ABSTRACT
Hepatitis A virus (HAV) has some life-threatening extrahepatic
complications, such as acute acalculous cholecystitis (AAC). We herein
reported a HAV-induced AAC case in a young female, who developed acute
liver failure (ALF) during the course of her disease and preform a
literature review.
Keywords: Hepatitis A virus, Acalculous cholecystitis,
HAV-induced AAC
INTRODUCTION
Hepatitis A virus (HAV), a positive-sense, single-stranded RNA virus in
the Picornaviridae family, was discovered in 1976 by Feinstone and
colleagues.1–3 HAV is transmitted through
person-to-person contact via the oral-fecal route from food and water
contamination.4 Infecting around 1.4 million cases per
year globally, HAV is seen all over the world; nevertheless, the
incidence of HAV has declined considerably in countries that implemented
vaccination and immunization.1,5,6 HAV mostly causes a
self-limited infection that is usually clinically
asymptomatic.7 Prodromal symptoms, which are more
common in children than adults, manifest as fever, malaise, nausea,
vomiting, and anorexia about one month after
exposure.2 The main symptoms in adults include
diarrhea and jaundice, while pediatric infections are often
asymptomatic.8
Although mostly self-limiting, HAV has several unusual and
life-threatening hepatic manifestations and complications, such as acute
liver failure, relapsing hepatitis and HAV-associated prolonged
cholestasis.9–11 Additionally, HAV has important and
less-distinguishing extrahepatic manifestations, including skin rash,
acute renal failure, myocarditis, guillain barre syndrome, ascites,
pleural effusion, and AAC.12–15 As a rare
extrahepatic manifestation of HAV, AAC is an acute inflammatory disease
of the gallbladder without evidence of cholecystolithiasis which
comprises 5-10% of all acute cholecystitis cases.16AAC usually manifests in critically-ill patients, especially those
hospitalized in the intensive care unit (ICU), and is associated with
several risk factors (e.g., fasting, total parenteral nutrition,
mechanical ventilation, shock, and sepsis) and high mortality (around
30-50%).17–19 The pathogenesis of AAC is
multifactorial, anatomical and functional, such as gallbladder ischemia,
bile excretion disorder, cholestasis, and microbial
infection.16,20
Herein, we reported a case of AAC as a complication of HAV in a
35-year-old female without any past medical history, provided a
comprehensive literature review, and discussed importance, challenges
and critical management of HAV-induced AAC.
CASE PRESENTATION
A 35-year-old white woman was presented with anorexia, fever, nausea,
nonbilious emesis and a five-day history of epigastric abdominal pain.
There was no history of dark urine and stool discoloration. She denied
any history of previous diseases such as sexual transmitted diseases or
malignancy, in addition to using tobacco, alcohol, and illicit drug use.
She was a housewife and had no history of contact with an individual
with similar symptoms. taking certain medication or recent travel in the
last 6 months and her family history was noncontributory. The
vaccination history of the patient has been done in full according to
the national protocol.
At the admission, physical examination showed body temperature of 37.3∘C (axillary), heart rate of 75 beats/minute, blood
pressure of 110/75 mmHg, and an icteric sclera. On the abdominal
examination, there was severe tenderness during pressure in the right
hypochondrium area (below the 9th-10th rib) during inhalation (positive
Murphy’s sign), without peritoneal signs or fluid wave. There was no
evidence of splenomegaly and hepatomegaly on abdominal palpation. Skin
examination revealed no evidence of characteristic skin lesions such as
palmar erythema, spider angioma, and/or caput medusae.
Blood counts showed a white blood cell count at 3.2 ×
109 /liter, hemoglobin level of 13.3 g/dl, and
platelet count is 162 × 109 /liter. The serum level of
aspartate aminotransferase (AST)
was 3665 IU/L (Normal < 40 IU/L), alanine aminotransferase
(ALT) 3036 IU/L (Normal < 40 IU/L), gamma glutamyl transferase
(GGT) 26 IU/L, (Normal < 40 IU/L) and alkaline
phosphatase (ALP) 116 IU/L (Normal < 206 IU/L). The laboratory
analysis revealed hyperbilirubinemia of 4.47 mg/dL (Normal <
1.1 mg/dL) with a conjugated bilirubin of 2.31 mg/dL. Further, the
C-reactive protein (CRP) level was 71 mg/L. Laboratory investigations of
the patient in the course of hospitalization are listed in Table 1.
Furthermore, on the evaluation of acute liver disease, the initial
routine liver testing was requested, in which positive
serologies for viral hepatitis suggested acute hepatitis A infection
(Table 2). Serologies was detected via Enzyme-linked immunosorbent assay
(ELISA), using a Roche Cobas C311 chemistry analyzer, HITACHI. In
additional investigations, serum levels of antinuclear antibodies (ANA),
anti-smooth muscle antibody (ASMA), and anti-liver kidney microsomal
type 1 (anti-LKM-1) antibody were measured, all of which were normal.
EBV IgM, IgG, and heterophile antibody were negative.
On imaging. abdominal ultrasound revealed liver and spleen with normal
parenchymal sizes and hepatic echotexture was homogenous without any
evidence of intra- and extrahepatic bile ducts dilatation (the diameter
of the common bile duct [CBD] were reported to 4 millimeters).
Notably a distend gallbladder with the thickened wall (16 mm) and
positive sonographic Murphy’s sign, in addition to perivesical liquid
collection without any calculous or sludge was observed on gallbladder
ultrasound exam (Figure 1). There was no evidence of pancreatic ductal
dilatation and peripancreatic lymphadenopathy.
Based on clinical, laboratory, and imaging findings, the presumptive
diagnosis was acute ACC as an extrahepatic complication of HAV. The
patient was being carefully monitored and treated with intravenous
fluids conservatively, while she patient became irritable which
gradually led to lethargy and disorientation to time. On physical
examination, she had asterixis, dyspraxia, slurred speech (indicating a
grade 2 hepatic encephalopathy), as well as a severe decline in liver
function (indicating of acute live failure) (Table 1).
With a diagnosis of ALF, she was immediately managed with close airway
and hemodynamic monitoring in the intensive care unit (ICU), while being
candidate for liver transplantation. To investigate the possible
etiologies of ALF in conjunction or addition to HAV, more thorough
laboratory studies including autoimmune hepatitis markers,
drug/acetaminophen screen, blood cultures, other viral studies, in
addition to head and abdomen computer topography (CT) scanning (Table
3). Based on the study results, we could not find any other suggestive
findings, and the most probable cause of ALF was HAV infection. Spiral
abdominopelvic CT-scan also demonstrated a markedly thickened and
edematous gallbladder wall and mild free fluid in right side of
abdominopelvic cavity without any obvious signs of gallbladder stone,
same as the previous ultrasonography (Figure 2). Moreover, consultations
with intensive care, gastroenterology specialist for metabolic
parameters monitoring, infection surveillance, and liver biopsy to
further confirm the suggestive cause was requested.
Nevertheless, the general condition of the patient was improving and the
patient became mentally alert, fully aware of the place and time,
communicating with the people very well and the asterxia was completely
gone, while being managed with just close monitoring and supportive
treatment with ursodeoxycholic acid (UDCA), and N-acetyl cysteine (NAC).
for another 7 days. Due to the relative recovery of the patient and the
downward trend of the patient’s liver enzymes titer, she was discharged
from the hospital with the recommendation to follow up in another 3
months. At the patient’s re-visit three months later, the patient did
not mention any clinical complaints. The serum level of liver enzymes
had reached the normal level (Table 1). Further abdominal
ultrasonography 3 months after admission demonstrated that the liver had
a normal size and parenchymal echo, intra and extrahepatic ducts had
normal size (CBD=4 mm), and gallbladder had normal wall thickness (less
than 3 mm) and without any calculous, sludge, and perivesical fluid
collections (Figure 3).
DISCUSSION:
AAC was first reported in 1844 by Duncan J in a fatal case of AAC
complicating an incarcerated hernia.21 In fact, AAC is
a type of acute cholecystitis which constitutes 5 - 10% of all acute
cholecystitis without presence of gallstones,19,22which occurs in the setting of gallbladder dysfunction and often occurs
in critically-ill patients in the ICU.19 AAC is a
life-threatening state in which the critical complications include
necrosis and perforation of the gallbladder.23
Microbial infections can be one of the main causes of
AAC.16 The most common microbial causes of AAC are: 1.
Gram-negative bacteria, such as K.bacillus, Samonella spp,
Brucellosis, Vibrio cholera , Coxiella burnetii , andleptospirosis , 2. gram positive bacteria, such asE.faecalis, S.fusarium spp, Lactococcus spp, Proteus, andPsuedomonas, 3. viral infections, such as Cytomegalovirus
(CMV), Epstein–Barr virus (EBV), Dengue virus, Human Immunodeficiency
Virus (HIV) and viral hepatitis (A, B, C,
E). 16,24–39
The main clinical features of AAC are fever, nausea and vomiting,
icterus, abdominal pain (mostly in the right upper quadrant), and
positive Murphy’s sign.22 Laboratory investigations
may show increased ALT, AST, ALK, total and direct bilirubin; however,
normal levels do not rule out the disease.40 The
initial AAC diagnosis is done clinically, which is confirmed with the
help of abdominal ultrasound.22 The five main
ultrasonographic diagnostic criteria of AAC are: 1. Gallbladder
distention; 2. Gallbladder wall thickening greater than 3.5 mm; 3.
Absence of stone (no acoustic shadow) or sludge in the gallbladder; 4.
Perivesical liquid collection; 5. Absence of intra- and extrahepatic
bile duct dilatation with a sensitivity, specificity, and accuracy
88.9%, 97.8%, and 96.1%, respectively.40,41
On the other side, in term of a rare etiology for AAC, HAV presents with
various clinical manifestations which are distinguishing in pediatrics
and adults. In pediatrics, most patients are asymptomatic; although
infection usually is symptomatic in adults.10 After an
incubation of period of 15-50 days, typical symptoms include fever,
malaise, nausea, vomiting, abdominal pain, dark urine, and jaundice
appear.42,43 HAV is usually self-limiting and improves
with supportive treatments such as hydration, antiemetics for severe
vomiting, and antipyretics for high fever.44 However,
the potential complications of HAV are ascites, pleural effusion, sinus
bradycardia, renal failure, hepatic necrosis and fulminating hepatitis,
and AAC.12,14,41
HAV-induced AAC is rare with only 29 reports from 1992 to 2022 consisted
of a total 71 patients in the literature; of these patients, 44 (61.9%)
were under 18 years old and 27 (31.8%) were over 18 years old (Table
3).The incidence of HAV-induced AAC in the adult population is less than
pediatrics, and it is mostly seen in the developing and endemic areas of
HAV;22,45 We found that the youngest patient was
2.5-year-old and the most elderly was
81-year-old.46,47 HAV-induced AAC can lead to
gallbladder perforation, cholangitis, pleural effusion, ascites, acute
pancreatitis, and co-infection with various microorganisms.
The case presented here is a 35-year-old female patient without any past
medical history with the clinical sign and symptoms relevant to
HAV-induced AAC which was confirmed by elevated liver function tests
(LFT), positive serology (HAV IgM +) and abdominal ultrasonography,
Despite being monitored and treated conservatively, our patient
developed hepatic encephalopathy and acute liver failure (ALF) suggested
by worsening LFT. Thus, she went under critical care as well as
consultation and investigation for further etiologies of ALF, while
candidate for liver transplantation. However, with just close monitoring
and supportive treatment (without performing any surgery or liver
transplant), the patient responded and her general condition improved.
The most important educational point of this study is that although HAV
infection is typically an asymptomatic and self-limited disease, it can
be associated with serious complications that may deteriorate patient’s
condition, prognosis and outcome. With prompt diagnosis of AAC,
consideration of rare microbial causes such as viral hepatitis such as
HAV, and implantation of close monitoring and conservative therapy,
serious complications (e.g., gallbladder gangrene and perforation), and
surgeries (i.e., cholecystectomy) can be prevented; even in young adult
patients without any past medical history in which this usually
self-limiting disease may progress rapidly towards hepatic
encephalopathy and ALF.
CONCLUSION
AAC is one of the rare extra-hepatic manifestations caused by HAV, in
which a person experiences worsening abdominal pain, progressive decline
in liver function, hepatic encephalopathy and ALF. Considering the
possibility of HAV-induced AAC can be vital to manage such a rarely
described condition and to prevent the critical and life-threatening
complication associated with this condition, such as necrosis and
perforation of the gallbladder