from hospital medical records from
February 1990 to February 1992. These records included
pertinent clinical information and sequential results of all
diagnostic tests performed when patients were in the
hospital.
Measurements
Detailed clinical history and a thorough physical
examination were performed in all cases with special
emphasis on recording hepatomegaly, jaundice, bleeding
manifestations, altered mental status, and stigmata of
liver disease. Cases of acute viral hepatitis, toxic and
drug-induced hepatitis, and chronic liver disease were
excluded by history, physical examination, and relevant
laboratory investigations. Laboratory tests included
complete blood count; urinalysis for albumin, sugar,
bile salts, bile pigment, urine urobilinogen; peripheral
blood smear for malarial parasites; and blood cultures in
patients suspected to have liver dysfunction, viral sero-
logical markers, including hepatitis-B surface antigen,
anti-hepatitis A virus immunoglobulin M, and liver
biochemical tests [serum bilirubin, serum alanine amino-
transferase (ALT), and prothrombin time], were obtained
on admission and repeated serially throughout the
duration of hospitalization. The complications of the
disease, type of antibiotics used, and final outcome were
recorded.
Results
Acute hepatitis was suspected in 19 patients on the basis of
fever, persistent vomiting, tender hepatomegaly, jaundice,

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 A. K. SHETTY ET AL.

Table 1
Clinical features and laboratory data in eight cases of typhoid hepatitis
Case No. 1 2 3 4 5 6 7 8

Age (years) 7 8 5 months 10 9 10 12 11

Sex M M M F M M M F
Fever þ þ þ þ þ þ þ þ
Jaundice þ þ þ ¹ ¹ þ þ ¹
Coma ¹ ¹ ¹ ¹ ¹ ¹ þ ¹
Hepatomegaly þ þ þ þ þ þ þ þ
Splenomegaly þ þ þ ¹ þ þ þ ¹
Serum bilirubin: total direct (mg/dl)
at diagnosis 3.2/2.6 2.5/1.5 2.5/1.8 0.8/0.5 0.9/0.5 5.8/4.0 5.1/4.2 0.6/0.3
at 2 weeks 1.0/0.5 0.6/0.4 0.9/0.6 0.6/0.4 0.6/0.3 1.8/1.2 3.2/1.8 0.6/0.3
Serum alanine transaminase (IU/l)
(nl < 40 IU/l)
at diagnosis 450 129 100 140 128 620 409 110
at 2 weeks 50 35 20 22 60 86 50 18

or altered mental status. Of these, eight patients with a final
diagnosis of typhoid hepatitis were identified (Table 1).
Six were males and two were females, with age ranging
from 5 months to 12 years. All cases presented with high
fevers (temperature exceeding 1048F), nausea, persistent
vomiting, and tender hepatomegaly. In addition, jaun-
dice was noted in five patients, splenomegaly was
present in six, and one patient developed hepatic
encephalopathy. Common clinical signs of typhoid
fever in adults12 such as relative bradycardia and rose
spots were not observed. Diagnoses considered on initial
admission included acute viral hepatitis (five cases),
malaria (two cases), and pyrexia of unknown origin (one
patient). Signs and symptoms of acute hepatitis developed
in all cases after an average of 11 days of high-grade
fever. None of the patients received antibiotic therapy
prior to hospital admission.
The total serum bilirubin ranged from 2.5 to 5.8 mg/dl
(median value of 3.2 mg/dl) with a predominantly
conjugated hyperbilirubinaemia. Elevation of ALT was
noted in all eight cases, with values ranging from 100 to
620 IU/l (median value of 134.5 IU/l, normal 3–30 IU/l).
All eight patients with typhoid hepatitis were treated
as inpatients. The choice of antibiotics used for treatment
included chloramphenicol (one patient), cefotaxime (one
patient), and ciprofloxacin (six patients). Clinical relief
was observed within a period ranging from 1 to 2 weeks
of starting antimicrobial therapy. One patient had a
stormy hospital course complicated by altered mental
status, gastrointestinal tract bleeding and abnormal
prothrombin time in addition to jaundice. The recovery
was uneventful in all cases and no deaths were reported.
The follow-up enzyme studies were found to correlate
with the clinical response.
Discussion
Typhoid fever is an acute febrile illness that constitutes a
major public health problem in many developing areas of
the world, including India.13;14 The disease is also being
increasingly reported from the developed world.2;15
Typhoid fever in the developed world is usually acquired
during foreign travel to regions where the disease is still
endemic,1 or from contact with chronic asymptomatic
carriers of Salmonella typhi from these areas.16;17 When
these carriers are food handlers, epidemic outbreaks have
occurred.18
Hepatic complications from typhoid fever were reported
as early as 1899 by Osler.19 Since then, several reports of
typhoid hepatitis have been described in adults.6¹9
However, very few reports detailing the spectrum of hepatic
injury in typhoid fever exist in the paediatric literature.10;11
Although hepatomegaly is seen in one quarter of typhoid
cases,3 clinically significant liver disease is uncommon.
The reported incidence of typhoid hepatitis varies from
0.4 to 6 per cent.6;11;20 The diagnosis of typhoid hepatitis
must be confirmed by isolation of Salmonella typhi in
blood or stool cultures in association with clinical and
biochemical findings of hepatitis. The spectrum of hepatic
manifestations in typhoid fever may include hepato-
megaly or elevated serum aminotransferases during the
typical febrile course of the disease; less frequently,
hepatic involvement may be a dominant feature and
the mode of presentation in typhoid hepatitis.6 Several
patient series have previously reported biochemical
evidence of hepatic dysfunction in 23–60 per cent of
cases.3;6;21 Biochemical evidence of hepatic insult without
hepatomegaly has also been reported in a minority of
patients.5
The present study was undertaken to highlight the
clinical and biochemical features of typhoid hepatitis.
All patients with typhoid hepatitis had evidence of tender
hepatomegaly. The overall incidence of clinical jaundice
in typhoid fever was 5 per cent. An additional 3 per cent
had symptomatic elevation of liver enzymes without
hyperbilirubinaemia. Since liver function testing was not
done as a routine investigation in all patients, we were
unable to quantify the overall incidence of elevated liver

288 Journal of Tropical Pediatrics Vol. 45 October 1999

A. K. SHETTY ET AL.
enzymes. The lack of testing for some viral serological
markers that are currently available, such as the antibody
to the hepatitis E, C, and even A viruses in the early part
of the study, could have resulted in our inability to
diagnose mixed infections with both Salmonella and a
hepatotrophic virus. However, this possibility seems
unlikely in view of the prompt response of the patients to
appropriate antibiotic therapy. The only significant
complications noted in the current series included hepatic
encephalopathy in one patient. In this study, all patients
survived their severe illness and completely recovered
from their symptoms.
In many tropical countries Plasmodium falciparum
malaria, typhoid fever, viral hepatitis, and amoebiasis
are common diseases of childhood. All four conditions
can present with fever and jaundice. Because malaria is
rather common and is associated with the greatest risk of
early complications, it is prudent to examine the thick
blood film for malarial parasites at presentation. In
P. falciparum malarial hepatitis, jaundice is an early
manifestation accompanied by pallor, haemoglobinuria,
and evidence of indirect hyperbilirubinaemia. The clinical
picture of typhoid hepatitis and acute viral hepatitis are
very similar, often leading to erroneous initial diagnosis.9
Lack of appropriate testing for Salmonella infection may
result in a considerable delay in making the diagnosis
and prompt initiation of appropriate therapy. While no
specific clinical features can be attributed to typhoid
hepatitis, the presence of continuous fever persisting
well beyond onset of jaundice favours typhoid hepatitis,
while in acute viral hepatitis, fever usually comes down
after the appearance of jaundice. Furthermore, the period
between onset of fever and onset of jaundice is usually
1 to 7 days in viral hepatitis, while typhoid hepatitis
usually occurs in the second week of illness. Biochemi-
cally, the peak levels of serum transminases are usually
lower in typhoid hepatitis compared to the markedly
elevated levels seen in acute viral hepatitis. The serum
lactic dehydrogenase (LDH) enzyme level can be helpful
in differentiating acute viral hepatitis from Salmonella
hepatitis, as well as toxic and ischaemic hepatitis.22 A
recent study found that the admission ALT/LDH ratio,
when both enzymes were expressed in multiples of upper
limit of normal, to be the best discriminator between
typhoid hepatitis and acute viral hepatitis.9 Histopathol-
ogy of the liver in typhoid hepatitis may range from non-
specific inflammatory changes to markedly cloudy
swelling, and focal areas of hepatocyte necrosis with
mononuclear cell infiltration. Marked hyperplasia and
aggregation of the Kupffer cells may result in the
formation of typhoid/mallory nodules, a typical feature
of typhoid hepatitis.6;21;23 These changes are reversible
and subside without residual damage.21 In addition,
dilatation and congestion of the hepatic sinusoids and
portal infiltration with mononuclear cells may be seen.6
Although percutaneous liver biopsy may help differ-
entiate typhoid hepatitis form acute viral hepatitis,24 this
procedure may be necessary only in the absence of a
definitive diagnosis.
Journal of Tropical Pediatrics Vol. 45 October 1999
The pathogenesis of typhoid hepatitis is unknown.
Researchers have postulated that systemic endotoxaemia
may not have a major role,7 although endotoxin production
at sites of multiplication of S. typhi, as in the liver, may
provoke a granulomatous or mononuclear inflamma-
tory response.11;25 Intestinal ulceration leading to invasion
of the liver by bacteria or toxin may also play a role, since
similar changes have been described in patients with
ulcerative colitis, regional ileitis, and invasive
amoebiasis.6
In conclusion, imported cases of typhoid fever may
occur more frequently in industrialized countries as a
result of increased world travel. Some cases of typhoid
fever may present with jaundice and may mimic the
clinical picture seen in malaria, viral hepatitis, and
amoebic liver disease. In endemic areas, the differential
diagnosis of a child presenting with fever and jaundice
should include typhoid hepatitis, since the condition
responds well to specific therapy and carries an excellent
prognosis. Although rare, physicians need to be aware of
this entity because early diagnosis will avoid unneces-
sary morbidity and mortality.
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