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Abstract

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome associated with environmental, genetic, autoimmune, and metabolic factors. Although the main burden of CP is chronic pain and pancreatic insufficiency, epidemiological data indicate that CP patients are at significantly higher risk of developing pancreatic ductal adenocarcinoma (PDAC). CP is a disease that requires complex management based on reducing the severity of symptoms, as there is no curative treatment available. Idiopathic chronic pancreatitis (ICP) is diagnosed after ruling out other possible causes and remains the second most common type of CP—8%–30% of cases. A distinction is made between early-onset ICP (EO-ICP) and late-onset ICP (LO-ICP) based on the age of onset. ICP is characterized by a milder course than CP of other etiologies. In particular, considering the subtypes of ICP, there is a tendency that pain occurs significantly more frequently in EO-ICP compared to alcoholic CP (ACP) and LO-ICP. In turn, diabetes and exocrine pancreatic insufficiency seem to develop much faster in patients with LO-ICP than in patients with ACP and EO-ICP. However, in CP associated with genetic causes, especially mutations in the serine protease 1 (PRSS1) and serine protease inhibitor Kazal type 1 (SPINK1) genes, a significantly higher PDAC risk is observed than in both ICP and ACP. Moreover, patients with ICP are considerably less likely to require intensive pain treatment, including gabapentinoids and opioids. All this translates into a lower frequency of hospitalizations and need for interventional treatment, both endoscopic and surgical. Given that ICP represents a substantial proportion of CP cases, this review highlights possible factors underlying the idiopathic etiology, clinical presentation, and diagnostic features. It summarizes the clinical management of ICP, including the treatment of pain, steatorrhea, diabetes, as well as pancreatic cysts and the risk of PDAC, highlighting differences in treatment patterns and the relative use of specific therapeutic modalities in comparison to other types of CP.

Keywords

chronic pancreatitis endocrine pancreatic insufficiency exocrine pancreatic insufficiency idiopathic chronic pancreatitis management pancreatic cancer pancreatic pseudocysts treatment

Introduction and epidemiology

Chronic pancreatitis (CP) is a complex fibro-inflammatory disorder of the pancreas that leads to chronic pain and progressive endocrine and exocrine function deficiency.^1,2 The disease leads to impaired social functioning, unemployment, frequent hospitalizations, and results in a significant reduction in patients’ quality of life.^3–6 As no curative treatment is available in CP, the management priority is the improvement of the patients’ quality of life.^4,5

The prevalence of CP is reported to range from 45.5 to 153.9 per 100,000 depending on the population studied and the diagnostic methods applied.^7–10 Probably due to heightened awareness of the disease and better diagnostic tools, the prevalence of CP is increasing.^8,10 The Danish study reported a prevalence increase between 1996 and 2016 from 126.6/100,000 to 153.9/100,000.¹⁰ Similarly, in a study in Sichuan Province in China, it was shown that between 2015 and 2021, the incidence of CP increased from 4.3/100,000 to 8.27/100,000, respectively.⁷

The risk factors and etiological factors for the development of CP, including toxic-metabolic, idiopathic, genetic, autoimmune, and obstructive causes, were initially incorporated into the TIGAR-O_V1 classification in 2001.¹¹ However, in 2019, the decision was made to update this classification to TIGAR-O_V2, so as to better capture the diverse risk and etiological factors.¹² TIGAR-O_V2 was designed to have a hierarchical checklist format.¹² The updated classification includes more detailed subcategories, as well as quantitative cut-offs for certain risk factors, like alcohol consumption, hypertriglyceridemia, and hypercalcemia. It also emphasizes smoking as an independent risk factor, taking into account current status and pack-years. Genetic risk factors and autoimmune causes are also better organized, with the focus on narrowing down the proportion of patients diagnosed with idiopathic chronic pancreatitis (ICP).¹²

ICP is defined as CP in which the causative factors have not been detected despite extensive testing.^2,13,14 In the ICP diagnostic process, the patient’s exposure to risk factors, such as alcohol, smoking, trauma, medication, and CP family history, have to be ruled out.^13,14 Furthermore, metabolic causes (e.g., hypertriglyceridemia, hypercalcemia) and autoimmune causes need to be eliminated, as well as mechanical, obstructive, and restrictive pancreatitis, based on endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI).^13,14 In patients with early onset of the disease and with a family history of pancreatic disease, genetic tests are also performed, most often for mutations in the serine protease 1 (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), and chymotrypsin C (CTRC) genes.^13,14 When all of those etiological factors are excluded, ICP may be diagnosed.^2,13,14

In a study published in 1994, Layer et al.¹⁵ noted a bimodal distribution of the age of onset of ICP symptoms. Accordingly, ICP was divided into early-onset ICP (EO-ICP) and late-onset ICP (LO-ICP) with a cut-off age of 35 years.¹⁵ In EO-ICP, the peak incidence occurs in the 2nd decade, while in LO-ICP, it is in the 6th decade.¹⁵ Layer et al.¹⁵ found major differences in the course of the disease between EO-ICP and LO-ICP. Almost all patients with EO-ICP (96%) experienced pain as the initial symptom, whereas it occurred in 54% of patients with LO-ICP.¹⁵ Patients with EO-ICP tended to develop exocrine and endocrine pancreatic insufficiency significantly later than patients with LO-ICP, at 26.3 versus 16.9 years and 27.5 versus 11.9 years from the onset of the disease, respectively.¹⁵ Median time of the pancreatic calcifications occurrence in EO-ICP was 24.9 years after the disease onset, and in LO-ICP, 19.4 years.¹⁵

Currently, ICP is the second most common type of CP after alcoholic pancreatitis.^8,16–20 Recent studies have shown that the cases of ICP account for 8%–29% of cases of CP.^8,16–20 Recent studies also indicate a similar prevalence of ICP in Asia and in Western countries. In a 10-year retrospective Chinese study, the ICP accounted for 12.9% of CP cases,¹⁷ whereas in a Japanese study involving 1734 CP patients, it yielded 20%.⁸ Western studies report a comparable proportion of ICP—a study involving 910 CP patients from 6 countries in the Scandinavian-Baltic region found ICP in 8% of patients.¹⁶ A higher frequency was reported by the Italian survey—17%.¹⁸ Furthermore, in patients with CP prospectively enrolled in two studies from the United States (US), 29% and 24% had an idiopathic etiology.^19,20 The considerable variability in the frequency of ICP is associated with many diagnostic difficulties, different diagnostic algorithms, the use of variable definitions of ICP, the performance of genetic testing to varying extents, and whether or not smoking is included as an independent risk factor.²¹

Women are significantly more likely than men to have non-alcoholic etiologies, including idiopathic.²² From a total of 521 patients with CP, idiopathic etiologies were found in 32% of women and 18% of men.²²

Etiopathogenesis

Data from recent studies indicate that acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and CP represent a disease continuum.^23,24 RAP is defined as two or more episodes of AP with a period of symptom resolution between them.²⁵ The pathogenesis of CP is described using the Sentinel Acute Pancreatitis Event theory.^24,26 According to this theory, the initial AP episode activates the immune system and may end in complete recovery or, if further exposure to risk factors is present, RAP, clinically noticeable or not, may develop.^24,26 This further leads to continued damage, irreversible structural changes, and the development of CP.^24,26 CP develops in 10% of patients experiencing AP and 36% experiencing RAP.²⁴ Among cases with idiopathic etiology, a retrospective study indicated that the cumulative risk of developing ICP over 10 years after idiopathic AP was 5.7%, which was significantly lower than the risk of ACP after alcoholic AP (17.9%).²⁷ The prevalence of ICP after idiopathic RAP (IRAP) was estimated to be between 17% and 47%.^28–30 By contrast, for alcoholic RAP, the frequency of progression to ACP is much higher—42%–80%.^24,31,32

Nevertheless, not all patients with CP are found to have pre-existing AP or RAP episodes, or at least not clinically symptomatic ones. In a study of 450 patients with CP, those with ICP (n = 101) were significantly less likely than those with non-idiopathic CP (n = 349) to have a previous symptomatic history of RAP, 53.1% and 68.6%, respectively.³³ Similarly, in another study, patients in the group that experienced RAP and developed CP were significantly more likely to have an alcoholic than an idiopathic etiology (49% vs 25%).³⁴

Pancreatic specimen evaluation after total pancreatectomy with islet autotransplant revealed differences in immune mechanisms and their potential role as essential regulators in ICP and hereditary chronic pancreatitis (HCP).³⁵ Flow cytometric analysis of pancreatic tissue showed that the frequency of macrophages (CD68+) was significantly higher in patients with ICP than in those with HCP.³⁵ In turn, the Luminex assay indicated significantly elevated levels of M2 macrophage cytokines (IL-4, IL-13), innate cytokines (IL-21, IL-23), and Th2 cytokines (IL-5, IL-9, and IL-13), as well as an increased amount of chemokines such as monocyte chemotactic protein 3 (CCL7), in the pancreatic tissue of patients with ICP compared to HCP.³⁵ It was shown that in the pancreas of patients with ICP, compared to HCP, there is a significantly elevated local level of innate immune cells, suggesting its predominant role in the pathogenesis of ICP.³⁵ On the other hand, significant increases in T-cell (CD3+) and various CD4+ T-cell subpopulations were detected with flow cytometry analysis in pancreatic tissue of patients with HCP but not in ICP.³⁵ These data may indicate that the adaptive immune response through differentiated, active T helper cells plays a role in HCP pathogenesis.³⁵

When comparing the occurrence of genetic variants in ICP with ACP or smoking-related CP (SCP) in US and Chinese studies, the rate is significantly higher.^36,37 Among 715 Chinese patients with ICP, 206 with ACP, and 140 with SCP, rare pathogenic variants in the PRSS1, SPINK1, CTRC, and/or CFTR genes using targeted next-generation sequencing were found in 57.1%, 39.8%, and 32.1%, respectively.³⁶ Among ICP patients, the majority—35.1%—had SPINK1 only, 7.6% had PRSS1 only, 2.8% had CFTR only, 0.8% had CTRC only, and 10.8% had pathogenic variants in more than one gene (the authors reported the frequency of each pathogenic genetic variant as a percentage of ICP patients with pathogenic variants, so for comparison, the results were converted to a percentage of the entire ICP group; Table 1).³⁶ Similarly, among subjects with ACP and SCP, most of them had SPINK1 mutation only—23.8% and 18.6% respectively, followed by PRSS1 only—9.2% and 7.1% respectively.³⁶

Table 1.

Frequency of pathogenic genetic variants in patients with ICP.

Reference	Population studied	Methods	% patients with pathogenic variants detected
Reference	Population studied	Methods	Pathogenic variant positive	PRSS1 only	SPINK1 only	CFTR only	CTRC only
Chang et al.⁴¹	ICP = 129	Heteroduplex + sequencing analysis	14.7% (19/129)	4.6% (6/129)	10.1% (13/129)	ND	ND
Masson et al.⁴⁰	ICP = 253	dHPLC, HRM, direct DNA sequencing, fM-PCR, Friedman, QFM-PCR	48.2% (122/253)	7.5% (19/253)	9.5% (24/253)	20.6% (52/253)	2% (5/253)
Jalaly et al.³⁸	ICP w/o IRAP = 26	Commercial testing^a	27% (7/26)	0%	7.7% (2/26)	19.2% (5/26)	0%
Zou et al.³⁶	ICP = 715	Targeted NGS	57.1% (408/715)	7.6% (54/715)	35.1% (251/715)	2.8% (20/715)	0.8% (6/715)
Gurakar et al.²¹	ICP = 98	Commercial testing^a	57% (56/98)	8.2% (8/98)	11.2% (11/98)	24.5% (24/98)	2% (2/98)

In the reviewed studies, the reporting of the frequency of individual pathogenic variants was inconsistent; therefore, they were converted to a percentage of the entire study group and/or recalculated to be consistent with the mutually exclusive approach.

Performed using commercial genetic testing; the specific analytical method was not specified.

CTRC, chymotrypsin C; dHPLC, denaturing high-performance liquid chromatography; fM-PCR, fluorescent multiplex PCR of Mantovani et al.; Friedman, method of Friedman et al.; HRM, high-resolution DNA melting analysis; ICP, idiopathic chronic pancreatitis; IRAP, idiopathic recurrent acute pancreatitis; ND, not determined; NGS, next-generation sequencing; PRSS1, serine protease 1; QFM-PCR, quantitative fluorescent multiplex-PCR; SPINK1, serine protease inhibitor Kazal type 1; w/o, without.

In the Lewis et al.³⁷ study conducted in the United States, significantly more pathogenic variants in SPINK1, CFTR, or CTRC genes were detected in EO-ICP patients (n = 61) compared to LO-ICP patients (n = 69) and ACP patients (n = 225), 49%, 23%, and 23%, respectively. CFTR mutation was the most frequently detected mutation regardless of etiology, and was detected far more often in patients with EO-ICP than in those with LO-ICP and ACP—in 36% (22/61), 15% (10/69), and 13% (30/225), respectively.³⁷ Similarly, the SPINK1 mutation was significantly more common in EO-ICP—in 24% (15/61), than in LO-ICP—in 9% (6/69) and ACP in 9% (21/225).³⁷

In an American retrospective study, Jalaly et al.³⁸ examined the prevalence of pathogenic genetic variants in PRSS1, SPINK1, CFTR, and CTRC genes in 134 patients with IRAP and/or ICP. Sixty-four (47.8%) of them had a total of 88 pathogenic genetic variants identified.³⁸ Pathogenic variants were detected significantly more often in subjects with IRAP who have developed ICP (56%, 42/75) and subjects with IRAP who have not yet developed ICP (54.5%, 12/22) compared to patients with ICP without a previous history of IRAP (27%, 7/26; Table 1).³⁸

Pathogenic genetic variants among patients with ICP are found in approximately 60% of patients or less, indicating that there are likely other unknown genetic or environmental factors that, alone or in combination, cause or influence the development of CP.³⁸ However, the increasing number of identified pathogenic variants contributing to the development of CP will likely explain the cause of pancreatitis in a larger percentage of patients in the long term.²¹

In IRAP and ICP, the use of complete gene sequencing (CGS) compared to other methods such as enzymatic amplification and selective exome sequencing significantly increases the likelihood of detecting genetic mutations, especially high-risk mutations such as a single copy mutation of PRSS1, homozygous mutations of CFTR, SPINK1, or CTRC, compound heterozygous mutations of CFTR, SPINK1, and/or CTRC.³⁹ US patients tested by CGS had a 5-fold higher probability of detecting any mutation than patients tested by remaining methods (42.2% vs 8.1%). In particular, a high-risk mutation detection rate was as much as 12-fold higher in patients tested with CGS than with other methods (18.3% vs 1.5%).³⁹

Considering the persistently high cost of genetic testing, its limited availability, and impact on the patient and family, it is crucial to adequately identify patients with ICP with pathogenic genetic variants.^38,39 Their prevalence in ICP generally is 12%–57%, in EO-ICP 38.2%–49%, while in LO-ICP 6.3%–23%.^{21,36–38,40,41} Therefore, genetic testing is warranted, in particular, in EO-ICP.^13,37,41 The analyzed studies show considerable variability in the frequency of detected pathogenic genetic variants (Table 1). This may be due to variations resulting from the different geographical regions in which the studies were conducted and the distinct characteristics of the populations studied.^37,42 In addition, different methods of detecting genetic changes may also contribute to this variability.³⁹ It is suggested that, with increasingly accurate genetic diagnostic methods, the proportion of patients with truly ICP may decrease.³⁷ The advantage of early detection of genetic mutations in patients with RAP and CP may prevent performing many costly, time-consuming, and often invasive tests for pancreatitis etiology determination.²¹ The genetic change detection is useful in assessing the risk of complications, patient prognosis, and may help the patients avoid alcoholic etiology stigmatization.¹³

ICP natural history

The Japan survey indicates that patients with ICP (n = 347) experience pain significantly less often than patients with ACP (n = 1171)—54.8% and 68.1%, respectively.⁸ Moreover, a prospective cohort study in the United States showed that patients with ACP were more likely to experience chronic pain than patients with CP from other causes.⁴³ A retrospective study in Germany involving 182 patients with CP (91 with ICP and 77 with ACP) found that sudden pain attacks caused by exacerbations of the disease were less common in ICP compared to ACP.⁴⁴ A retrospective study from New Delhi, India, with a median follow up of 3.5 years involving 668 patients with EO-ICP, 207 patients with LO-ICP, and 540 patients with ACP showed that pain was most common in patients with EO-ICP (90%), less common in patients with ACP (83.7%), and least common in patients with LO-ICP (68%).⁴⁵ Similarly, in a prospective study, pain as the initial symptom more frequently affected patients with EO-ICP (100%, 21/21) and with ACP (95%, 251/265) than those with LO-ICP (48%, 22/46).⁴⁶ However, some other studies from India indicate that ICP in this region appears to present with a high frequency of pain not only in EO-ICP but also in LO-ICP. In a study of patients from Northern India, it was observed that pain affected 95.1% of patients with EO-ICP and 100% of patients with LO-ICP.⁴⁷ Similarly, in Southern India, over 90% of patients with ICP (both EO-ICP and LO-ICP) experienced pain.⁴⁸

The recent multicenter European cohort study showed that CP patients with SPINK1 gene mutations (mainly c.101A > G) are more likely to experience pain compared to patients with ICP, with a rate of 79.8% and 62.6%.⁴⁹ On the other hand, a Chinese study observed that patients with SPINK1 mutations (predominantly c.194 + 2T > C) were significantly less likely to experience pain in the course of CP compared to ICP patients without these mutations—20.7% (12/58) and 2.3% (1/43), respectively.⁵⁰ In addition, the mean Izbicki pain score (ranges from 0 to 100, higher scores indicate more severe pain) was lower in patients with the SPINK1 mutation—31 ± 21 versus 54 ± 21.⁵⁰ Differences in the frequency of pain occurrence depending on the presence of the SPINK1 mutation in these studies may be influenced by various dominant pathogenic genetic variants and their mechanisms, as well as by the characteristics of the studied population and the difficulty of reporting pain. Therefore, it should be emphasized that the literature data are limited and inconclusive, and further research is necessary to verify these findings.

According to recent studies, a painless course of CP occurs in about 10% of patients.^51,52 Among patients with the painless course of the disease, 56.9% of them had idiopathic/genetic, 32.4% had alcoholic, and 8.9%—other etiologies.⁵¹ The primary painless course was by far the most common in patients with LO-ICP—52% and much less frequent in ACP (5%) and EO-ICP (0%).⁴⁶ In summary, it appears that pain in the course of ICP occurs less frequently than in the course of ACP, but is particularly rare in the course of LO-ICP, while it is common in EO-ICP. However, compared to the global population, patients from South Asia appear to experience pain in the course of ICP significantly more often, especially in LO-ICP. Recent studies indicate that smoking is a factor that significantly increases the risk of pain in the course of CP.^8,45,53 However, the proportion of smokers among ACP patients appears to be significantly higher than among ICP patients, which may also contribute to the more frequent occurrence of pain in the former group.^8,45 In a Japanese study involving 1171 patients with ACP and 347 with ICP, ever smokers accounted for 85% and 39.8% of them, respectively.⁸ Smoking and drinking alone were not risk factors for pain, but heavy alcohol abuse (⩾80 g ethanol per day) and ever smoking in a synergistic way increased the risk of pain in patients with CP (odds ratio (OR) = 1.75).⁸ In turn, in the Indian study, patients with a history of smoking also represented the higher proportion in ACP patients (n = 540) than in ICP patients (both EO-ICP (n = 668) and LO-ICP (n = 207))—28.1%; 1.5% and 5.31%, respectively.⁴⁵ The multivariable Cox regression analysis performed there showed that no history of smoking and age of onset more than 35 years are predictors of earlier pain resolution.⁴⁵ Similarly, in a study based on the Scandinavian Baltic Pancreatic Club database involving 932 patients with CP, multivariate regression models were used, to show that both alcohol abuse (more than 1 year of consuming 5 or more units of alcohol per day) and a history of smoking (>100 cigarettes in a lifetime) were significantly associated with the occurrence of pain in the course of CP–OR = 1.66 and OR = 1.94, respectively.⁵⁴

In turn, the fact that LO-ICP patients experience pain less frequently than EO-ICP patients does not seem to be well explained by current evidence, but it may be related to changes that occur with aging.^55,56 The pathophysiology of pain in CP involves mechanisms related to neuroplastic changes in central pain pathways, pancreatic neuropathy, and both peripheral and central sensitization.^57,58 On the other hand, aging can reduce sensitivity to pain, especially to milder, moderate stimuli, and also reduce neuroplasticity and the nervous system’s capability to generate and maintain pain sensitization.^57,59 This may result in reduced, atypical pain perception in patients with LO-ICP.

Steatorrhea, as the major clinical manifestation of pancreatic exocrine insufficiency (PEI), usually appears late in the disease course, when pancreatic lipase secretion lowers by 90%.¹³ In a prospective study, it was found that patients with ICP develop steatorrhea less frequently and later, compared to patients with ACP.⁶⁰ Considering the entire follow-up period, with a median duration of 7.6 years, steatorrhea was found in a total of 20.8% of patients with ICP and 29.7% of patients with ACP.⁶⁰

Agarwal et al.⁴⁵ indicate that patients with ICP develop steatorrhea later—median time after disease onset in EO-ICP is 24 years, in LO-ICP 18 years, and in ACP 16 years. Patients with ICP are not constantly exposed to the proinflammatory effects of toxins, unlike those with ACP.^2,33 Alcohol in patients with ACP has a direct toxic effect on pancreatic acinar cells and may also promote microcirculation disorders and progressive parenchymal ischemia.² This may contribute to the faster rate of pancreatic parenchymal damage and earlier development of PEI in patients with ACP compared to ICP.

In a long-term study conducted in China, involving CP patients enrolled between 2000 and 2013 and followed up for a median time of 7.6 years, diabetes mellitus (DM) was diagnosed in a total of 26.1% of ICP patients, which was lower than in the ACP group—38.9%.⁶⁰ This pattern persisted regardless of the duration of the disease: 5 years after disease onset, the prevalence of diabetes in ICP yielded 18% and in ACP 20.8%, and after 10 years 21.7% and 29.7%, respectively.⁶⁰ In a German study, the median time to develop diabetes from CP onset was 27 years in EO-ICP, 28 years—in HCP and 8 years in ACP.⁴⁶ In New Delhi, India, authors observed that DM occurs the earliest in LO-ICP (median time 5.83 years; n = 207), in ACP later (median time 11.5 years; n = 540), and in EO-ICP the latest (median time 28 years, n = 668).⁴⁵ The prevalence of diabetes on presentation was reported in 20.3% of patients with LO-ICP, 10.2% with ACP, and 5.1% with EO-ICP.⁴⁵ After 10 years of disease duration, diabetes was observed in 62.7%, 45.1%, and 26.3%, respectively.⁴⁵ In turn, in a study of 155 CP patients from Northern India, diabetes at the time of diagnosis was reported in 34.8% (8/23) of patients with LO-ICP, 22% (13/59) with ACP, and 17.1% (7/41) with EO-ICP, but this difference was not statistically significant.⁴⁷ Furthermore, among patients from Southern India, the prevalence of diabetes in the course of ICP was even higher—LO-ICP—69.1% (65/94) and EO-ICP—41.4% (46/111).⁴⁸ It appears that diabetes tends to develop earliest and most frequently in patients with LO-ICP, followed by those with ACP, and slowest and least frequently in those with EO-ICP. However, it should be emphasized that although this trend is generally observed, available studies suggest that individuals from South Asia, particularly from India, show a higher prevalence of DM in the course of ICP, especially LO-ICP, compared with Western populations, as well as populations from East Asia.

In patients with EO-ICP, the tendency for diabetes to develop more slowly than in patients with ACP may also be explained by the toxic effect of alcohol and pancreatic destruction, including the islet cells.² Alcohol abuse leads to increased reactive oxygen species production and endoplasmic reticulum stress in pancreatic beta-cells, which are highly susceptible to their harmful effects due to low levels of H₂O₂-inactivating enzymes.⁶¹ In addition, long-term alcohol consumption may promote tyrosine nitration of the glucokinase enzyme, leading to its structural changes, and therefore a reduction in its activity and disruption of glucose metabolism.⁶¹ These processes contribute to disturbances in insulin synthesis and secretion by beta-cells, their dysfunction, and apoptosis.⁶¹

In turn, the faster development of diabetes in patients with LO-ICP than in those with EO-ICP may be due to pancreatic beta-cells age and lose their function, and they may have a reduced capacity for regeneration and adaptation.^45,62,63 Current research indicates that in humans, despite the aging process, unlike exocrine parenchyma, the overall mass of pancreatic beta-cells remains relatively well preserved.^64,65 In turn, rodent studies have even described an increase in endocrine parenchyma in aged mice.⁶⁴ This is consistent with the age-related accumulation of senescent beta-cells characterized by increased volume.^62,64 A decrease in the proliferative capacity of pancreatic beta-cells with age has also been observed, but in adults, it is also physiologically quite low, so this decline should not have a significant impact on the total mass of beta-cells.⁶⁴ In addition, changes in transcription in the pathway linking glucose stimulation and insulin secretion, impaired Ca²⁺ homeostasis, and increased accumulation of lipid droplets were observed in aging pancreatic beta-cells.⁶² These processes may disrupt insulin secretion and impair beta-cell function in patients as they age, which may also contribute to the higher rate of diabetes in LO-ICP patients than in EO-ICP patients. In addition, early DM in LO-ICP is probably due to decreasing insulin sensitivity with age, reduced physical activity, and numerous comorbidities and their treatment.^62,66,67

In a prospective-retrospective study with a median follow-up time of 9.8 years, 1633 ICP patients with or without DM were evaluated.⁶⁸ Kaplan–Meier analysis and Cox regression were used to identify potential independent risk factors for developing diabetes.⁶⁸ As a result, biliary stenosis (hazard ratio (HR) = 2.518) and steatorrhea (HR = 2.006) were significant risk factors in multivariate analysis.⁶⁸

The suggested explanation for the association between steatorrhea and biliary stenosis with an increased risk of DM is the fact that both are already indicative of advanced severe CP with advanced fibro-inflammatory damage to the pancreatic parenchyma.^68,69 Furthermore, the authors suggest that single main pancreatic duct (MPD) lesions, such as MPD pancreatic stone alone, MPD stenosis alone, or MPD stenosis combined with stone, may be protective factors compared to combined MPD lesions, defined as combination of ductal stricture, intraductal stones, and dilatation of pancreatic duct (PD) in the body or tail of the pancreas.⁶⁸ The latter are usually associated with a generally more severe course of ICP and therefore a higher risk of developing DM.⁶⁸ In another study, in 118 men with EO-ICP, it was indicated with a multivariate analysis that a history of cigarette smoking (OR = 4.2), the presence of pancreatic calcifications (OR = 7.7), age over 40 (OR = 9.2), and a positive family history of DM (OR = 3.5) were the risk factors for the DM development.⁴⁸

Diagnostic testing

CP diagnosis is particularly challenging in the early stages of the disease, when there are no pathognomonic lesions consistent with CP yet, such as pancreatic calcifications.⁷⁰ The diagnosis of CP is usually made based on clinical symptoms, imaging studies, and pancreatic function tests.^13,14

Imaging studies

According to the American College of Gastroenterology guidelines, when CP is clinically suspected, the first imaging test performed should be computed tomography (CT) or MRI.¹⁴ In imaging studies in CP, calcifications in the pancreas or its ducts are characteristic, but dilatation of the MPD and its branches, enlargement of the pancreas, atrophic changes, and fibrosis may also occur.⁷¹

A study of 2037 patients found pancreatic calcifications in 83.9% of patients with ACP (n = 404) compared with 73% of patients with ICP (n = 1633).⁶⁰ Similarly, a survey of the Japanese population reported the presence of calcifications in 71.7% of patients with ACP and 63.4% of patients with ICP.⁸ In line with this is the Lewis et al.’s³⁷ study, where pancreatic calcifications were also slightly more common in ACP compared to ICP (both EO-ICP and LO-ICP). On the other hand, in an Indian study, calcifications were the most common in EO-ICP (85%, n = 668), and of similar frequency in LO-ICP and ACP, 75.8% (n = 207), 76.3% (n = 540), respectively.⁴⁵ A significantly increased frequency of calcifications in the course of ICP was also reported in the population of Southern India.⁴⁸ In a study by Rajesh et al.⁴⁸ involving 111 patients with EO-ICP and 94 with LO-ICP, pancreatic calcifications were found in as many as 95.5% and 97.9% of patients, respectively.

It appears that the development of pancreatic calcifications during CP may also be influenced by genetic mutations. A Chinese study involving 1061 patients with CP (715 with ICP, 206 with ACP, and 140 with smoking-related CP) identified a significantly higher risk of pancreatic stones in those with mutations in the SPINK1, PRSS1, CTRC, or CFTR (CP mutation-positive vs CP mutation-negative—90.3% vs 78.1%, respectively).³⁶ In addition, among ICP patients with detected mutations, the age of detection of pancreatic stones was 13.6 years earlier than in mutation-negative ICP patients.³⁶ Furthermore, in a study of German patients, significantly more pancreatic calcifications were detected in patients with SPINK1 gene mutations than in those with PRSS1 mutations.⁷²

Generally, calcifications appear to be slightly more frequent in ACP than in ICP (Table 2); however, pathogenic genetic variants may also influence the tendency to form calcifications. On the other hand, the population of South Asia, especially India, ICP (both EO-ICP and LO-ICP) is characterized by a marked increased tendency to develop calcifications.

Table 2.

Comparison of CP symptoms and complications depending on etiologies.

Symptom	ACP	ICP	EO-ICP	LO-ICP	References
Pain	68.1%–95%	54.8%–82.4%	89.97%–100%	48%–100%	8, 15, 37, 45 –49, 60
Primary painless course	3.7%–14%	8.2%	0%–4%	11.6%–52%	15, 37, 46, 49, 60
DM	30%–66%	26.3%–49.9%	30%–41.1%	28%–69%	8, 15, 37, 45, 46, 48, 49, 60
Median time after the onset	8–19.8 years	30 years	27–28 years	5.8–11.9 years
PEI	36%–96%	45%–78%	30%–86%	36%–91%	15, 33, 37, 46, 48, 49
Median time after the onset	5–13.1 years	25 years	14–26.3 years	16.9 years
Steatorrhea	29.7%	20.8%	x	x	45, 60
Median time after the onset	16 years	x	24 years	18 years
Calcification	59%–86%	63.4%–73%	46%–95.5%	37%–97.9%	8, 15, 37, 45, 46, 48, 60
Median time after the onset	6–8.7 years	x	9.5–24.9 years	19.4 years
Pancreatic pseudocyst	23.3%–46%	14.7%	7.4%–33%	9%–28%	15, 37, 45, 46, 48, 60

ACP, alcoholic chronic pancreatitis; CP, chronic pancreatitis; DM, diabetes mellitus; EO-ICP, early-onset chronic pancreatitis; ICP, idiopathic chronic pancreatitis; LO-ICP, late-onset chronic pancreatitis; PEI, pancreatic exocrine insufficiency; x, not determined.

To standardize the interpretation of the CP changes on CT, the modified Cambridge classification (CC) has been proposed.⁷³ When no changes are found on CT or MRI, and CP is still suspected, EUS should be performed.¹⁴ It has been recognized that EUS is the most sensitive diagnostic method in CP, especially in the early stages of the disease.¹³ The Rosemont criteria were proposed to standardize the interpretation of imaging findings on EUS in CP.⁷⁴

A retrospective study evaluated 182 patients diagnosed between 2000 and 2014 with confirmed CP.⁴⁴ The study aimed to analyze the severity of morphologic changes in CP on CT depending on the etiology of CP and their correlation to functional assessment.⁴⁴ EUS-adapted CC (I–IV) was used to assess the severity of imaging changes according to the then-German S3 guidelines.⁴⁴ Among the patients studied, 91 patients (50%) had a known idiopathic/unknown etiology, 77 were alcoholic (42.3%), and 14 were autoimmune (7.7%).⁴⁴ It was observed that Cambridge scores are relatively similarly distributed in patients with both ICP and ACP.⁴⁴ However, advanced CC stages were observed less frequently in ICP than in ACP, with stage IV in 30.8% and 42.9%, respectively.⁴⁴ In contrast to ICP and ACP, lower (I/II) Cambridge scores strongly prevailed in the autoimmune etiology and were found in as many as 87.7% of the subjects in this group.⁴⁴ Overall, it was suggested that more severe morphologic changes occur slightly more frequently in ACP than in ICP.

Pancreas function tests

To diagnose PEI, non-invasive tests are most commonly performed. The most widely used is fecal elastase-1, with the cut-off value below 200 µg/g.^13,75 An alternative of limited accessibility is the ¹³C-mixed triglyceride breath test.^13,76 PEI should be diagnosed as early as possible, considering its serious consequences, including steatorrhea, impaired absorption of fat-soluble vitamins (A, D, E, K), malnutrition, sarcopenia, osteopenia, and osteoporosis.^2,13,76 Therefore, according to European guidelines, tests assessing exocrine pancreatic function should be performed in every patient with newly diagnosed CP, and then repeated annually or when the first symptoms suggestive of PEI occur.¹³ The onset and rate of progression of pancreatic insufficiency in CP vary according to the etiology.¹³ In CP of alcoholic etiology, it develops faster and has a more severe course than in idiopathic or genetically determined CP.^13,46 A prospective study evaluated 343 patients with CP, who were classified into 4 groups—ACP (n = 265), EO-ICP (n = 21), LO-ICP (n = 46), and HCP associated with PRSS1 mutation (n = 11).⁴⁶ It was shown that exocrine insufficiency, defined as fecal chymotrypsin ⩽120 µg/g or fecal elastase ⩽200 µg/g, developed significantly faster in cases of ACP than in other etiologies. The median time to develop exocrine insufficiency for ACP patients was 5 years, compared with 14 years for EO-ICP and 22 years for HCP.⁴⁶ In line with this, in the study by Rajesh et al.⁴⁸ PEI (fecal elastase <200 µg/g) was found significantly less frequently in patients with EO-ICP—34.4% than in patients with LO-ICP—53.2%. It has been observed that with age, the volume of the exocrine pancreas parenchyma decreases and structural changes occur, leading to fibrosis and fatty replacement of the pancreatic parenchyma.⁶⁵ This may influence the faster development of PEI in patients with LO-ICP compared to EO-ICP.

Early stages

However, in the early stages of CP, when typical radiological changes are not yet present, the correct diagnosis of CP is significantly more challenging.⁷⁷ In particular, when there are no obvious risk factors, especially alcohol abuse, that would suggest a diagnosis of CP.⁷⁸ Therefore, in the case of a patient with ICP, making the correct diagnosis and differential diagnosis can be even more difficult. Consequently, these patients may be misdiagnosed, potentially influencing estimates of the true prevalence of ICP.

As early-stage ICP may manifest itself through dyspeptic symptoms, one of the diseases with which ICP may be misdiagnosed is functional dyspepsia (FD).⁷⁹ FD is defined as the presence of one or more symptoms such as early satiety, postprandial fullness, epigastric pain, and burning, in the absence of any diagnosed organic causes to explain them.⁸⁰ Therefore, differential diagnosis in patients with dyspepsia, between FD and CP in the early stages, in the absence of abnormal findings in laboratory or imaging tests such as ultrasound, CT, or upper endoscopy, especially in patients without risk factors for CP or FD, is considerably difficult.⁷⁹ A Spanish prospective, observational, cross-sectional study included 213 patients with epigastric pain suggestive of epigastric pain syndrome (EPS)—one of the three main subtypes of FD, along with postprandial distress syndrome (PDS) and overlapping EPS and PDS syndrome.⁷⁸ These patients had no diagnosed or suspected conditions explaining the cause of their symptoms, including gastrointestinal diseases.⁷⁸ In addition, patients with a history of alcohol abuse (>80 g/day) were excluded from the study.⁷⁸ The subjects underwent EUS examination of the pancreas, which was evaluated based on EUS criteria for CP diagnosis.⁷⁸ At least 5 criteria were found, and CP was diagnosed in 18 patients (8.4%).⁷⁸ In turn, 34 patients (15.9%) had 3–4 EUS criteria for CP.⁷⁸ In this group, MRI/secretin-enhanced MRCP and endoscopic pancreatic function test were additionally performed, diagnosing CP in another 27 patients (12.7% of total).⁷⁸ Ultimately, CP was diagnosed in 21.1% of the study participants (45/213).⁷⁸ FD was diagnosed in 65.3% (139/213) of patients, gastrointestinal mucosal lesions in 11.3% (n = 24/213), and other causes explaining the symptoms in 2.3%.⁷⁸ In turn, in the study by Sahai et al.,⁸¹ 40% of patients (61/156) with dyspeptic symptoms had at least 5 CP criteria on EUS examination, which was comparable to the frequency in patients with dyspepsia and factors indicating pancreatic disease (history of pain radiating to the back; abnormalities in pancreatic enzymes; chronic diarrhea/steatorrhea; previous attempt at endoscopic retrograde pancreatography; or abnormalities in the pancreas in other imaging studies). By contrast, among control patients who underwent EUS for other indications, only 10% fulfilled at least 5 CP criteria on EUS.⁸¹

Furthermore, selecting patients with dyspeptic symptoms that may be caused by CP and who would benefit from EUS is challenging.⁷⁸ Previous studies, in which the Lundh test was performed and stimulated secretion of pancreatic enzymes and bicarbonate after a meal was assessed, showed that abnormally low secretion is found in up to 35% of patients with dyspepsia.^82,83 In turn, a proportion of these patients may be affected by underlying CP.^79,83 In a study by Hashimoto et al.,⁷⁹ early stages of CP were detected on EUS in 64% of patients (16/25) with symptoms of EPS and abnormalities in serum pancreatic enzyme tests for amylase, lipase, trypsin, and PLA2. However, further research is needed to help determine the connection between abnormalities in pancreatic enzyme tests, particularly serum tests, in patients with FD, and the changes observed on EUS, as well as their relevance to the early stages of CP.⁷⁹ Furthermore, as differentiating between CP, especially of unknown cause, and FD is difficult in clinical practice, it may lead to misdiagnosis and may compromise the accuracy of epidemiological data on these diseases.

Pancreatic complications

Pseudocysts

Pancreatic pseudocysts (PPC) are fluid accumulations surrounded by a distinct wall, resulting from disorders or damage to the PDs, such as obstruction, periductal fibrosis, and calcifications in the course of AP, trauma, or CP.^84,85

Recent studies revealed a lower rate of PPC development in ICP, in both early (7.4%–33%) and late (9%–28%) forms, compared to ACP (23.3%–46%; Table 2).^37,45,46,60 Liu et al.⁸⁴ in a study of 1633 patients with ICP, at a median follow-up of 9.8 years, found the pseudocysts in 14.7% of them.⁸⁴ With multivariate Cox regression analysis, the following risk factors for development of pseudocysts in ICP were pointed out—male sex (HR = 2.093), history of severe AP (HR = 4.651), and chronic pain and pathological changes in the MPD.⁸⁴ PPC are often asymptomatic. In some cases, vomiting, nausea, pain, or complications such as infection, cyst rupture, bleeding, or compression of surrounding vessels and organs occur, and endoscopic or surgical treatment is indicated.^13,86 In a retrospective study of patients treated between 2014 and 2020 for symptomatic PPCs, the vast majority—74% (14/19)—had alcohol-related pancreatitis, 21% (4/19) idiopathic, and only 5% (1/19) biliary-related.⁸⁷ Similarly, among 50 patients who underwent endoscopic treatment for symptomatic PPCs between 2003 and 2006, 19 had alcohol-related CP, compared to 1 with ICP and 30 patients with other diagnoses (21 with acute biliary pancreatitis and 9 with pancreatic trauma).⁸⁸ In ICP, pseudocysts are less common, and medical interventions are less often required compared to ACP.

Cancer

CP is also a risk factor for pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), in particular.^13,89 The risk of developing PDAC increases with the duration of the CP.⁹⁰ However, this risk varies significantly depending on the etiology of CP.⁹⁰ Patients with genetic CP, especially those associated with PRSS1 and SPINK1 gene mutations, along with patients with inherited syndromes such as Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome (HNPCC), familial adenomatous polyposis, and hereditary breast and ovarian cancer are at particularly high risk of developing PDAC.^{13,49,60,91–93} The cumulative risk of developing pancreatic cancer in patients with CP associated with a mutation in the PRSS1 gene is 19% at age 60, and 12% at age 60 for the SPINK1 gene.^49,91 The most likely cause of the significantly higher risk of pancreatic cancer in patients with genetic CP compared to idiopathic and alcoholic etiology is prolonged exposure to inflammatory processes due to the early onset and longer duration of the disease.^13,89 The risk of developing PDAC in patients with both idiopathic and alcoholic CP (ACP) is significantly lower than in patients with CP with a genetic background.^13,49,60,91 In a study by Cartelle et al.³³ of 101 patients with ICP and 349 patients with non-idiopathic CP, there was no significant difference in the frequency of PDAC between these groups, and it was 5% (5/101) and 4% (12/349), respectively. Similarly, in a study of 1633 patients with ICP and 404 patients with ACP, pancreatic cancer was observed in 1.1% of patients with ICP and 0.7% of patients with ACP, which was not different.⁶⁰ A slightly higher incidence of PDAC development in the course of ICP (EO-ICP—0.9%–3.7%; LO-ICP—6.6%–7.7%) was observed in South Asia, but still significantly lower than in the course of genetic CP.^45,48 An important risk factor for pancreatic cancer is smoking, which doubles the risk in the general population.^94,95 In addition, in the case of CP, and especially in cases of genetic CP, cigarette smoking as a confounding and aggravating factor further increases the risk of malignant transformation.⁹⁵ It is suggested that smoking by patients with genetic CP reduces the age of onset of pancreatic cancer by approximately 20 years compared to non-smoking patients.⁹⁶ In addition, a multicenter study based on an international database using multivariate Cox proportional hazards analysis showed a significant impact of smoking, but also heavy alcohol abuse (>39 g/day), on the development of pancreatic cancer, with HR = 2.69 and HR = 1.62, respectively.⁹⁷ They also indicated that 10 years after quitting smoking and drinking, patients achieved a risk of developing PDAC comparable to that of people who have never smoked or abused alcohol (HR = 0.95 and HR = 0.88).⁹⁷ The impact of alcohol on the development of pancreatic cancer is also confirmed by a large meta-analysis of 30 cohort studies involving patients recruited between 1980 and 2013 with a median follow-up time of 15.6 years.⁹⁸ Alcohol consumption of 30–60 g/day was associated with a 12% higher risk, and consumption of 60 g/day or more with a 32% higher risk of developing PDAC than consumption of 0.1–5 g/day.⁹⁸ Therefore, it is strongly recommended that patients with CP abstain from alcohol and quit smoking as soon as possible.⁹³ Diabetes is a risk factor for PDAC and may also occur as a consequence of it.⁹⁴ It is also suggested that the co-occurrence of CP and the development of diabetes will further increase the risk of PDAC.⁹⁹ A Taiwanese cohort study found that patients with both CP and newly diagnosed diabetes with a duration of less than 2 years had an exceptionally high risk of developing pancreatic cancer compared to subjects without these factors (HR = 33.5).¹⁰⁰ Analyses of other databases also confirm this relationship, but indicate a lower increase in risk—HR = 4.7–12.1.^99,101,102 In summary, the risk of malignant transformation is significantly lower in both ICP and ACP compared to genetic CP, and the development of pancreatic cancer in CP may be influenced not only by hereditary predisposition, but also by acquired and environmental factors such as smoking, alcohol, and diabetes.

Treatment

The main purpose of treating all forms of CP is to reduce discomfort from CP symptoms and improve the quality of life.^4,5 A healthy balanced diet, but without fat restriction, is recommended for all patients.¹⁰³ Alcohol abstinence and smoking cessation are strictly recommended.¹⁴

Maintaining a healthy lifestyle can also help control glycemia.¹³ The treatment of diabetes resulting from CP is mainly based on insulin therapy, especially in patients with severe malnutrition, due to its beneficial anabolic effect in this case.¹³ However, it should be used with caution due to the high risk of hypoglycemia in this type of diabetes, caused by the lack of effective counter-regulation due to impaired glucagon function and the possibility of increased peripheral insulin sensitivity.^2,99 However, in the case of mild hyperglycemia in patients with ICP, the use of metformin may be considered, unlike in patients with CP who continue to abuse alcohol, as they are at risk of lactic acidosis.¹³

Pancreatic enzyme replacement therapy (PERT) is recommended for the treatment of PEI, as it increases the absorption of fats and nitrogen and increases the levels of fat-soluble vitamins and trace elements, which reduces the risk of malabsorption effects such as malnutrition, sarcopenia, and osteoporosis.^14,104 In addition, PERT reduces the severity of gastrointestinal symptoms, reduces abdominal pain, and steatorrhea.^14,104 It contributes to an overall improvement in patients’ quality of life and a lower mortality rate.^14,104

Treatment of pain, the most common symptom of CP, is carried out according to the WHO analgesic ladder, starting with non-opioid drugs.¹³ However, in ICP, there is no need for complex pain management.³³ In a retrospective study conducted in the United States between 2016 and 2021, comparing a group of ICP patients (n = 101) with a group of non-idiopathic CP patients (n = 349), significantly lower use of opioid and gabapentinoid drugs was reported (29.6% vs 54.4%; 34% vs 52.3%, respectively).³³

Endoscopic treatment is used because it is assumed that increased pressure in the PD or the presence of PD deposits causes pain. It is performed in patients with pain and the presence of ductal strictures or deposits.¹⁰⁵ PD stones are removed using extracorporeal shockwave lithotripsy (ESWL) and endoscopic retrograde cholangiopancreatography (ERCP), and in PD stenosis, pneumatic dilatation and stent placement are used.¹⁰⁵ As in CP with other etiologies, in patients with ICP, ESWL and endotherapy have positive effects, reducing pain or decreasing its intensity and the need for analgesics.^106,107 A long-term follow-up study enrolled 636 patients with painful idiopathic chronic calcific pancreatitis who underwent ESWL.¹⁰⁷ Patients were divided into two groups based on follow-up time: the intermediate group (2–5 years; n = 364) and the long-term group (>5 years; n = 272).¹⁰⁷ In both groups, patients experienced significant pain relief after ESWL.¹⁰⁷ In the intermediate group, 68.7% (250/364) of patients had no recurrence of pain, and in the long-term group, it was 60.3% (164/272).¹⁰⁷ In addition, after the procedure, 93% of patients reported a significant improvement in quality of life compared to before the procedure.¹⁰⁷

It has been suggested that endoscopic treatment may delay the development of diabetes in patients with CP, especially ICP.¹⁰⁸ A follow-up cohort study analyzed 507 CP patients enrolled in the study between 2011 and 2012 and followed until 2018, 326 (64.3%) with ICP compared to 181 patients with alcohol and/or smoking-related CP.¹⁰⁸ Among the patients, 283 underwent ductal intervention, of whom 239 had ESWL with pancreatic sphincterotomy and PD stenting, 26 had ERCP with pancreatic sphincterotomy and PD stenting, and 18 people had Frey surgery/lateral pancreaticojejunostomy alone.¹⁰⁸ It was shown that in patients with ICP, the median time to the development of diabetes from the onset of symptoms was significantly delayed in those who underwent ductal intervention (median time—5.9 years) compared to those who did not (median time—2.5 years).¹⁰⁸ By contrast, in patients with non-idiopathic CP (ACP/SCP), the time to develop diabetes from the onset of symptoms was similar in both groups.¹⁰⁸

The indications for surgical treatment include chronic abdominal pain and/or local complications of CP, such as biliary duct strictures, pseudocysts, duodenal obstruction, PD fistula, pseudoaneurysm, and cancer suspicion.^105,109 In the context of long-term pain relief in patients with CP and PD obstruction, surgical interventions should be considered as the first-line option.¹⁴

Resection, decompression, or mixed surgical techniques are performed.¹³ Available studies show that patients with non-ACP, including ICP, require surgical intervention less frequently than those with ACP.^110,111 A Danish prospective randomized study included patients with CP requiring intervention for chronic pain and qualified for early surgical or endoscopic intervention early in the course of the disease.¹¹⁰ In both groups, CP was predominantly alcohol-related, accounting for 77% (34/44) in the early surgery group and 61% (27/44) in the endoscopy group. In comparison, the frequency of idiopathic etiology was significantly lower—early surgery—16% (7/44), endoscopy—27% (12/44).¹¹⁰ Less common etiologies included hereditary (early surgery 2% (1/44), endoscopy 2% (1/44)) and other causes.¹¹⁰ Similarly, a prospective study conducted between 1997 and 2019 included patients undergoing surgical treatment for chronic pain and/or complications of CP.¹¹¹ A total of 161 patients were enrolled, of whom 61.3% (110/161) had pain as the sole indicator, 19.3% had pain and complications as indicators, and 12.4% had complications alone.¹¹¹ Among the CP patients who underwent surgery, as many as 143 (88%) had an alcoholic etiology, compared to 18 (12%) patients with a non-alcoholic etiology.¹¹¹ In addition, multivariate regression analysis showed that alcoholic etiology, compared to non-alcoholic etiology, was a significant factor increasing mortality (HR = 2.27).¹¹¹

Prognosis

As a group, patients with CP have reduced survival rates compared to the general population.^111–114 A multicenter study of 2015 patients with CP showed that their mortality rate is 3.6-fold higher than that of participants without CP.¹¹² The survival rate decreases significantly with the duration of the disease: after 5 years, it is 97%, after 10 years, it was 70%–86.3%, and after 20 years, it was 45%–63%.^112,114 The prognosis and survival rate are significantly poorer in patients with ACP than in patients with non-ACP, including ICP.^60,111–115 In ACP, the median survival time is 20–24 years, compared to approximately 20% higher survival in patients with non-ACP, including ICP.¹¹⁶ This is consistent with the fact that most causes of death in patients with CP are not directly attributable to the disease itself, but are associated with chronic alcohol abuse and/or smoking.^114,117 The most common causes of death include smoking-related cancers, cardiovascular disease, and alcohol cirrhosis.^114,117

Conclusion

ICP, compared to CP of other etiologies, is characterized by a much milder course and a more favorable prognosis. Especially when compared to ACP, patients with ICP experience less frequent and shorter episodes of pain during the course of the disease, and they also develop exocrine and endocrine pancreatic insufficiency less frequently and later in life. However, there is a tendency that when comparing ICP subgroups, EO-ICP shows a significantly more aggressive pain course not only than LO-ICP but also than ACP. In turn, the rate of progression to both exocrine and endocrine pancreatic insufficiency may be significantly faster in LO-ICP than in ACP and EO-ICP. Nevertheless, the incidence of calcifications and complications of CP, including PPCs, is significantly lower in ICP than in ACP. In addition, the risk of malignant transformation into pancreatic cancer in patients with ICP, like in those with ACP, is significantly lower than in genetic CP. However, findings from South Asia suggest that while overall trends are broadly comparable to those observed in Western countries and East Asia, the course of ICP in this region may differ. It appears to be characterized by a higher frequency of pain, including in LO-ICP, a higher incidence of diabetes, and calcifications. This may reflect certain genetic factors specific to the population of this region or environmental exposure. Nevertheless, available studies indicate that patients with ICP have better treatment outcomes and are less frequently in need of complex pain management, including gabapentinoids and opioids. The lower incidence of complications contributes to less frequent hospitalizations and invasive therapeutic procedures, both endoscopic and surgical. All this results in a significantly better prognosis for patients with ICP than for those with other etiologies.

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iDs

Kinga Knopczyk

Ewa Małecka-Wojciesko

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Idiopathic chronic pancreatitis: clinical highlights

Abstract

Keywords

Introduction and epidemiology

Etiopathogenesis

ICP natural history

Diagnostic testing

Imaging studies

Pancreas function tests

Early stages

Pancreatic complications

Pseudocysts

Cancer

Treatment

Prognosis

Conclusion

Footnotes

Appendix

Acknowledgements

Declarations

ORCID iDs

References