| Abstract|| |
Introduction: Chronic pancreatitis and liver disease are two conditions that commonly co-exist in chronic alcoholics with variable incidences. Aim: To evaluate frequency pancreatitis in patients with a history of chronic alcohol abuse. Materials and Methods: A total of 390 autopsies over 11 year's period were included in the study. Gross and microscopic assessment of liver and pancreas were performed. Available clinical and laboratory parameters were recorded. Results: Age ranged from 22 to 65 years with a mean age of 45.32 years. All 390 consecutive patients included in the study were males. Majority of the patients had primarily presented with alcohol related liver diseases whereas few had presented with features of pancreatitis. Micronodular cirrhosis was present in 292 cases. Features of chronic pancreatitis were observed in 42 cases and 8 of these cases had associated changes of acute hemorrhagic pancreatitis. Prevalence of pancreatitis was more in cirrhotics as compared to non-cirrhotics, and acute pancreatitis was mostly seen in non-cirrhotics. Dominant pattern of fibrosis was perilobular followed by periductal, intralobular and diffuse. Conclusion: Chronic pancreatitis as evidence by the presence of parenchymal fibrosis was more frequently observed in alcoholic cirrhosis cases than that in non-cirrhotic alcoholic liver disease, thereby suggesting common underlying pathobiology in the development of fibrosis in liver as well as in pancreas.
Keywords: Acute and chronic pancreatitis, alcohol related liver disease, calcification, chronic alcohol abuse, fat necrosis, pancreatic ductal mucinous metaplasia
|How to cite this article:|
Agrawal P, Vaiphei K. Histomorphological features of pancreas and liver in chronic alcoholics - an analytical study in 390 autopsy cases. Indian J Pathol Microbiol 2014;57:2-8
|How to cite this URL:|
Agrawal P, Vaiphei K. Histomorphological features of pancreas and liver in chronic alcoholics - an analytical study in 390 autopsy cases. Indian J Pathol Microbiol [serial online] 2014 [cited 2020 Jul 5];57:2-8. Available from: http://www.ijpmonline.org/text.asp?2014/57/1/2/130842
| Introduction|| |
Co-existence of alcoholic related liver disease and pancreatitis has been a matter of debate and the involved mechanisms have been variously explained by many investigators. ,,,,,,, The clinical and pathological association between pancreatitis and alcohol abuse is well recognized ,, but the frequency of co-existing alcoholic related pancreatitis (AP) and liver disease (ALD) is less well-studied and the reported estimate is just about 0.04 to 5%.  There are two schools of thoughts with respect to the events involved in disease development both in live rand pancreas. One school suggests frequent co-existence of chronic pancreatits and chronic alcohol related liver disease. ,,,, The other school however believes that alcoholic pancreatitis is infrequently seen in alcoholic liver cirrhosis. , Chronic pancreatitis and chronic liver disease are reportedly two conditions that have well-defined precursor lesion. Recent studies have proposed chronic pancreatitis to develop through stimulation of stellate cells into myofibroblasts, which are responsible for the production of collagen and parenchymal fibrosis, and similarly there is also activation of stellate cells in liver along with steatosis and steatofibrosis ultimately resulting in liver parenchymal fibrosis and cirrhosis. ,,, However, a molecular study has referred to important role of genetic polymorphism in the pathobiology of pancreatic diseases.  A recent study from southern part of the country had shown that alcoholic cirrhosis patient had significantly higher cumulative intake of alcohol and more number of years of intake of alcohol compared to alcoholic chronic pancreatitis.  The purpose of the present study was to evaluate effects of chronic alcoholism in liver and pancreas in patients who died of alcohol related chronic liver disease by examining the histological changes in pancreas and liver.
| Materials and Methods|| |
In a period from January 2001 to May 2011, 390 medical autopsies were included for the analysis. All patients had a documented history of chronic alcohol abuse and clinically presented with one or more of the following problems, i.e. clinical and biochemical evidences of severe liver damage and died of either hepatic encephalopathy, gastrointestinal bleeding, hepatorenal failure, pancreatitis or sepsis. All autopsies were performed within the first few hours after death, mostly within the first 2 h. Post-mortem autolysis was differentiated from ante-mortem changes histologically. Consent for autopsy was obtained from first degree relative of the diseased in all cases. Multiple representative tissue blocks were taken from different areas of liver and pancreas. In addition to routine H and E staining done in all the sections, reticulin, Mason's trichrome and Elastic Van Giesen stainings were also carried out in selected liver and pancreatic sections according to indication. All patients included in the study were male as only male patients were admitted in the hospital with a history of chronic alcohol abuse. Cut off for normal range of the liver weight as 1200 to 1300 gms. Any liver weight less than 1200 gms was documented as having reduced in weight and any liver weight more than 1300 gms was documented as having increased in weight. Histopathology of the alcoholic liver disease included steatosis, steatohepatitis, sclerosing hyaline necrosis and cirrhosis. Changes in pancreas were documented as acute pancreatitis characterized by necrosis of pancreatic parenchyma and surrounding fat, variable amount of hemorrhage and necrotizing inflammation. Fibrosis was graded subjectively as mild, moderate and severe depending on the extend of fibrosis at perilobular and intralobular parenchyma based on Kloppel and Maillet.  Similarly, degree of chronic inflammatory cells were also graded subjectively as mild, moderate and heavy. Observations were expressed in percentages and comparison was done by Chi-square test, a P-value less than 0.05 was considered as significant. Exclusion criteria on histology of pancreas:
i. Pancreases showing focal fine intralobular fibrosis, and
ii. Cases showing terminal peripancreatic fat necrosis with no inflammatory cell response were not considered as a case of acute pancreatitis.
| Results|| |
There were 390 patients who had presented with clinical evidence of chronic liver disease with a definite history of chronic alcohol abuse. Age ranged from 22 to 65 years with a mean of 45.32 years. Liver weight was increased in 288(74%), 90(23) cases had reduced liver weight and 12(3%) had normal weight. Cirrhosis of micronodular type was documented in 292(75%) cases and 98 cases were non-cirrhotics. Grossly visible hemorrhagic pancreatitis was observed in 8; changes of chronic pancreatitis in the form of firm and fibrotic pancreas which were slightly shrunken were documented in 34 cases. There were 20 patients who had diagnosis of pancreatitis clinically. At autopsy, there were altogether 42 cases (10.7%) which had exhibited features of pancreatitis.
Grossly liver weight ranged from 900–2600 gm. Liver was enlarged and overweight in 288 cases, shrunken with a reduced weight in 90 cases and normal in 12 cases. Cirrhotic livers cut slices were firm to feel and showed dominantly micronodules with few larger nodules and the nodules size ranged from 2 to 13 mm. Many of the cirrhotic livers which were overweight were pale and fatty [Table 1]. There were many livers which showed exaggerated mottling of alternate light and dark areas on their cut surfaces. There was no grossly visible portal vein thrombosis, areas of hemorrhages or necrosis within liver parenchyma. Histological parameters studied included micro and macrovesicular steatosis, ballooning degeneration, mallory hyaline, hepatocyte necrosis, portal tract and lobular inflammation, fibrosis in portal tract including bridging, pericellular and perivenular, cholestasis and bile duct proliferation. These features were studied both in cirrhotics and non-cirrhotic cases [Table 2].
Pancreas in all cases was available for gross assessment. Change of pancreatitis was observed in 42 cases. Pancreas in 29 cases was small and firm to feel due to large areas of diffused parenchymal fibrosis [Figure 1]a. In seven cases, pancreas was bulky due to grossly enlarged and swollen pancreas with adhesion to surrounding fat and hemorrhages. Soft tissues were difficult to separate from underlying pancreas and the pancreas could not be delineated clearly from the surrounding adherent soft tissue. [Figure 1]b In six cases, the firm and fibrotic pancreas were bulky due to large areas of saponification/calcification of the surrounding fat and within pancreatic parenchyma which was showing features of acute on chronic pancreatitis. There was prominence of the ductal system in 5 of the 29 chronic pancreatitis cases on gross. In rest of the cases, pancreas appeared normal. Histopathological features examined were pancreatic acinar and islet cells, ductal status, acute and chronic inflammation, necrosis (involving pancreatic lobules, blood vessels and perilobular soft tissue), hemorrhages, fibrosis noting its location and extend and saponification/calcification [Figure 2]a and 2b]. None of the cases showed intraductal calcification. The pancreatic acinar cell status was directly correlated with extent of parenchymal replacement fibrosis [Figure 2]c and 2d]. The islet cells were well preserved and were of normal morphology even in the areas where there was loss of acinar cells. The ductal system was well preserved and in many there was mainly periductal fibrosis [Figure 3]a. Of the 29 cases with histological evidence of chronic pancreatitis, there were 12 cases which showed periductal fibrosis and mucinous metaplasia in the ductal lining epithelial cells [Figure 3]a and in one there was focal squamous metaplasia of the ductal lining epithelial cells [Figure 3]b. None of these 12 cases showed significant dysplasia of the ductal lining epithelial cells. In three cases, the ductal lumen was seen to contain thick inspissated secretion. No intraductal calcification was observed in any of the cases. Cases with hemorrhagic pancreatitis showed large areas of necrosis involving the pancreas and surrounding soft tissue with heavy acute inflammatory cell infiltration [Figure 3]c. Blood vessels also showed necrosis and some of them were seen to have fibrin thrombus [Figure 3]d. The detail histopathological features observed in the cases showing chronic and or acute pancreatitis are shown in [Table 3]. The most dominant pattern of fibrosis was perilobular followed by periductal, intra-lobular and diffuse patterns. Histological changes were observed in combinations in many cases. Parenchymal calcification was observed in eight cases with cirrhosis. Hepatic macrovesicular steatosis was demonstrated in 17% of the cases with chronic pancreatitis, microvesicular steatosis in 14%, ballooning degeneration in 21% and Mallory hyaline in 18.5% of the cases (Chi-square test, P > 0.05). More number of chronic pancreatitis was observed in cirrhotics than in non-cirrhotic cases, and most of the acute pancreatitis was seen in non-cirrhotic cases [Table 4] and [Table 5].
|Figure 1: (a) Gross photograph of a pancreas which small and shrunken by replacement fi brosis seen as whitish firm areas. (b) Grossly swollen and discoloured by hemorrhages|
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|Figure 2: (a) Low power photomicrograph showing peripancreatic fat and f pancreatic parenchymal necrosis (H&E, ×140). (b) Low power photomicrograph showing peripancreatic fat necrosis with hemorrhage (H&E, ×140). (c) Low power photomicrograph showing extensive replacement fibrosis of the pancreas and aggregates of residual Islets of Langerhan and lymphoid aggregates (H&E, ×140). (d) Low power photomicrograph of the same area observed as in fi gure 2C in connective tissue staining to highlight densely collagenised stroma entrapping residual Islets of Langerhan (Massonsæs trichrome, ×140).|
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|Figure 3: (a) Medium power photomicrograph to show mucinous metaplasia of ductal lining epithelium and lightly PAS positive luminal secretion (Alcian blue - PAS, ×400). (b) Medium power photomicrograph to show dilated duct fi lled with thick mucinous secretion and squamous metaplasia of lining epithelium (H&E, ×240). (c) Medium power photomicrograph showing necrotic muscular artery entrapped within necrotic tissue with fi brin thrombus (H & E, ×240). (d) Low power photomicrograph showing pancreatic parenchymal fat infi ltration, interlobular fi brosis and septal fat necrosis (H & E, ×140).|
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|Table 4: Prevalence of pancreatis in patients with alcoholic liver disease|
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|Table 5: Dominant pathologic pancreatic features of chronic pancreatis in cirrhotic and non-cirrhotic patients|
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| Discussion|| |
The coexistence of liver diseases and pancreatitis has been attracting the attention of many investigators although the mechanisms have been variously explained. Except for viral hepatitis liver diseases have not been seriously considered as an etiological factor of pancreatitis. ,,,,,,, Despite the strong association between excessive alcohol consumption and development of chronic pancreatitis, alcohol alone is not sufficient to lead to the disease, only a small proportion of chronic alcoholics (5-10%) develop chronic pancreatitis.  Role of environmental factors, genetic profile or their interaction in determining susceptibility is still poorly understood.  Amongst the environmental factors, smoking has been found to be independent factor associated with chronic pancreatitis.  After all pancreatic disease is a complex disorder resulting from multiple defects, which, when combined, lead to failure of control systems and metabolic homeostasis.  Understanding the roles played by certain genes, proteins, types of cells and pathways involved in interactions may provide better understanding of the pathogenesis of the disease.  Hayakawa et al., have proposed more than one theory in an attempt to explain the mechanisms responsible in the development of pancreatitis of alcoholic etiology.  The first one based pancreatic histology showed ductal closures secondary to increased protein content in pancreatic juice, which led to obstruction, fibrosis, and calcification. Most patients already have some degree of parenchymal injury when presenting with the first acute crisis.  The second theory refers to acinar cell injury secondary to direct toxic effect of ethanol which leads to inflammation which culminates in fibrosis. This hypothesis is based on metabolites of alcohol, such as ethyl esters of fatty acids, causing depletion of adenosine triphosphate (ATP) and loss of calcium regulation, leading to mitochondrial damage and increased susceptibility to activation of intra pancreatic trypsinogen.  Alcohol also results in up regulation of systems that mediate production of cytokines and other pro-inflammatory molecules like protein kinase C, nuclear factor κB and activator protein 1, and generate reactive oxygen species.  All these events would result in chronic inflammatory process and activation of pancreatic stellate cells and thereby fibrosis.  And acute and chronic pancreatitis may not be independent entities as both often are observed together and both could be part of the spectrum of manifestations of the same disease.  However, there are evidences that support the theory that there is a link between alcohol consumption and development of acute and chronic pancreatitis. ,,
In the present study, we observed histological features of acute and chronic pancreatitis and are closely related to well-established features in pancreatitis associated with chronic alcoholism. Role of alcohol as the underlying causative factor for pancreatitis has been explained variously; Hayakawa et al., had given two hypothesis where the pancreatic cells are directly involved.  Another hypothesis according to Renner et al.,  is that as the damaged liver fails to catabolize secretin and cholecystokinin which stimulate the secretion of pancreatic juice. When these effects continue together, the pancreas may become highly vulnerable to various pathogenic stimuli. Since alcohol abuse without liver disease does not affect chronic pancreatitis, the liver involvement may play a role in the development of chronic pancreatitis in alcoholism.  We also observed a close association between chronic pancreatitis and cirrhotic alcoholic liver disease thus indicating that there may be some genetic factors also which may be responsible for the development of subclinical pancreatitis in patients with alcoholic liver disease. In a study by Pace et al.,  a high prevalence of pancreatic injury was also observed in association with the precursor of liver cirrhosis like severe hepatic steatosis. In this subgroup 45% had pancreatic fibrosis and 17% had chronic pancreatitis, accounting for more than 60% of the cases. In the subgroup of cases with mild steatosis only 8% also had a chronic pancreatitis and 31% had pancreatic fibrosis, suggesting a strong relationship between the severities in the subgroups. Very few studies, the majority with small patient number, show a relatively high association of both the diseases. Kochhar et al.,  assessed the prevalence of pancreatic ductal changes in patients with alcoholic liver disease of different stages. In about 40% of the cases ductal changes were found in endoscopic retrograde cholangiopancreatography, but there was no difference in the prevalence of pancreatic changes in cirrhotic in comparison to non-cirrhotic patients. Gullo et al.,  found an incidence of liver cirrhosis diagnosed by liver biopsy of 14% in 50 patients with chronic pancreatitis. A review of 1022 autopsy cases with alcoholic liver cirrhosis showed a prevalence of chronic pancreatitis and pancreatic fibrosis of 20%. 
Our results are in contrast with several studies that have evaluated the relationship between chronic pancreatitis and liver cirrhosis, as well as possible common risk factors. Nakamura et al.,  investigated a possible association between alcoholic chronic pancreatitis and alcoholic liver cirrhosis and tried to identify factors relating to them. In this study, the patients were grouped by endoscopic retrograde cholangiopancreaticography grading and Child-Pugh classification. The results showed a nonparallel relationship between the severities of the two diseases. The authors concluded that different risk factors might confer susceptibility to alcoholic chronic pancreatitis versus alcoholic liver cirrhosis which may explain the nonparallel relationship between the severities of the two diseases. Another study by Angelini et al.,  in 40 patients with alcoholic chronic pancreatitis and 32 patients with alcoholic liver cirrhosis, found in contrast with our results, a relationship between both groups only in the minority of cases. Caradonna et al.,  found only prevalence ~7% chronic pancreatitis in patients with alcoholic liver cirrhosis. A comparison of nutritional profiles of patients with alcohol-related pancreatitis and cirrhosis by Noel-Jorand et al.,  found behavioral differences in patients with chronic pancreatitis and liver cirrhosis, and concluded therefore that alcoholic chronic pancreatitis and alcoholic liver cirrhosis belong to different subgroups. However, our observations suggest the two conditions closely related. Moreover precursor lesions of cirrhosis and chronic pancreatitis like steatosis and pancreatic fibrosis were frequently present in the same individual suggesting the common risk factors being predominant. Our study was designed to examine our hypothesis that alcoholic liver and pancreatic injuries are closely associated disease conditions in the chronic alcoholics. We are also aware of the limitation that are existing in our study, in particular we have no information about the exact quantity of daily alcohol intake, the type and the maunfacturere or the source of the alcohol consumed and the duration of the drinking. And the analysis of tissue damage that had been carried out is semiquantatative especially for the pancreas.
More recently, stellate cells (PSCs) have been studied more in detail in the pathogenetic fibrotic process of chronic alcohol related injuries in liver and pancreas. ,, Stellate cells are believed to be activated directly by alcohol and its metabolites and also by cytokines and growth factors released during alcohol-induced pancreatic and hepatic necroinflammation. Activated PSCs are the key cells responsible for producing the fibrosis by their property of acquisition of myofibroblastic property.
Efforts to identify clinically relevant factors that may explain the susceptibility of some alcoholics to chronic liver and pancreatic injuries have been underway for several years. An unequivocal, functionally characterized, association is yet to be identified in clinical studies, although in the experimental setting, endotoxin has been shown to trigger overt pancreatic injury and to promote disease progression in alcohol-fed animals.
Of the 20 patients who were clinically diagnosed as patients with chronic alcoholic pancreatitis, 8 had hemorrhagic pancreatitis at autopsy, and in two patients there were significant pancreatic fibrosis in gross and microscopic examinations. In terms of the natural history of the disease, the traditional view among pancreatologists was that the condition was a form of chronic pancreatitis from the beginning, punctuated during its course by acute exacerbations.  However, current opinion has reverted to the ''necrosis-fibrosis'' hypothesis, first proposed in 1946 by Comfort et al.,  that alcoholic pancreatitis begins as an acute process, which progresses to chronic irreversible pancreatic damage as a consequence of repeated acute attacks. This idea is now well supported by several clinical and experimental studies. ,,,,
Vonlaufen et al., have assessed the impact of withdrawal or continuation of alcohol on establishedpancreatitis and shown that in contrast to the persistence of established injury upon continuation of alcohol, withdrawal of alcohol resulted in a significant reduction in the indices of pancreatic injury in the form of edema, hemorrhage, acinar cell vacuolization and acinar necrosis. Though we do not have the exact duration, amount of alcohol intake and time events in the development of the pancreatic diseases, but observation of acute necrotizing and hemorrhagic pancreatitis in our cases support the concept of necrosis-fibrosis hypothesis in the process of pancreatic cell injury as the result of chronic alcohol abused.
In conclusion, pancreatitis is not a rare phenomenon in chronic alcoholics with alcoholic chronic liver disease. And severity of the pancreatic pathology does not correlate with the severity of the co-existing liver pathology.
| Acknowledgement|| |
Patients and their families who had given consent for autopsy.
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Department of Histopathology, PGIMER, Chandigarh - 160 012
Source of Support: This study was supported by the National Science
Foundation for Post-doctoral Scientists of China (No.20080430849),
foundation for Sci and Tech Research Project of Shaanxi, (No2010K12-02),, Conflict of Interest: The undersigned certify that this manuscript, or
parts wherein, have not been submitted to any other journal and that
all authors are aware of and agree to the content of the paper and their
being listed as an author.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]