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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1649_Библиотеки_им_академика_М_И_Перельмана.pdf
In: Acute Pancreatitis ISBN: 978-1-63485-229-6
Editor: Shane Copeland © 2016 Nova Science Publishers, Inc.
Chapter 1
ACUTE PANCREATITIS IN CHILDHOOD
Gilles Duvoisin
1,2
and Chee Yee Ooi
2,3,
1
Department of Paediatrics, Lausanne University Hospital and
University of Lausanne, Lausanne, Switzerland
2
Department of Gastroenterology, Sydney Children’s Hospital,
Randwick, NSW, Australia
3
Discipline of Paediatrics, School of Women’s and Children’s Health,
Faculty of Medicine, University of New South Wales,
Sydney, NSW, Australia
ABSTRACT
Acute pancreatitis (AP) in children is increasingly recognized to be a
challenge for affected patients and their families, their treating physicians
and surgeons, and the health care system. An increase in incidence of
paediatric AP has been reported. The incidence of paediatric AP was
estimated at 3.6 to 13.2 per 100,000 per children per year, which is within
the range of incidence reported for adult AP. Genetic contributions to the
development of pancreatitis, especially in acute recurrent and chronic
pancreatitis, are now increasingly recognised.
This chapter will review the clinical characteristics of acute
pancreatitis in children based on the clinically based diagnostic criteria
for childhood pancreatitis, which until recently was not available. The
Corresponding author: Dr (Keith) C. Y. Ooi, Discipline of Paediatrics, School of Women’s and,
University of New South Wales, Australia. Email: keith.ooi@unsw.edu.au.
Gilles Duvoisin and Chee Yee Ooi
2
diagnostic criteria are based on symptoms, biochemical and imaging
evidence of pancreatitis, with two of the three criteria required to
diagnose AP. Although abdominal pain is the most common clinical
manifestation, it may be absent in up to one third of paediatric patients.
The diagnostic yield and concordances for serum pancreatic enzymes and
imaging for the diagnosis of paediatric AP will be discussed.
There is currently no consensus on the definition for the severity of
AP in children. However, there are now predictors of severity for AP that
has been developed and validated in children. The management of AP
remains driven by adult studies and recommendations. Treatment is
directed at the underlying aetiology as well as supportive measures. Early
fluid resuscitation and early enteral feeding has been recent additions to
the limited armamentarium available in AP. Its application in children
with AP is promising but lacking in evidence. Potential future therapies
in AP that may apply to children will also be discussed.
1. INTRODUCTION
The pancreas is a transversely oriented retroperitoneal organ. Although it
does not have well-defined anatomic divisions, surroundings vessels and
ligaments delineate the organ into a head, body, and tail. The pancreas has
dichotomous roles: endocrine and exocrine. Regarding the exocrine portion of
the pancreas, ductal cells form the tubules that secrete bicarbonate and fluid to
help flush pancreatic enzymes produced by the acinar cells into the duodenum.
Acute pancreatitis is an inflammatory disorder of the pancreas. The
alterations cause oedema by microvascular leakage, necrosis of fat by lipase,
an acute inflammatory reaction, proteolytic destruction of pancreatic
parenchyma, and destruction of the blood vessels leading to intestinal
haemorrhage. Its severity may vary from a mild disease, self-remitting to a
fulminant, life-threatening process.
Acute pancreatitis in children is a well recognised disease. Acute
pancreatitis may present with a wide-range of clinical presentations in
childhood from gastrointestinal symptoms of nausea, vomiting and abdominal
pain to non-specific manifestations such as irritability, fever and tachycardia.
In recent years, there has been a rise in the incidence and admission rates
for acute pancreatitis in children [1, 2]. Despite this, paediatric acute
pancreatitis has been a relatively poorly studied condition compared to the
adult form. The understanding and the management of this condition is
predominantly based on a historical approaches and extrapolated from the
adult perspective. However, there are significant differences between the
Acute Pancreatitis in Childhood
3
paediatric and the adult form of acute pancreatitis regarding the aetiology, the
clinical presentation, the severity and its complications [3]. For this reason,
further studies are required to enhance the specific knowledge related to
paediatric acute pancreatitis.
This chapter will review the clinical characteristics of acute pancreatitis in
children based on the diagnostic criteria for childhood pancreatitis, which until
recently was not available. The diagnostic criteria are based on symptoms,
biochemical and imaging evidence of pancreatitis, with two of the three
criteria required to diagnose acute pancreatitis. In addition, we will describe
the burden of paediatric acute pancreatitis as well as its aetiology.
Furthermore, we will summarise the recommendation of its management and
how the complications can be documented and addressed. Finally, we will
discuss emerging therapies.
2. BURDEN OF DISEASE: INCIDENCE AND
LENGTH OF HOSPITALISATION
2.1. Incidence
In adults, acute pancreatitis is on the rise and has become the leading
gastrointestinal cause of hospitalization in the US [4]. Similarly, acute
pancreatitis in children has become an increasingly recognized disease.
Several single centres around the world have reported the incidence of acute
pancreatitis. A rise in the admission rates of children with acute pancreatitis
had been described [5, 6]. In addition, retrospective studies in Melbourne,
Australia and in Pittsburgh, US, which took into account the catchment
population, described an incidence of 3.6 per 100,000 children from 0 to 15
years old/year and 13.2 per 100,000 children/year, respectively [2, 7]. In
comparison, the incidence reported in adults with acute pancreatitis range from
4.8 to 38 per 100,000/year.
What are the reasons for this increase of incidence of acute pancreatitis in
children? Undoubtedly, the answer is complex and likely multifactorial. There
are several hypotheses. Firstly, there may be an absolute increase in the case of
acute pancreatitis leading to this observation. Nevertheless, as far as we are
aware, none of the causes responsible for acute pancreatitis in children has
shown a specific upwards trend. Secondly, the increase of incidence may be
related to a referral bias, as the catchment population is not fully considered in
Gilles Duvoisin and Chee Yee Ooi
4
the majority of the studies. For instance, an increased number of patients may
have been directly referred to the tertiary care centre by their clinician, instead
of their community hospitals [8]. The incidence may be biased if theses cases
are reported without adding the population of these areas to the catchment
population of the tertiary care centre. Thirdly, it was documented than an
increased awareness of acute pancreatitis in children has lead to an increased
testing for amylase and lipase. Simultaneously, it was associated with an
increase of the reports of episode of acute pancreatitis [2]. It was postulated
that this effect was responsible for 94% of the change in all the admissions.
2.2. Length of Hospitalisation
The length of hospitalisation for an episode of acute pancreatitis varies
regarding the severity of its manifestation and the underlying condition. If the
episode is non-complicated, the median length of stay was reported from 5
days (IQR 3-10) to 8 days and the average length between 15 and 24 days [6,
8, 9]. The length of stay of children less than 2 years old with acute
pancreatitis was significantly longer when compared with the group of 3-10
years and 11-20 years. In adults, in comparison, it was described that the
length of stay for a mild acute pancreatitis was between 3 to 5 days [4].
3. PATHOPHYSIOLOGY
Since the observation by Chiari in 1886, the paradigm of acute pancreatitis
has been described as the autodigestion of the pancreas triggered by premature
auto-activation of trypsin. Physiologically, trypsin, a serine protease, is
activated by the enterokinase produced by the brush border of the duodenum.
In acute pancreatitis, the early pathogenesis possibly includes a pathologic
cytoplasmic calcium response to a pancreatic insult (e.g., drug induced
pancreatitis, bile acids metabolite, ethanol, etc.) [10]. This dysregulation may
lead to a premature intrapancreatic activation of trypsinogen to trypsin [11,
12]. Trypsin then induces a cascade of activation of other protease leading to
further insult to the pancreas.
Nevertheless, recent studies suggest that a multifaceted paradigm should
be considered, composed of several paralleled independent pathway
contributing to the pancreatic injury [13]. The zymogen activation pathways
and the inflammatory pathway are beginning to be clarified, both pathways are
Acute Pancreatitis in Childhood
5
thought to be sufficient to trigger acute pancreatitis [10]. However, their link is
still debatable. Regarding the inflammatory pathway, proinflammatory
cytokines such as tumour necrosis factor (TNF) and interleukin-1 (IL-1)
may contribute to the activation of a key transcriptional factor: nuclear factor
B (NF B). Recently, a novel protein kinase C (PKC), presenting several
isoforms, has been suggested to mediate the activation of NF B [14].
The relative contribution of the zymogen activation pathway and the
inflammatory pathway is one of the central interrogation in the
pathophysiology of acute pancreatitis at present and further studies are
required to specify their interactions. As a result of this complexity and the
expected common pathophysiologic pathway between the adult and the
paediatric form of acute pancreatitis, a complete description of the
pathophysiology of acute pancreatitis goes beyond the scope of this chapter.
4. AETIOLOGY
Defining the aetiology of an episode of acute pancreatitis is a complex
question. However, the cause should be determined for several important
reasons. Firstly, some aetiologies may require a specific treatment such as
biliary acute pancreatitis and these interventions should not be delayed.
Secondly, some patients may have susceptibility for recurrent episodes (e.g.,
genetic mutations) and patients may benefit from assessing subsequent
modifiable risk factors (e.g., alcohol or tobacco smoke exposure) to prevent or
limit further episodes. Finally, clinicians should be able to discuss the
prognosis/natural history with the patients and their family and knowing the
aetiology is crucial in this setting.
Various studies have been performed to identify the aetiology of acute
pancreatitis; however most of them are based on adult populations [15, 16]. In
adult pancreatitis, gallstones and alcohol predominate as aetiological factors
and account for up to 70% of cases. In children, the aetiology of acute
pancreatitis is more diverse and alcohol ingestion is rarely reported as a cause
of pancreatitis in children.
The true frequency of the various aetiological factors in paediatric acute
pancreatitis remains unclear. The vast majority of published studies are
retrospective in nature and have various limitations. First, the diagnosis of
paediatric acute pancreatitis proposed by the INSPPIRE consortium is not
unanimously used in the literature due to its recent publication [17]. To the
Gilles Duvoisin and Chee Yee Ooi
6
same extent, the nomenclature of the causes is not shared among the studies.
Secondly, a bias may be related to the clinicians’ knowledge and expertise.
Finally, the extent of the investigations is debatable and may be responsible
for the heterogeneity of the so-called “idiopathic” acute pancreatitis.
In 2013, Bai et al. performed a literature review of the aetiology of
paediatric acute pancreatitis [5-7, 9, 18-26]. Bai and colleagues reported that
the most frequent causes for paediatric acute pancreatitis are: biliary disease,
medications, idiopathic, multisystem diseases and trauma. Infections,
hereditary pancreatitis and metabolic diseases are less common causes of acute
pancreatitis in children.
4.1. Biliary Disease
Biliary disease, which includes gallstones, biliary sludge, as well as other
structural anomalies of the biliary and/or pancreatic tree such as choledochal
cyst account for 10-30% of the aetiology of paediatric acute pancreatitis.
Simplistically, these causes are associated with obstructed or reduced outflow
of pancreatic secretions. In contrary to the adult form, the presence of
pancreatic tumour is rare.
The management of biliary disease causing acute pancreatitis differs from
the other causes of acute pancreatitis in that it may improve and/or future
episodes may be preventable with specific intervention. For these reasons,
Coffey et al. developed a simple clinical tool to predict biliary aetiology for
acute pancreatitis in children. The “biliary pancreatitis triad” of (a) serum
gamma-glutamyl transpeptidase ≥40 U/l, (b) alanine aminotransferase ≥150
U/l and (c) lipase ≥15 x upper limit of normal, performed within 48h of
presentation, was reported to be significantly associated with the presence of
an underlying biliary cause. When two of the three items were met, the
“biliary pancreatitis triad” was predictive of an underlying biliary cause with a
sensitivity of 89% and a specificity of 95% (OR 150.4, p < 0.001). Among
children who did not fulfil at least two of the three items, the negative
predictive value reached 98%, i.e., a biliary cause was unlikely to be
responsible for acute pancreatitis. This simple tool, established in a
retrospective study, requires validation from larger multicentre prospective
studies [27].
Acute Pancreatitis in Childhood
7
4.2. Medications
Although medications have been reported to contribute up to 25% of acute
pancreatitis in children, the true extent of medication-induced pancreatitis is
difficult to study and the relevant paediatric literature is sparse. Published
cases have frequently consisted of single case reports lacking adequate
documentation including whether the diagnostic criteria for acute pancreatitis
was fulfilled and if a sufficiently comprehensive range of investigations were
performed to rule out more common causes of pancreatitis such as biliary or
anatomic. In addition, most reported cases lacked a re-challenge of the
suspected medication. The suspect medication(s) may indeed be the cause of
the pancreatitis (idiosyncratic reaction or dose-related), be a co-factor or a
bystander. The most common medication implicated in paediatric acute
pancreatitis include valproic acid, L-asparaginase, prednisone, and
azathioprine or 6-mercaptopurine.
Different mechanisms have been postulated to explain how drugs may
trigger acute pancreatitis. Valproic acid-induced acute pancreatitis, for
instance, is an example of a dose-related side effect [28]. Idiosyncratic
reactions, likely mediated by direct immunological effects, has been
speculated to be the cause for azathioprine-related acute pancreatitis [29].
Several authors have proposed classification systems to categorise and
link medication risk for acute pancreatitis in adults. Karch et al. [30] proposed
that classification should be based on the temporal relation between the
medication exposure and the manifestation of acute pancreatitis. Three
parameters should be examined: the time between the exposure of the
medication and the presentation of the acute pancreatitis, the resolution of the
episode following the discontinuation of the medication, and finally, the
recurrence of pancreatitis if the exposure of the medication was repeated [30].
More recently Trivedi et al., proposed a classification for medication-induced
pancreatitis based on the number of cases reported in the literature and the
presence of a positive rechallenge [31]. In addition to this concept, Badalov et
al. highlighted the role of the latency of effect, which refers to a time-frame
from the introduction of the medication to the onset of pancreatitis [32]. The
latency can vary from less than 24 hours to greater than 30 days.
In 2015, the INSPPIRE consortium reported a summary of these
recommendations and proposed the need to gather detailed information
regarding any suspected medication as part of the initial work up: onset of use,
dosing, duration of use before onset of acute pancreatitis [33].
Gilles Duvoisin and Chee Yee Ooi
8
4.3. Idiopathic
Despite the increased recognition of the various causes of acute
pancreatitis (including genetic and metabolic causes), the aetiology of acute
pancreatitis may remain elusive in 13% to 34% of cases [34]. However, it has
been reported that in infants, aetiologies are more frequently determined. Park
et al. [8], in a retrospective study, documented the aetiology of acute
pancreatitis in children and according to age. In children less than 2 years old,
an underlying aetiology was identified for all episodes of acute pancreatitis.
4.4. Multisystem Diseases
Multisystem diseases that affect adults with acute pancreatitis differ from
children. Accounting for one third of the aetiology of acute pancreatitis in
children, systemic diseases include a variety of conditions such as sepsis,
haemolytic uraemic syndrome and systemic lupus erythematous [34]. As
multisystem diseases require a complex management with often several
treatments, the concomitant medications used should be considered as possible
contributing factors as described in section 4.2.
4.5. Trauma
Trauma has been reported as a cause of acute pancreatitis in 9% to 40% of
episodes [7, 22, 26]. Blunt trauma is the most common injury in children. In
contrast to adults, penetrating trauma are rare in children. Despite its relative
protection in the retroperitoneal space, blows to the epigastrium in motor
vehicle accidents, sport injuries, bicycle handlebar, falls and child abuse might
lead to its injury due compression forces on the pancreas against the vertebral
column [35]. The contusion of the pancreas involves rupture of minor or major
components of the ducts. The released pancreatic enzymes, which become in
the contact with the parenchyma, may trigger an inflammatory cascade. It is
important for clinicians to recognise that pancreatic injury is rarely a solitary
injury and a coexistent injury to another abdominal organ is found in 90% of
cases [36].
Acute Pancreatitis in Childhood
9
4.6. Infections
Infections have been reported to be linked with acute pancreatitis in less
than 10% of children. However, it is a challenge to determine whether the
identified infectious agent was indeed the cause of the pancreatitis, a co-factor,
an “innocent bystander.” The most frequent infectious agents described in the
literature include viruses (mumps virus, hepatitis A virus, rotavirus, hepatitis E
virus, varicella-zoster virus, adenovirus and coxsackie B4) and bacteria
(Mycoplasma pneumonia, Moraxella catarrhalis). The presenting symptoms
and clinical signs should conduct to specific investigations; therefore, the list
is non exhaustive. Even if most of the cases are caused by viruses, specific
treatment for bacterial pancreatitis might improve the outcome of the episode.
4.7. Genetic
Genetic causes account for about 3% of patients with acute pancreatitis [6,
21]. However, the prevalence of an underlying genetic predisposition to
developing pancreatitis varies depending on whether the study cohort involves
only children with the first episode of acute pancreatitis or children with acute
recurrent pancreatitis and chronic pancreatitis. To complicate matters further,
genetic factors may be present in isolation or identified together with other
genetic or non-genetic risk factors. In addition, interpretation of genetic tests
results can be complicated, with identification of mutations or variants not
necessarily indicative of being disease-causing. Genetic counselling is
recommended when genetic testing is undertaken.
Various genetic mutations have now been identified as causative/
predisposing factors for pancreatitis. Here, we briefly discuss the three most
commonly identified mutations. The cationic trypsinogen (PRSS1) and
pancreatic secretory trypsin inhibitor (SPINK1) genes are well-recognized
mutations. Their role in the pathophysiology of acute pancreatitis demonstrate
how mutations affect the auto-regulatory and homeostatic pathways,
predisposing affected individuals to the development of pancreatitis.
Mutations in the PRSS1 gene promotes trypsinogen activation (i.e., mutation
leads to a gain of function), increasing the risk of episode of acute pancreatitis.
In contrast, SPINK1 acts as a defence mechanism against premature activation
of trypsin in the pancreas. Mutations that reduce its activity (i.e., mutation
leads to a loss of function) is associated with an increased risk of acute
pancreatitis. The cystic fibrosis transmembrane conductance regulator (CFTR)
Gilles Duvoisin and Chee Yee Ooi
10
gene plays a complex role by flushing ductal proteins released from the acinus
into the duodenum, as well as regulating the intraluminal pH through
bicarbonate secretion.
4.8. Metabolic
Metabolic diseases were seen in 5% to 6% of patients with acute
pancreatitis [6, 7, 21, 22, 24]. This is a heterogeneous group of diseases which
may contribute to acute pancreatitis in children differently, either as a
predisposing factor or an absolute risk factor. Unlike some of the other causes,
metabolic conditions may be modifiable or correctable. Hence, its
identification may reduce the risk of future episodes. A detailed review of the
most frequent metabolic risk factors, namely hypertryglyceridemia,
hypercalcemia and chronic renal failure, was recently described [33].
Hypertryglyceridemia above 1000 mg/dl (88.6 mol/l) was described as an
absolute risk for pancreatitis. If the child presented elevated levels of serum
tryglyceride of 500 to 1000 mg/dl (44.3-88.6 mol/l), it was suggested that this
represented a predisposing factor. Even though the underlying mechanisms are
not fully understood, two hypothesis have been postulated [37, 38]. Firstly,
pancreatic microcirculation may be altered by the hyperviscosity from
chylomicrons, leading to ischemia. Secondly, free fatty acids, resulting from
the transformation of triglyceride within the pancreas, may directly induce
injury in the acinus and capillaries.
Primary hyperparathyroidism should be suspected in the setting of mild
persistent hypercalcemia (above 10.7 mg/dl or 2.675 mmol/l) and further
investigations to evaluate the underlying cause is recommended [33]. The
regulation of intra-acinar calcium is crucial as the level of calcium influences
the activation/inactivation of trypsin. For example, high serum levels of
calcium promotes activation of trypsinogen and prevent trypsin inactivation.
As hypercalcemia can be easily identified and management, it should be
included in the diagnostic evaluation of acute pancreatitis.
Acute pancreatitis has been reported in adults with chronic renal failure.
The pathogenic mechanisms of acute pancreatitis in chronic renal failure
remain unclear but is likely multifactorial and related to systemic vascular
disease, medications, hyperparathyroidism and hyperlipidemia. To confound
matters, in the setting of chronic renal failure, there is delayed clearance of
amylase and lipase which may make the diagnosis of acute pancreatitis
challenging if based solely on serum pancreatic enzyme levels [39, 40]. The