Two forms of hereditary chronic pancreatitis.

We report 11 families of hereditary pancreatitis characterized by the presence of calculi in pancreatic ducts. These were classified as (1) calcic lithiasis (one family with five cases), in which the calculi are composed of >95% calcium salts; and (2) protein lithiasis in 10 families, in which the calculi are composed of degraded amorphous residues of lithostathine, the pancreatic secretory protein that inhibits calcium salt crystallization. In both forms, transmission appears to be dominant. The average age at clinical onset of symptoms is 15 years. The clinical progression seems to be less severe than in alcoholic chronic pancreatitis (alcoholic calcic lithiasis). This report shows for the first time that hereditary chronic pancreatitis is a group of at least two diseases having a similar clinical picture and pathological features but different chemical compositions of calculi. This leads us to propose a revised Marseille-Rome classification.

Pancreatic lesions and modifications of pancreatic juice in tropical chronic pancreatitis (tropical calcific diabetes).

Seventeen Indian patients from Kerala State and 13 Indian controls were submitted to a dietary inquiry. Indian patients and controls had a low fat intake (40.8 g +/- 12.1 and 34.5 g +/- 11.0 per day, respectively) and a moderately low protein intake (52.8 +/- 9.5 and 47.8 +/- 11.3 g per day); 11 patients and 6 controls did not consume cassava. Pure nonactivated pancreatic juice was collected at endoscopy in 10 Indian patients who presented with tropical calcific diabetes, 12 apparently normal controls from the same area, and 23 apparently normal French controls. The only significant differences between Indian and French controls was a decreased pancreatic protein response to cerulein and an increased calcium concentration in the Indian subjects. The pancreatic juice of Indian patients was characterized by decreased volume, normal bicarbonate concentration, increased protein concentration when the acinar cells were not stimulated, with no response to cerulein, increased calcium concentration, and normal citrate concentration. These changes are very similar to the changes observed in French patients with chronic alcoholic pancreatitis. The lesions of 14 surgical resection pancreatic specimens from South Indian patients presenting with tropical pancreatitis were compared to pancreata from French patients presenting with chronic alcoholic pancreatitis. The only difference was that intraductal plugs, lesions of the duct epithelium, and retention cysts or pseudocysts were less frequent in Indians. These results show that the two nutritional forms of pancreatic lithiasis, alcoholic and tropical, have similar histological lesions and biochemical modifications of pancreatic juice.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute pancreatitis is not a cause of chronic pancreatitis in the absence of residual duct strictures.

It has been shown that intraductal injections of bile salts into the bile-pancreatic ducts of dogs or rats were immediately followed by acute hemorrhagic pancreatitis and, some months later, by persisting chronic pancreatitis. The study described in this article was designed to test the assumption that these chronic lesions were due to ductal strictures secondary to the toxic effect of bile salts. The bile-pancreatic ducts of 100 rats were injected with 0.2 ml of a solution containing 4 microM Na taurodeoxycholate and 0.2 microM trypsin. The 66 survivors were killed at intervals from 1 day to 2 months following the induction of acute pancreatitis. Four to six sections were done in the first series, and serial 15-micron sections of the entire pancreas were taken from rats surviving 2 months. These showed that from the sixth day on, the largest ducts draining pathological areas were obstructed by fibrosis. Distal to this obstruction, intralobular ducts were dilated and their epithelia flattened or atrophied. Acini were atrophied and replaced by peri- and intralobular fibrosis. Lesions were limited to areas drained by obstructed ducts, with the rest of the parenchyma being normal. We conclude that in experimental animals, as in human beings, chronic lesions that persist after acute pancreatitis are due to duct obstruction, not to acinar necrosis.

[Hereditary protein lithiasis and calcium lithiasis: two different forms of hereditary pancreatitis]. / Lithiase protéique et lithiase calcique héréditaires: deux formes différentes de pancréatite héréditaire.

We previously reported that the most frequent cases of chronic pancreatitis were the consequence of pancreatic lithiasis and that there were different forms of pancreatic lithiasis with different etiologies and composition of calculi. The most frequent form is the calcic lithiasis, generally due to nutritional disorders. The second most frequent form is proteic lithiasis. In this paper, we report 1.) Ten hereditary cases on a total of 36 patients presenting with proteic lithiasis (age at clinical onset 15 +/- 12 years); 2.) one hereditary case on a total of 150 patients with proteic lithiasis. In these two different maladies, the transmission seems to be dominant, autosomal with incomplete penetrance. Hereditary pancreatitis is therefore a group of at least two different diseases, hereditary protein lithiasis, the most frequent one and hereditary calcic lithiasis exceptional.

[Pancreatic lithostathine inhibitor of calcium carbonate precipitation: structure-function relationship]. / La lithostathine pancréatique inhibiteur de la précipitation du CaCO3: relations structure-fonction.

Pancreatic juice is naturally supersatured in calcium and bicarbonate ions. A mechanism controlling CaCO3 crystal formation and growth is therefore necessary to prevent duct clogging. Lithostathine, a glycoprotein synthesized by acinar cells and secreted in pancreatic juice, could be involved in such a control. Lithostathine significantly delayed crystal nucleation and inhibited growth of CaCO3 crystals from supersatured solutions. Lithostathine adsorbed to sites specifically inhibiting crystal growth with a dissociation constant Kd = 0.9 x 10(-6) mol/L. The glycosylated N-terminal undecapeptide generated by limited trypsin hydrolysis of lithostathine, inhibited CaCO3 crystal growth with a Kd = 3.4 x 10(-6) mol/L similar to that of lithostathine. On the contrary, the carboxy-terminal polypeptide (lithostathine H) was inactive. The N-terminal undecapeptide of lithostathine is therefore essential to the inhibitory activity of the protein on CaCO3 crystal growth.

Chronic pancreatitis and diabetes.

Chronic pancreatitis is defined by a persistent destruction of the pancreatic parenchyma replaced by fibrosis. The lesions generally start in the exocrine gland, islets being attacked later in the fibrosis. The two most frequent forms are: 1. Chronic calcifying pancreatitis which is a pancreatic lithiasis responsible for more than 95% of chronic pancreatitis. In its most frequent form, calculi are built up of more than 98% calcium salts together with fibres of a degraded residue of lithostathine, a secretory protein. This disease is related (i) in most countries to alcohol, protein, fat and tobacco and (ii) in certain tropical countries to malnutrition (low-fat, low-protein diet) for some generations. A causative role for cassava and kwashiorkor is improbable. The mechanism of calcium precipitation is partly explained by the calcium-saturation of pancreatic juice and the decreased biosynthesis of lithostathine S, the secretory protein preventing crystallization. As a rule, diabetes (and steatorrhoea) appear after a clinical evolution characterized by recurrent attacks of upper abdominal pain, generally lasting some days with transiently increased concentrations of pancreatic enzymes in serum. When diabetes appears, pain frequently disappears. Complications are mostly observed in the first 10 years of clinical evolution. 2. Obstructive pancreatitis is due to an obstacle (tumours, scars) in the pancreatic duct. It is rarely a cause of diabetes. Diabetes due to chronic pancreatitis is characterized by the low incidence of ketosis and the high incidence of insulin-induced hypoglycaemia. Patients are generally thin. Serum insulin levels, either basal or stimulated, are decreased. Glucagon is less affected. Angiopathies and retinopathies are less frequent than in non-insulin-dependent diabetes. Neural complications are fairly frequent. The diagnosis is generally easy because diabetes appears at a late stage of the disease. The treatment generally requires insulin.

[Description of a new disease: pancreatic lithiasis with radiolucent calculi]. / Description d'une maladie nouvelle: la lithiase pancréatique à calculs radiotransparents.

118 patients presenting with pancreatic lithiasis were consecutively observed in our service. They underwent both an endoscopic pancreatography and god plain films of the abdomen. Calculi were classified in 3 groups: 1) Radiolucent calculi (17 cases, 5 females; 4 hereditary cases) are build up of amorphous residues of lithostathine S. They are not related to either alcohol, diet or tobacco. 2) Target calculi (27 cases, 4 females; 3 hereditary cases) have a radiolucent core as in 1 and a peripheral calcification. They are a late evolutionary stage of radiolucent lithiasis. The frequency of females and of hereditary cases is significantly greater in form 1 + 2 than in form 3. These two forms are a newly described disease without relationship with nutrition, alcohol or tobacco but the peripheral calcification of radiolucent calculi is favoured by alcohol and tobacco. This disease could be hereditary. 3) Calcic lithiasis (74 cases, 8 females, 2 hereditary cases) is the most frequent form of pancreatic lithiasis. Its cause is nutritional.

Inhibition of nucleation and crystal growth of calcium carbonate by human lithostathine.

Pancreatic juice is naturally supersaturated in calcium and bicarbonate ions. A mechanism controlling CaCO3 crystal formation and growth is therefore necessary to prevent duct clogging. The present study shows that lithostathine, a glycoprotein present in human pancreatic juice at a concentration in the range of 10 mumol/L, could be involved in such a control. Lithostathine in concentrations greater than 1.5 mumol/L significantly delayed crystal nucleation and inhibited growth of preformed CaCO3 crystals from supersaturated solutions. Adsorption of lithostathine on crystals was shown by immunodetection. Albumin also adsorbed on CaCO3 crystals, but neither albumin nor other pancreatic secretory proteins inhibited crystal nucleation or growth. Lithostathine adsorbed to sites specifically inhibiting crystal growth with a dissociation constant (Kd) = 0.9 x 10(-6) mol/L. The glycosylated amino-terminal undecapeptide generated by limited trypsin hydrolysis inhibited CaCO3 crystal growth with a Kd = 3.0 x 10(-6) mol/L, similar to that of lithostathine. On the contrary, the carboxy-terminal polypeptide was inactive. A synthetic undecapeptide identical to the N-terminal end but not glycosylated was equally active. The activity disappeared upon digestion of the undecapeptide with V8 protease. The N-terminal undecapeptide of lithostathine is therefore essential to the inhibitory activity of the protein on CaCO3 crystal growth.

Perfusäo intradiodenal de caseína: um novo método de avaliaçäo de funçäo pancreática: resultados preliminares / Intraduodenal casein perfusion: a new method to evaluate the pancreatic function: preliminary results

Os autores apresentam os resultados preliminares de uma nova metodologia de avaliaçäo funcional pancreática, utilizando a perfusäo intraduodenal de hidrolisado de caseína através da tubagem duodenal com sonda tipo Sarles (duplo lume). O estudo compreendeu um tempo basal (B) de 20 minutos, seguido da perfusäo duodenal de caseína, 65ml em 15 minutos, seguidos de três períodos de 15 minutos (pós-caseína - PC). Ao término do terceiro período, é feita injeçäo intravenosa de secretina 1 UN/kg + ceruleína 75 ng/kg seguida de dois períodos de 15 minutos (pós-hormônio - PH). O recolhimento do suco duodenal é feito por meio de trompa a vácuo com aspiraçäo contínua. O suco gástrico é desprezado e as dosagens de lipase, quimotripsina, bicarbonato e cloro foram realizadas nos tempos B, PC, PH. A populaçäo concernente a esta parte do estudo compreendeu 15 voluntários normais. Os resultados mostraram significante aumento do débito secretor total na estimulaçäo pós-caseína PC com níveis inferiores, mas comparável à estimulaçao hormonal. Nao houve diferença significativa nas médias das concentraçôes máximas de lipase e quimotripsina entre os tempos B, PC e PH, mas observamos débito enzimático três vezes maior em PC e cinco vezes PH, em relaçäo ao tempo basal. Os autores demonstraram as possibilidades do método mas no momento estäo testando a perfusäo de soluçäo contendo caseína e ácido oléico, na tentativa de maior estimulaçäo enzimática (trabalho em curso).

[Description of a new disease, pancreatic lithiasis with radiotransparent calculi]. / Description d'une maladie nouvelle, la lithiase pancréatique à calculs radiotransparents.

118 patients presenting with pancreatic lithiasis were consecutively observed in our service. They underwent both an endoscopic pancreatography and good plain films of the abdomen. Calculi were classified in 3 groups: 1) Radiolucent calculi (17 cases, 5 females; 4 hereditary cases) are build up of amorphous residues of lithostathine S. This disease is not related to either alcohol, diet or tobacco. 2) Taget calculi (27 cases, 4 females; 3 hereditary cases) have a radiolucent core as in 1 and a peripheral calcification. They are a late evolutionary stage of radiolucent lithiasis. The frequency of females and of hereditary cases is significantly greater in form 1 + 2 than in form 3. These two forms are a newly described disease without relationship with nutrition, alcohol or tobacco but the peripheral calcification of radiolucent calculi is favoured by alcohol and tobacco. This disease could be hereditary. 3) Calcic lithiasis (74 cases, 8 females, 2 hereditary cases) is the most frequent form of pancreatic lithiasis. Its cause is nutritional.

A case of primary non-Hodgkin lymphoma of the pancreas.

Non-Hodgkin pancreatic lymphoma is a rare disease. Its diagnosis is difficult without histological examination. Ultrasonographic, computed tomodensitometric, and endoscopic retrograde cholangio-pancreatographic findings are not pathognomonic. The better prognosis of these tumors, compared to adenocarcinoma, and their sensitivity to chemotherapy, implies the need for pathologic examination of every pancreatic tumor.

Radiolucent and calcified pancreatic lithiasis: two different diseases. Role of alcohol and heredity.

One hundred and eighteen consecutive patients presenting with pancreatic calculi have been studied by means of plain films of the abdomen and endoscopic retrograde cholangiopancreatography. Patients were divided into the following groups: 1) Evenly calcified calculi, 74 patients, 66 men, aged at onset (M +/- SM) 40 +/- 10 years; daily consumption of alcohol, 157 +/- 121 g, and of tobacco, 26 +/- 15 cigarettes. Two patients presented with another case in the same family. Composition of calculi--at least 95% calcium salts and a degraded form of lithostathine S (formerly called PSP S2-5)--was similar in the Occidental alcoholic and in the tropical form: calcified calculi are probably related to alcohol and nutritional disorders. 2) Radiolucent stones, 17 patients, 12 men and 5 women, aged at onset 38 +/- 18 years. These patients had a low alcohol and tobacco consumption. There were four familial cases. 3) Radiolucent core with a calcified shell (target calculi), 27 cases, 23 men; age at onset, 38 +/- 15 years; daily ethanol consumption, 111 +/- 93, and tobacco, 19 +/- 15 cigarettes. There were two familial cases. It has been shown that these calculi originated from transparent calculi that later calcified. The frequency of women and of familial cases was significantly greater in groups 2 + 3 than in group 1. The consumption of alcohol and tobacco and the proportion of men were significantly lower in group 2 than in groups 1 and 3. We discuss the role of heredity in lithostathine precipitation and of alcohol in calcium precipitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis?

In a case control study alcohol intake and tobacco use were assessed between 1975 and 1987 in 103 male patients suffering from alcoholic cirrhosis of the liver, in 145 patients with chronic pancreatitis, and in 264 control subjects. The patients with chronic pancreatitis were significantly younger than the patients with cirrhosis (mean (SD) age 41.92 (2.4) v 60.9 (11.6) years). Among the patients with chronic pancreatitis, 94% were both smokers and drinkers compared with 83% of patients with cirrhosis of the liver. The relative risks for each disease were calculated by conditional multiple logistic regression. Whereas daily intake of alcohol was a major risk factor for both cirrhosis of the liver and chronic pancreatitis, smoking was significantly related only to the risk of having chronic pancreatitis. Moreover, the mean age at onset of pancreatitis was lower among smokers.

Definitions and classifications of pancreatitis.

The historical progress of medical knowledge has followed two primary courses. One course has been based mostly on pathology: the description of specific groups of features and of the corresponding causes and symptoms, i.e., the description of different diseases that are progressively distinguished one from another. At the present time, disorders of molecular biology as well as pathological lesions are increasingly playing a role in the definition of diseases. The second course is a preliminary step to the first: when pathological data have not been available, patients have been classified according to symptoms. This does not lead to the description of the diseases but rather of the syndromes. It is puzzling to see that this obsolete method is still commonly used in pancreatology.