Pancreatic diseases have been observed with increasing frequency in recent years. While part of this increase is certainly due to a better clinical and diagnostic knowledge of these diseases, the possibility of a real increase cannot be ruled out. Acute pancreatitis, which is the subject of this paper, is the most frequent pancreatic disease and is also the one that often presents hard to solve diagnostic problems and especially therapeutic ones. We must know it well to dominate it, and unfortunately this is not always the case.

AETIOLOGY
Acute pancreatitis is an inflammatory disease that can occur in an oedematous form and in a necrotic one: oedematous pancreatitis is the most frequent (75-80% of cases), while the necrotic one is fortunately less frequent (20-25% of cases).
Its incidence in populations in industrialized nations is not well known, but should be approximately 40-50 cases per one hundred thousand inhabitants a year. Its aetiology is extremely variable, though alcohol and cholelithiasis are often (about 80% of cases) responsible factors. I recently conducted a study on acute pancreatitis in various European countries to examine certain aspects numbering also aetiology.
1,068 patients were evaluated; their mean age was 52.8 years, ranging from 10-95 years. Males were the most affected sex. The most frequent aetiological factors were cholelithiasis (37.1%) and chronic alcohol abuse (41.0%).
The aetiology was idiopathic in 13% of cases and it was extremely variable in the remaining 8.9% (hyperlipaemia, pancreatic diseases, surgery, kidney transplants etc.) (Table 1)
Considering aetiological factors by country, there emerged relevant differences concerning cholelithiasis and alcohol (Table 2).
In Germany these two factors have a similar frequency (respectively 34.9% and 37.9%), in Hungary alcohol prevails on cholelithiasis cases (60.7% vs. 24.0%), in France there is a slight prevalence of alcohol (38.5% vs. 24.6%), while Greece and Italy present a clear prevalence of cholelithiasis on alcohol (respectively 71.4% vs. 6.0% and 60.3% vs. 13.2%).
Differences between the first three countries and the second group are statistically significant. Differences were also observed in the relations between aetiology, sex and age (Table 3).
There is a prevalence of men on women (90.6% vs. 9.4%) in cases presenting an alcoholic aetiology, while women prevail in the cholelithiasis group (59.8% vs. 40.2%). The mean age of a pancreatitis attack is 42.6 years for cases with an alcoholic aetiology and 59.9 years for those with a biliary aetiology.
This data gives evidence that:
1) alcohol is the most frequent aetiological factor in acute pancreatitis in north European countries while cholelithiasis prevails in southern Europe;
2) the high percentage of those forms distinguished by an alcoholic aetiology indicate a prevalence of men on women;
3) the mean age for the disease’s onset is much lower in alcoholic forms compared to biliary ones. The reasons behind the higher incidence of acute pancreatitis in the alcoholic aetiology group in the north and of cholelithiasis in southern Europe are not clear; the different alcohol consumption and frequency of cholelithiasis in these countries can be a cause. In Hungary, where alcoholic forms have a great prevalence, the most frequently consumed alcoholic drink has a very high alcohol content and this could increase its toxicity for the pancreas.

PATHOGENESIS
It is generally acknowledged that acute pancreatitis is caused by an autodigestive process of the pancreas carried out by its enzymes that have been inappropriately activated in the gland. Tripsin is activated first and in turn it activates the other proenzymes. In physiological conditions the pancreas has various protective mechanisms that prevent the activation of these enzymes:
1) digestive enzymes are synthesized as inactive proenzymes and are later activated only in the duodenum;
2) in pancreatic cells these proenzymes are isolated in cytoplasmic vacuoles where they do not come in contact with other enzymes;
3) both tissue and pancreatic secretions contain various inhibitors of digestive enzymes. It is not clear how the intrapancreatic activation of tripsin and the destruction of protective mechanisms take place. In biliary pancreatitis it seems to be triggered by a bile stone obstructing the papilla of Vater.
The subsequent sudden increase in pressure in pancreatic ducts would cause pancreatitis. Concerning acute alcoholic pancreatitis, many authors, including myself, believe it occurs in a pancreas that was already the site of chronic pancreatitis. In particular, it is secondary to the obstruction of excretory ducts performed by protein plugs that are one of the first lesions in chronic alcoholic pancreatitis.
These two theories believe that ductal, biliary or pancreatic obstruction is the first pathogenic event in both forms of pancreatitis, but what takes place in the cell is still not very clear. A recent theory surmises a block in the secretion of digestive enzymes in the pancreatic cell.
These enzymes would hence be located together with lysosomial enzymes in large intracellular vacuoles. In these vacuoles, a lysosomial enzyme, cathepsin B, would activate tripsinogen, which in turn would activate the other pancreatic enzymes (elastase, phospholipase A, carboxypeptidase, etc.) with subsequent digestion of the pancreas and acute pancreatitis. Besides tripsin would activate other enzymic systems (kallikrein-kinin, the complement), which would contribute to the multi-organ damage typical in necrotic pancreatitis.
High concentrations of the toxic oxygen radical form at an early stage, contributing to pancreatic damage. It is not clear why acute pancreatitis is mild and oedematous in most cases and necrotic in others. It is possible that in most cases intrapancreatic protective mechanisms prevail on activated digestive enzymes and pancreatitis remains oedematous. If the enzymes prevail, the necrotic form will occur.

CLINICAL PRESENTATION
The clinical picture varies considerably depending on the disease’s gravity. Abdominal pain is the only important symptom in oedematous forms and the disease will heal in a few days. Many other symptoms and complications can occur, besides pain, in necrotic forms and progress is very serious and at times fatal.
The disease’s main symptoms are reported in Table 4. Pain is present in almost all cases. Generally it has a sudden onset, soon reaches its peak and persists, without interruption, for many hours (at least 10-12 hours) or days. It is very acute and is located in the epigastrium from which it can radiate to the hypochondria, the back and the entire abdomen.
Pain can be absent in very acute and often fatal forms that complicate surgery for serious pathologies generally of the thoracic aorta and of the heart. Vomiting, nausea and anorexia are frequent, besides fever, which is generally high. High temperatures suggest necrotic tissue infection or other infectious processes.
The physical examination is generally negative in the oedematous forms, apart a certain tenderness in the epigastrium. There can be mild and transitory jaundice due to oedema in the head of the pancreas that presses against the bile duct. Persistent jaundice is the expression of stones obstructing the bile duct and/or cholangitic processes.
Especially necrotic forms can present rigidity of the abdominal wall, reduction or disappearance of intestinal sounds, tachycardia, hypotension, shock, tachypnoea, dyspnoea, disorientation, mental confusion, hallucinations and ecchymosis along the hips (Grey-Turner’s sign) and/or in the periumbilical region (Cullen’s sign). Often the gravity of pancreatitis may not correspond with findings of the physical examination of the abdomen.

COMPLICATIONS
Various complications, both local and general, can occur to aggravate the disease’s progress, especially in its necrotic forms (Table 5). Local complications most frequently number pseudocysts and necrotic tissue infections. Pseudocysts (30-40% of cases) can be single or multiple and variable in size; they generally tend to heal spontaneously. They can cause persistent pain and an increase in serum pancreatic enzymes. Necrotic tissue infection (30-40% of cases) occurs within 2-3 weeks from the disease’s onset. It is a very serious complication that generally requires surgery. Abscesses are generally less frequent. Systemic complications most often number hypovolaemia and hypotension, which appear especially when fluid intake is not adequate. Necrotic forms, especially the most serious ones, can present other cardiovascular, pulmonary, renal, metabolic, cerebral and coagulatory complications (Table 5).

DIAGNOSIS
There are many laboratory and diagnostic tests that are useful to confirm the diagnosis, evaluate the seriousness of pancreatitis and establish its aetiology. Laboratory tests High serum pancreatic enzymes. Serum tests of amylase and lipase are the most useful diagnostic methods. These enzymes increase immediately at the onset of pancreatitis and normalize within 3-6 days.
They may remain high when persistent phlogoses or pseudocysts are present. There are no relations between the gravity of pancreatitis and the extent of the increase. Often patients suffering from oedematous pancreatitis have very high values while those with necrotic pancreatitis, especially if serious and widespread, have lower values.
The two enzymes’ sensitivity is very high (90-100%); their lipase specificity is excellent (95-100%). There are also other high serum pancreatic enzyme conditions, both pathological and not, that must be known to perform a correct diagnostic evaluation. High serum pancreatic enzymes in non-pancreatic diseases. We must keep in mind that serum pancreatic enzymes can increase in various pathological conditions such as hepatic diseases, especially cirrhosis, renal failure, diabetes, Crohn’s disease, ulcerative colitis, AIDS and others.
These cases present pancreatic damage, which is often chronic, but can at times be acute. Even certain drugs used to treat these diseases (5-aminosalicylic acid, mesalamine, azathioprine, dideoxyinosine, pentamidine, etc) can be the cause of high serum enzymes. A serum increase of only amylase may have a salivary cause (salivary gland diseases) or be the expression of macroamylasemia, in which case, urine amylase is normal. Chronic, non-pathologic, high serum pancreatic enzymes. An increase in serum pancreatic enzymes can also occur in healthy individuals, in the absence of all symptoms and with a functionally and morphologically normal pancreas.
This new syndrome, described recently by me, is characterized by a chronic increase in all serum pancreatic enzymes; their values generally fluctuate with bouts of normal values too. This high serum pancreatic enzyme disease presents both a sporadic form and a familial one. For diagnostic purposes it is important to keep in mind that we must be sure that the individual who presents high serum pancreatic enzymes is healthy, has never had disorders that can be referred to the pancreas and that ultrasound scans and abdominal CAT scans are normal. I believe it a good practice to make this diagnosis after having monitored the patient for 6-12 months and having noticed persistent high serum pancreatic enzymes with no pathology. I wish to mention that, in rare cases, an increase in serum pancreatic enzymes can be noticed in healthy individuals who present a mutation of the Cystic Fibrosis Transmembrane Regulator gene. Other investigations. Other investigations are extremely useful towards the evaluation of the disease’s gravity.
Table 6 reports those suggested by Ranson many years ago. Other patterns have been later proposed, numbering the well known APACHE-II that considers many variables: cardiac frequency, respiratory frequency, arterial pressure, partial O2 pressure, arterial pH, serum potassium, serum sodium, creatinaemia, hematocrit and white blood cells. It is worth mentioning that these and other patterns proposed have certain limits and their sensitivity and specificity are less than 100%.
The metering of C-reactive-protein, which increases in necrotic forms, of transaminases, ã-GT and alkaline phosphatase, which increase in pancreatitis rising from biliary lithiasis, is extremely useful. Especially transaminase and ã-GT metering is very useful in the apparent absence of aetiology; if these indexes are found to be high it means that pancreatitis has been caused by a stone in the bile duct that could have already been expelled. Interleukin-6 is an acute phase protein that soon increases in acute necrotic pancreatitis (it reaches its peak within 24-36 hours from the onset of the disease) and can then be useful towards the disease’s early diagnosis. However, currently there are no metering assays that are simple enough, hence they are little used in clinical practice. Other recently proposed tests are the dosage of CAPAP (activation peptide of procarboxypeptidase) and TAP (activation peptide of tripsinogen) in serum or in urine.
They could contribute towards the diagnosis and evaluation of the gravity of pancreatitis, but are expensive and not easy to perform. Imaging diagnostic procedures A barium X-ray of the abdomen and a chest X-ray supply non specific but useful information. The first can show the conditions of the ileum and it is generally localized (control intestinal ansa) and the second the presence of pleuropulmonary complications. Ultrasound scanning and CAT scans are the most important investigations. Ultrasound scanning, in the absence of meteorism that prevents a clear view of the pancreas, clearly shows pancreatic lesions, pseudocysts and accumulation of abdominal fluids.
When performed by expert doctors, it can be the only diagnostic investigation in oedematous pancreatitis. CAT scans are essential especially in necrotic pancreatitis as they clearly show the site and extent of necrosis, accumulation of pancreatic and extra-pancreatic fluids and possible other complications.
Its sensitivity and specificity are virtually 100%. Ultrasound scanning and CAT scans are also very useful to establish the aetiology of biliary pancreatitis caused by pancreatic diseases, traumas, etc. Retrograde cholangiography with papillotomy and removal of stones is recommended in patients with bile duct lithiasis, jaundice and possible cholangitis. We must keep in mind that stones in the bile duct are often expelled spontaneously, hence the performance of this test must be carefully evaluated and reserved for special cases. MRI and other more sophisticated techniques do not add information to that supplied by ultrasound scanning and CAT scans.
Differential diagnosis
A differential diagnosis must be made with perforated peptic ulcers, mesenteric infarction, intestinal obstruction and severe cholecystitis. In general terms, an accurately taken case history and carefully conducted physical examination enable especially expert physicians to make a correct diagnosis. If doubts persist a laparotomy is recommended, as it can be useful both towards diagnosis and treatment.
Prognosis
The prognosis is favourable in all or almost all patients with acute oedematous pancreatitis.
The mortality rate is still high in the necrotic form. My recent study on acute pancreatitis in Europe reported a global mortality rate of 7.8% (83 on 1,068 cases).
Of the 589 patients suffering from oedematous pancreatitis only 6 (1%) died (Table 7); these were aged patients suffering from other associated diseases too. Of the 479 patients suffering from necrotic pancreatitis, 77 (16.1%) died due to complications of the disease. 16.1% is a lower incidence than in the past but I consider it still high and every effort must be made to reduce it. No relevant differences have been observed in mortality associated with the aetiology of pancreatitis (Table 7).
Treatment
Pancreas at rest, pain control and adequate IV intake of fluids are the main therapeutic measures. Fasting is essential to maintain the pancreas at rest. Treatment generally also involves the nasogastric tube, which greatly contributes to reducing gastrointestinal bloating. NSAIDs are generally effective against pain and meperidine and pentazocine can be administered against very acute pain. The maintenance of intravascular volume through the infusion of appropriate volumes of fluids and electrolytes is an essential therapeutic measure.
The patient must be carefully monitored and liquid loss must be evaluated and appropriately counterbalanced. The use of antibiotics is not deemed necessary in oedematous forms in the absence of infectious complications. Opinions concerning necrotic forms do not agree, some believe antibiotics should be administered as a preventive measure in all cases, both in the presence of an infection in the necrotic tissue and in its absence too.
Others instead believe they should be administered only in the presence of an infection.
Considering highly active antibiotics on the pancreas, I wish to mention imipenem and cefuroxime. The use of gabexate mesilate, a tripsin inhibitor, is debated. Its use can be justified in patients who are examined soon after the onset of pancreatitis, before necrosis starts spreading. In patients with oedematous pancreatitis, 4-5 days of treatment may suffice, after which period feeding can gradually be recommenced.
They can be discharged after 7-8 days’ hospitalization. The course to follow in patients with necrotic pancreatitis depends on the presence and absence of complications. If there are no complications, the course is similar to the previous one, with the difference that hospitalization is slightly longer (10-12 days). If there are complications, these must be adequately treated, the patient must possibly be moved to an intensive care or semi-intensive care unit and monitored and treated with special attention.
Once pancreatitis is treated, its cause must be treated. If it is lithiasis, it requires an early surgical intervention. If it is alcohol, the patient must be convinced to definitely give up drinking. Other causes must be carefully investigated and treated. Failure to treat the aetiological cause predisposes to recurrences.
Acute recurrent pancreatitis
As there are no recent studies on this form of pancreatitis, I examined the incidence of this disease in Europe to evaluate its frequency, aetiology and mortality.
Of the 1,068 European patients with acute pancreatitis I already mentioned, 288 (27%) suffered from a recurrent form. The incidence is high, though it was higher in the past. Of these 288, 211 (73.3%) were men and 77 (26.7%) were women.
Their mean age was 43 years, ranging from 16 to 95 years (Table 8). Concerning aetiology, alcohol was the most frequent factor (164 cases, 57%), followed by cholelithiasis (72 cases, 25%), idiopathic forms (30 cases, 10.4%) and diverse factors such as hyperlipaemia, pancreas divisum, cystic distrophy of the duodenum, intraductal mucinous pancreatic tumour, pancreatic gastrinoma and ERCP (22 cases, 7.6%).
The prevalence of alcohol was observed especially in Germany, Hungary, and France and to a much lesser degree in Italy and especially in Greece, where biliary pancreatitis prevails. In most cases (74.3%), it was the second attack of pancreatitis, which suggests that attacks do not recur repeatedly.
This can be due to the fact that, currently, the cause is treated at an early stage. In the alcoholic form acute attacks generally occur in the early stages of an underlying chronic pancreatitis and then their frequency drops especially if the patient stops drinking. Concerning the mortality rate, 17 (5.9%) of the 288 patients studied died. They all suffered from necrotic pancreatitis.
Focusing only on patients with necrotic pancreatitis (No. = 141), the incidence of deaths is 12.1%, which is slightly lower than the incidence observed in non-recurrent acute pancreatitis (18.6%), but not in a statistically significant manner. It is interesting to notice that most deceased patients, 14 on 17, were on their second attack of pancreatitis. It is possible that a frequent recurrence of attacks makes the disease less serious (reduction of normal parenchyma due to previous attacks?).
Since pancreatitis has a tendency to recur when its cause has not been treated, it is obvious that every effort must be made on a therapeutic level to remove the cause no sooner possible.
Translated by interpres sas

Lucio Gullo
Direttore Istituto di Medicina Interna,
Facoltà di Medicina e Chirurgia,
Università di Bologna, Ospedale S. Orsola, Bologna
E-mail:gullo@med.unibo.it