Journal of Gastroenterologyand Hepatology (1998) 13, 745-750

REVIEW

Salmonella hepatitis
C H U T I M A PRAMOOLSINSAP A N D VIKIT VIRANUVATTI*

Division of Gastroenterology and Tropical Medicine, Department of Medicine, Ramathibodi Hospital,

Mahidol University, Bangkok, Thailand and *Division of Gastroenterology, Faculty of Medicine,
Siriraj Hospital, Mahidol University, Bangkok, Thailand

Abstract Typhoid fever is often associated with abnormal liver biochemical tests, but severe hepatic
involvement with a clinical feature of acute hepatitis is a rare complication. There have been more than
150 cases of salmonella hepatitis reported from both developed and developing countries. The docu-
mented incidence varies widely from less than 1% to 26% of patients with enteric fever. The possible
associated factors for development of salmonella hepatitis are virulence of the organisms, delayed treat-
ment and poor general health of the patients. The pathogenesis of severe hepatic involvement in sal-
monella infection may be multifactorial and includes endotoxin, local inflammatory andor host immune
reactions. Clinical jaundice in salmonella hepatitis usually occurs within the first 2 weeks of the febrile
illness. Hepatomegaly and moderate elevation of transaminase levels are common findings. Extreme
hepatic dysfunction with hepatic encephalopathy is a rare coexisting complication in salmonella hepati-
tis. A positive culture for salmonella from blood or stool is essential to differentiate salmonella hepati-
tis from other causes of acute hepatitis. Hepatic pathology is characterized by the presence of typhoid
nodules with marked hyperplasia of reticuloendothelial cells. The prognosis is usually good as salmo-
nella hepatitis responds well to a specific antibiotic therapy and jaundice resolves with clinical improve-
ment. The clinical course can be severe with a mortality rate as high as 20%, particularly with delayed
treatment or in patients with other complications of salmonella infection. As enteric fever is a common
infection, the recognition of salmonella hepatitis is of clinical importance.

Key words: jaundice, salmonella, typhoid hepatitis.

INTRODUCTION affect almost all major organs of the body. Extraintesti-

Enteric fever is an acute systemic disease caused by
ingestion of food or water contaminated with the organ-
ism Salmonella typhi or Salmonella paratyphi. The infec-
tion occurs worldwide and is still an important public
health problem in many developing countries. Each
year, the infection affects more than 16 million people
worldwide with at least 600 000 deaths.'j2 The annual
incidences of typhoid fever in 1995 in developing coun-
tries were 150 per 100 000 population in South Africa
and are highest in Papua New Guinea and Indonesia
where more than 1000 cases per 100 000 population
are each reported.'
The usual pathological site of salmonella infection is
the lymphoid tissue of the gastrointestinal tract.
Haematogenous dissemination of the organism or its
endotoxin results in systemic involvement which can
nal systemic involvement can cause multiple and even
fatal complications and these include liver, central
nervous system, gall-bladder, kidney, lung and heart.3
Hepatic involvement in typhoid fever is classified into
two groups: either hepatomegaly or abnormal bio-
chemical tests, where hepatic involvement is of no clin-
ical significance or hepatic involvement as the dominant
feature and often clinical jaundice is the mode of pre-
sentation. Mild hepatic involvement with slightly abnor-
mal liver function tests is common in salmonella
infection and is found in 50% of cases, while isolated
hepatomegaly occurs in 25% of the patients. Such mild
hepatic involvement is not associated with significant
organ dysfunction and responds well to specific treat-
ment.
Severe hepatic involvement in typhoid fever was first
described in 1899 by Osler, who documented eight

Correspondence: Dr Chutima Pramoolsinsap, Division of Gastroenterology and Tropical Medicine, Department of Medicine,
Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
Accepted for publication 1 August 1997.
746 C Pramoolsinsap and V Viranuoatti

cases with hepatomegaly and jaundice out of 1500 cases Table 1 Reports of salmonella hepatitis
of typhoid feverq4The condition was previously called
'hepatitis typhosa' and is now termed 'salmonella No. cases Jaundice in
hepatitis' because the clinical features of jaundice may Typhoid Salmonella salmonella
be dominant as in other common causes of acute Year Countries fever hepatitis (%) hepatitis
hepatitis. Severe hepatic involvement has also been
described in paratyphoid infection,536 although it 18994 UK 1500 8 (0.5%) +
appears to be less common than in typhoid infection. 19467 UK 360 13 (3.6%) +
'Salmonella hepatitis' is now used to cover jaundice 1961' Iran 530 6 (1.1%) +
caused by an infection with either S. typhi or S. paraty- 19679 Chile 3476 14 (0.4%) +
phi and the condition is now being recognized as a 19745 Sri-Lanka 92' 5 (5.4%) +
definite entity. 19761° Vietnam 15 4 (26.6%) +I-
1977" Thailand 108 1 1 (10.2%) +/-
1977" Brazil 189 14 (7.4%) +I-
198113 Spain 130 2 (1.5%) +/-
DEFINITION AND EPIDEMIOLOGY 198414 India 925 5 (0.5%) +
A standard definition of 'salmonella hepatitis' has yet to
1988" India 36 3 (8%) +
be established, but jaundice as a predominant feature
199016 India 210 10 (4.8%) +
in typhoid fever with hepatomegaly and abnormal liver
199117 Singapore 370 5 (1.4%) +
function tests have been used in most studies or reports. 1972" USA 1* +
The present review included reports of typhoid hepati- 197819 India 1* +
tis or salmonella hepatitis in which S. typhi or S. pamty- 198l2' Africa 1* +
phi were isolated from either blood, bone marrow 1986" Mexico 8 +I-
and/or stool cultures. 198922 India 4* +
Salmonella hepatitis has been documented from both 199423 Africa I* +
endemic and non-endemic areas. As shown in Table 199524 Turkey 1* +
l,4,G24 and including many other documented case 19966 USA 27 +
there have been more than 150 cases of sal-
monella hepatitis reported in the literature. The major- *Associated with other complications of typhoid fever;
ity of the reports are in patients with typhoid infection *including 34 cases with paratyphoid fever.
but it can also occur in patients with paratyphoid infec-
tion. The organisms most often responsible for the com-
plication of hepatitis in the paratyphoid group are S.
paratyphi, types A and B.3"36The reported incidence of Salmonellosis is an important infection in immuno-
salmonella hepatitis ranges from 0.426% of cases of compromised hosts, in particular human immunodefi-
typhoid fever and is highest from a study in Vietnam." ciency virus (HIV)-positive patients. In comparison
The most frequent reports are from India where 4-8% with the normal population, salmonella infection is
of patients with typhoid fever had salmonella hepatitis. 15-100 times more common in patients with HIV-
Some of the reported patients are associated with other positive/acquired immunodeficiency syndrome
(AIDS).4W3
complications of typhoid fever (e.g. en ~ ep h a lo p a th y ,'~ ~ ~ ~ The most commonly isolated serotypes in
bleeding diathesis19~z0~z4 or renal failure;'83z5Table 1). an HIV-positive subgroup are Salmonella enteritidis and
Nevertheless, salmonella hepatitis is not mentioned Salmonella typhim~rium.~'Recurrence of salmonella
in several large reviews of severe complications of sal- infection is likely to be more common in these patients
monella infection (e.g. typhoid intestinal p e r f ~ r a t i o n ~ ~and has been reported in 337 of 70 551 patients with
jaundice due to bacterial infection3' or salmonella bac- AIDS.43 Although severe complications are more
teraemia with septic metastasi~~~). The variation in the common in immunocompromised hosts, the incidence
occurrence of salmonella hepatitis in the literature of salmonella hepatitis in HIV-positive groups has yet
could be due to differences in the endemicity of enteric to be elucidated.
fever, in recognition of the disease as well as the avail-
ability of early specific treatment.
There are no known definite predisposing factors for PATHOGENESIS
salmonella hepatitis, although the occurrence appears
to be more common in adult male patients, but can also Humans are the only reservoir of salmonella infection.
occur in 4-10-year-old childrenz2and in the elderly. As Salmonella typhi or S. paratyphi enters the body through
salmonella hepatitis appears to be more common in the the mouth and penetrates the lymphoid tissue of the
East, it is not yet clear whether there is a relationship gastrointestinal tract. Haematological dissemination
between a genetic susceptibility to the bacterial toxin in then takes the organism to the reticuloendothelial cells
an individual. The hepatic involvement has been pro- of the liver, spleen and bone marrow. The hepatic retic-
posed to be more common and more likely to be severe uloendothelial system plays a major role in engulfing the
in patients with anaemia, malnutrition, poor health and invading bacteria by producing granulomatous lesions
in those with relapsed infections or when a latent infec- and diffuse inflammatory changes.The pathogenesis of
tion is activated.15 salmonella hepatitis is not entirely clear, but is proba-
Salmonella hepatitis
bly multifactorial and includes either direct hepatic
damage from endotoxin or from the inflammatory
p r o ~ e s s ~andor' , ~ ~ secondary
~ damage to the host
immune mechanism^.^^^^^^^'
The severity of hepatic pathological lesions in typhoid
fever has been found to correlate with clinical severity
and microbiological properties of more virulent strains
of S. typhi, suggesting that virulence of the organisms is
an important determinant of hepatic damage. Intact sal-
monella bacilli have been found in the liver of patients
with salmonella hepatitis.21Hepatic lesions have been
found to be more severe in infection with virulent
strains of H1-d flagellar serotype while strains lacking
Vi antigen are less infective and less virulent.45A6
genotypes of S.typhi are found to be associated with
disease s e ~ e r i t y . *This
~ > ~ ~evidence suggests that liver
injury in salmonella infection may occur following local
inflammatory reactions of virulent strains or by release
of endotoxin within the reticuloendothelial cells.47 cells and there is always marked hyperplasia of Kupffer
Experiments in rabbits have shown that injection of S.
zyphi endotoxin produces focal necrosis of liver cells;
lesions closely resemble pathological findings in
patients with salmonella he pa ti ti^.^' The hepatic lesion
in the studied rabbits showed marked infiltration of
mononuclear phagocytes in the areas of necrosis and
Kupffer cells filled with debris.48Nevertheless, further
clarification is needed for the pathogenic role of endo-
toxin in salmonella hepatitis, as circulating endotoxins
are detected only in some reports of patients with
typhoid fever.49
A host immune-response reaction has been suggested
as important in the pathogenesis of vital organ dys-
function in typhoid infection." An immunofluorescent
study of liver biopsies demonstrated deposits of conju-
gated antibodies (anti-immunoglobulin (Ig)G, IgM,
IgA) and complement components C3 in the epithelial
cells of the bile canaliculi of patients with salmonella
he pa ti ti^.'^ A similar finding of immune complex depo-
sition has been observed in renal biopsy tissue from
patients with typhoid fever.51
The mechanism of jaundice in salmonella infection is
still obscure but may be similar to other bacterial infec-
. ~ ~injury
tions which are m ~ l t i f a c t o r i a lAn ~ ~ ~ of the hepa- The clinical picture of patients with salmonella hepati-
tocytes' secretory function with or without hypoxia is
caused by bacillary t ~ x a e m i a . ~In~ .addition,
~~
hepatitis, increased haemolysis, granulomatosis hepati-
tis, cholangitis and portal phlebitis may all contribute
to the development of jaundice in salmonella hepatitis.
Encephalopathy is a rare complication of typhoid
fever and occasionally occurs in patients with salmo-
nella hepatitis.'9323 It is not known whether this neuro-
logical manifestation is due to hepatic impairment from
salmonella hepatitis or salmonella s e p t i ~ a e m i a . ' ~ , ~ ~ ~Hepatomegaly
Disseminated intravascular coagulation, another clini-
cal feature of an extreme hepatic dysfunction, has been
reported in some patients with salmonella hepati-
tis19,20,24 but it rarely occurs with hepatic encephalopa-
thy.Ig Phospholipase A2 has been found to be elevated
in severe patients with salmonella hepatitis with
neurological manifestation^.'^ Although asterixis or
flapping tremor has not been found in encephalopathy
associated with salmonella hepatitis, the pathogenesis
of hepatic encephalopathy remains to be elucidated
747
because the number of reported cases remains
scanty.
PATHOLOGY
The liver pathology in typhoid infection is characterized
by the appearance of focal non-specific reactive hepati-
tis.5i35 In salmonella hepatitis, the histological pattern
under both light and electron microscopes shows mild
hepatitis in which there is marked reticulo-endothelial
hyperplasia with many lymphoid cells in the hepatic
sinusoids. The hepatic cell lesion is particularly evident
Some during jaundice, manifested by reticulum endoplasmic
dilatation, mitochondria1 alteration and biliary can-
aliculus injury.12Although the diffuse hepatic lesion as
seen in viral hepatitis is not always seen in salmonella
hepatitis,55S. typhi can be occasionally detected in liver
cells. These Kupffer cells tend to aggregate as a granu-
loma formation known as 'typhoid nodules' consisting
of a collection of macrophages, mononuclear cells with
infiltration of perisinusoidal and portal spaces, with or
without central n e c r ~ s i s .The
~ ~ ' typhoid
~ nodules appear
to be characteristic of typhoid fever and are situated in
the parenchyma of the outer one-third of the liver lobule
or randomly distributed throughout the l o b ~ l e . ' ~ ' ~ ? ~ ~
Patients with elevated transaminase usually show more
altered histopathological lesions including the presence
of isolated necrotic hepatic cells, but the correlation
between the laboratory and histopathological finding is
still lacking. Other associated histological abnormalities
are mild cholestasis, cloudy swelling and the presence
of small fat globules in the hepatocytes. There is usually
no ductular lesion seen in salmonella hepatitis, except
in one study in which the section was similar to lep-
tospirosis.12
CLINICAL FEATURES
tis is similar to the classical picture of enteric fever. In
toxic addition to high fever, acute toxaemia and other pro-
dromal symptoms, jaundice usually occurs as one of the
presenting symptoms during the first week of the febrile
In untreated cases, jaundice may be delayed
from the second to the fourth week of the illness.I2The
duration of jaundice varies with the clinical course of
enteric fever, but in almost all patients, jaundice will
resolve with clinical recovery.
'~ is a common feature and found in
almost all patients with typhoid hepatitis and in 50%
or more of paratyphoid he pa ti ti^.^ The documented
hepatomegaly ranges from just palpable to 2-4.5 cm
and even 10 cm" below the right costal margin. Other
less commonly associated physical signs include
splenomegaly and relative bradycardia.6Liver abscesses
and cholangitis are other rare complications of hepatic
involvement in salmonella hepatitis."" In some severe
patients, salmonella hepatitis may occur with other
complications of typhoid fever (e.g. e n c e p h a l i t i ~ , ' ~ ~ ~ ~ ~ ~ ~
748 C Pramoolsinsap and V Viranuvatti

myocarditis,I2 renal or bleeding diathe- many other febrile causes of jaundice, particularly
sis19,20,24). during the first 5 days of illness. In most areas, acute
Neuropsychiatric manifestation in typhoid fever is viral hepatitis and other non-infectious causes of hepati-
an important complication and includes delirium, tis6,33,59 (e.g. toxic or alcoholic hepatitis) are major
obtundation, stupor and coma, typhoid meningitis, differential diagnoses of salmonella hepatitis. In
encephalomyelitis, transverse myelitis with spastic developing countries, salmonella hepatitis may mimic
paraplegia, Guillain-Barri syndrome, peripheral and many other infectious disease^'^^^^^^^ (e.g. leptospirosis,
cranial neuritis and psychosis.' The clinical pictures of malaria, rickettsia1 infection, amoebic abscess, brucel-
typhoid encephalopathy in patients with or without losis, tularaemia, tuberculosis, visceral leishmaniasis or
severe liver involvement are similar and range fiom mild toxoplasmosis).
delirium to psychosis, mania or marked Abnormalities of liver biochemical tests in salmonella
These neurological presentations of encephalopathy are hepatitis are usually less marked than those found in
indicative of progressive disease unaltered by specific acute viral hepatitis, but are often non-specific. In com-
therapy.52In Thailand, neuropsychiatric manifestations parison with acute viral hepatitis, patients with salmo-
in typhoid fever including parkinsonism have been nella hepatitis usually have lower bilirubin levels, less
reported, but these occur as a rare c~ m p lica tio n .~ .~ ~ transaminase elevations and lower peak serum ALT and
AST, but higher peak lactic dehydrogenase (LDH).6
The ALT/LDH ratio may be the best discriminator of
the two conditions as it is usually less than 4.0 in sal-
LABORATORY FINDINGS monella hepatitis but greater than 5.0 in acute viral
Abnormalities of liver biochemical tests are commonly hepatitis.6 In hepatic ischaemia or acetaminophen
found in patients with typhoid fever. In more than half injury, the reported ALTLDH ratio is usually lower
the patients with typhoid fever, including uncompli- than 1.5.59
cated cases, mild elevation of transaminases and alka- Diagnosis of salmonella hepatitis should be consid-
line phosphatase occur in the second and third week of ered in acute febrile hepatitis with relative bradycardia
A three to five-fold elevation of serum and a left shift of white blood cells. A routine practice
transaminase is the most characteristic laboratory of obtaining blood culture from febrile patients with
abnormality, occurring in approximately 94% of cases jaundice is helpful in establishing the diagnosis. The
of typhoid fever.58 Hyperbilirubinaemia (serum biliru- bone marrow aspirate culture seems to be the best bac-
bin > 1.8 mg/dL) is present in up to 23% of cases.56In teriological confirmation, as salmonella recovery has
one recent study, 90% of patients with typhoid fever been found in 8595% of patients with enteric fever,
had elevation of fasting and postprandial serum bile including those who had received antibiotic^.^^ The
acid levels, which returned to normal after appropriate Widal's test is of limited diagnostic value, particularly
antibiotic treatment.40 in endemic areas and in patients with chronic liver
disease, as 27% of these were found to be falsely posi-
In patients with salmonella hepatitis, biochemical
' ~ ~ ' ~tive6'
liver function tests are always a b n ~ r m a l . ~ ~The ~ ' ~ The recent serological diagnostic test detecting
derangement is more severe than in cases of uncompli- antibodies to S. cyphi lipopolysaccharide is promising,
cated typhoid fever. Serum bilirubin levels usually range with 92% sensitivity and 98% specificity.62Other pos-
from 2 to 6 mg/dL but can be as high as 10-16 mg/dL. sible causes of jaundice may have to be excluded
There is usually a two to five-fold elevation of transam- as jaundice in typhoid fever may be caused by other
inase levels (or approximately 300 units) but they rarely coincidental or superimposed infections (e.g. hepatitis
rise to more than 1000 units. Alkaline phosphatase is A virus33 or malaria6'). The presence of a typhoid
either normal or slightly elevated (by 20-30 units). In nodule with Kupffer cell hyperplasia is characteristic of
more than 66% of patients with salmonella hepatitis, salmonella hepatitis and liver biopsy may help to dif-
serum levels of aspartate transaminase (AS") are higher ferentiate it fiom acute viral hepatitis.
than alanine transaminase (ALT).6 Cholesterol levels
are normal or slightly elevated, but usually below
300 mg/dL. As with uncomplicated typhoid infection,
the white cell count is usually not increased, but shows TREATMENT A N D PROGNOSIS
a left shift. Thrombocytopaenia is common and can be
found in 25% of cases. There are no characteristic fea- A successful treatment requires prompt diagnosis for
tures of other biochemical findings or serum protein use of an appropriate antibiotic. The choice of antibi-
levels. A prolonged prothrombin time has been docu- otic for treatment of salmonella hepatitis is the same as
mented in up to 41% of patients, although this is not for treatment of uncomplicated enteric fever. The three
usually of clinical ~ignificance.~~ fist-line antibiotics (i.e. chloramphenicol, trimetho-
prim-sulphamethoxazole or amoxycillin) are widely
used in developing countries. Antibiotic sensitivity
should be tested in all isolated strains because of an
DIAGNOSIS AND DIFFERENTIAL increasing problem of salmonella resistance to one or
DIAGNOSIS two of these first-line antibiotic^.^^^ A high-grade sal-
monella resistance to all of the three antibiotics has
Salmonella hepatitis is often present with acute hepati- been found in some endemic areas (i.e. Pakistan, India,
tis and its clinical features are indistinguishable from China and the Arabian gulf).66For multidrug-resistant
Salmonella hepatitis
strains, fluoroquinolones o r the third-generation
day course of
cephalosporins are both e f f e ~ t i v e . ~5~ A
fluoroquinolone is the treatment of choice in uncom-
plicated enteric but a longer duration of 7-14
days is recommended in severe salmonella infection.65
Supportive treatment is important in salmonella hepati-
tis. Nutritional or vitamin supplementation is required
in cases of malnutrition or anaemia.
Despite severe hepatic involvement, the prognosis
of salmonella hepatitis is usually good; in particular
in patients with early diagnosis. Jaundice including
hepatomegaly and splenomegaly usually resolves within
2-3 weeks after successful treatment of the infection.
Elevation of transaminase or alkaline phosphatase
usually persists for 10-1 5 days and may have a longer
duration than jaundice. T h e reported mortality rates
in salmonella hepatitis range from O6 to 20%.16 T h e
prognosis is worse when the disease occurs in patients
with malnutrition or anaemia who receive limited,
delayed medical care and in patients with multiple
complications.
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