PRSS1與SPINK1基因型胰臟炎臨床病程之比較與探討

Abstract

胰臟炎是一個全球性的健康問題，它具有不同的病因。胰臟炎的致病因子包括長期喝酒、高脂血症、高鈣血症等代謝性原因及遺傳，1996年首次報告知道基因的變化也是引起胰臟炎很重要的因素。而有一些在排除上述原因後，仍無可能原因者稱為不明原因，大概佔所有慢性胰臟炎的20-30%。 慢性胰臟炎最常見的症狀就是上腹疼痛，典型症狀會伴隨著背痛，患者在疼痛時往往會彎著上半身，屈起膝蓋(成蝦子狀)。而疼痛往往持續了好幾個小時才會慢慢緩和下來。胰臟炎疼痛的頻率、持續的時間、嚴重程度與進食與否的關係也不一。慢性胰臟炎的診斷須綜合病史，臨床症狀、胰臟功能評估和影像檢查。然而，對於早發或初發的慢性胰臟炎，其實很難被發現，也很難診斷，因為在早期可能完全沒有症狀，這時須配合個人之既往病史與家族史、有無新發生的糖尿病等來考慮慢性胰臟炎存在之可能。 基因型胰臟炎是一種罕見早發性慢性胰臟炎。除了可能很年輕就被診斷，在35歲以前稱為早發型，其他病程、形態特徵和實驗室的檢驗表現跟其他慢性胰臟炎可以十分相似，但罹患胰臟癌的風險卻大不同。國內對於基因型胰臟炎的研究與了解，知之甚少。本研究針對帶有PRSS1 或 SPINK1 突變的基因型胰臟炎患者，比較其臨床病程之差異。並針對發病年齡之不同來做分析其症狀表現(如疼痛)和胰臟炎併發症，我們發現慢性胰臟炎的疼痛，在早發與晚發型之基因型胰臟炎有所不同：早發型之基因型胰臟炎與發生type A疼痛及同時有type A與type B疼痛的發生率，都有顯著的差異(p=0.002 vs p=0.001)。我們更進一步作多變項分析發現有鈣化者發生type B疼痛的風險上升；而有糖尿病者，其發生type A或同時發生type A B疼痛的風險值均下降。 對於胰臟酵素的需求，PRSS1突變的基因型慢性胰臟炎(GCP)，對於胰臟酵素使用的需求也有顯著上升(p=0.021)。而在管制類止痛劑的使用，不同基因型的胰臟炎對於管制類止痛劑的需求並沒有顯著的不同。但在早發型之基因型胰臟炎的患者需要使用管制類止痛劑的比率，有顯著的上升(p=0.039)。 在多變項分析中，胰臟鈣化會增加病人發生type B疼痛，它的風險值(OR)為8.93 (95%的信賴區間為1.82-73.68；p=0.007)。在發病時間之不同的研究中，早發型(≦35歲)會增加病人有type A B疼痛的機會，其風險值為94.56 (95%的信賴區間為3.46-2582.49; p=0.007)。具有脂肪便症狀的病人發生type A B疼痛的機會較高，其風險值為39.11 (95%的信賴區間為1.38-1106.36；p=0.032)。有糖尿病的病人，發生type A的疼痛機率較低，其風險值為0.15 (95%的信賴區間為0.03-0.69； p=0.015)。最後，針對基因型胰臟炎但從來沒有發生疼痛的病人，我們發現有糖尿病的病人較不會有疼痛的症狀，其風險值為0.15(95%的信賴區間為0.03-0.71；p=0.017) 。 在73位病人中，有6人已罹患胰臟癌，佔8.2%，在基因型之慢性胰臟炎病人得到胰臟癌的發生率是一般台灣人的700-800倍(一般為每10萬人口約10-11人)且胰臟癌的發生年齡比其他偶發胰臟癌的發生約早了10歲。我們的研究是針對華人基因型慢性胰臟炎病程第一個完整長期追蹤報告，研究的內容提供了我們對基因型慢性胰臟炎有進一步的了解，也提供我們在未來有更多需要進一步去研究和努力的目標，包括疼痛對病人生活品質的衝擊量表，疼痛的介入性治療以及胰臟癌篩檢。

Pancreatitis is a global health problem with different etiologies. The etiology including toxic (alcohol, hypertriglycemia, hypercalcemia et al.,) obstructive, autoimmune, genetic and idiopathic. The first genetic alteration related to human pancreatitis has been reported in 1996 which was considered an important etiology of pancreatitis. Nowadays, mutations of cationic trypsinogen gene (PRSS1) or serine protease inhibitor Kazal-type 1 (SPINK1) gene has been regarded as the most common two genes causing genetic pancreatitis. The most common symptom of chronic pancreatitis is pancreatic pain. Usually the diagnosis of chronic pancreatitis should integrate history, clinical symptoms and imaging or even pathology. Most of the chronic pancreatitis were diagnosed at late stage. It is a great challenge to diagnose chronic pancreatitis in early stage because of it usually lack early symptoms. Besides, personal and family history, the development of newly-onset diabetes et al. might also provide some clue to clinical diagnosis of chronic pancreatitis. Genetic pancreatitis is a rare form of chronic pancreatitis which may present symptoms at different age, from vey young to old. The clinical presentation, progression, laboratory tests and even morphological and pathological findings were not different from alcoholic chronic pancreatitis. In this study, we analyzed the genotype and phenotype correlation in patients with genetic pancreatitis who enrolled prospectively since 2003. Patient were excluded for analysis if any other known combined etiology such as autoimmune, pancreatic divisum et al. Genetic mutation was defined by presence of PRSS1 or SPINK1 mutations by direct sequencing. The clinical demographic data, symptoms, onset of age, clinical course, complications, influence of environmental factors exposure to tobacco and alcohol, diabetes, and occurrence of pancreatic cancer were included for analysis. We stratified patient by two ways: according to genotype and onset of age for further analysis. Univariate and multivariate analysis were performed for predicting different types of pain. We found that early onset of genetic chronic pancreatitis was an independent prognostic factor of predicting of type A pain (p=0.002) and type A B pain (p=0.001). Patient with genetic chronic pancreatitis carrying PRSS1 mutation was associated higher frequency of need of enzyme supplement (p = 0.021). Patients with early onset of disease had higher frequency of use of narcotic analgesics (p = 0.039). Multivariate analysis revealed pancreatic calcification was associated with higher risk of development of type B pain with and odds ratio 8.93 (95% CI: 1.82-73.68, p = 0.007). Early onset of age and steatorrhea were independent predictors of development of type A B pain (p = 0.007 and p = 0.032 respectively) with an OR 94.56 and 39.11 in multivariate analysis. Diabetes was an negative predictor of development of type A pain (OR 0.15, 95% CI: 0.03-0.69, p = 0.015) Diabetes also an predictor of pain-free course in multivariate analysis. There were 6 patients of 73 (8.2%) patients complicated with pancreatic cancer. The incidence rate of pancreatic cancer in our genetic chronic pancreatitis cohort were about 700-800 times compared to normal population of Taiwanese. Furthermore, the mean age of pancreatic cancer in our GCP cohort were 10 years younger than sporadic pancreatic cancer in Chinese in Taiwan. This observation arose the importance of surveillance of pancreatic cancer in patients with genetic chronic pancreatitis in our population. Our study was the first prospective and comprehensive study of genetic chronic pancreatitis. The information disclosed in the pilot study help us to underlying more regarding the clinical course of genetic chronic pancreatitis. The evaluation of impact of pain to patients, intervention of pain, and surveillance of pancreatic cancer in the special groups of chronic pancreatitis awaits further study in the future.