Insights into the development of alcoholic chronic pancreatitis at Soweto, South Africa: a controlled cross-sectional study.

OBJECTIVE: We asked why so few working-class Africans of Soweto have chronic pancreatitis (CP) when alcoholism is the norm. METHODS: Twenty-one alcoholics with acute psychosis but normal pancreas were investigated for lifestyle, micronutrient status, electrophilic stress, and iron overload. RESULTS: Alcoholics consumed more ethanol daily than did 14 previously studied patients with CP (P = 0.003); cigarette usage was similar; both groups had even poorer vitamin C status than 14 healthy controls, and no participant had iron overload. The CP group had higher scores for exposure to occupational xenobiotics than did alcoholics (P < 0.05), with lower plasma glutathione (P = 0.047) and urinary inorganic sulfate (P = 0.009). Further analysis identified hyperhomocysteinemia in the alcoholic set, with lower vitamin B12 (P < 0.001), higher folic acid (P = 0.003), and similar vitamin B6 levels compared with controls. CONCLUSIONS: The transition from alcoholism to CP in Soweto is associated with occupational exposure to xenobiotics. Among detoxification systems that are strained thereby, glutathione and inorganic sulfate depend on methionine intake, which is ample in Sowetans, whereas vitamin C, which exerts a glutathione-sparing effect, is deficient. Hence, a daily tablet of vitamin C may enable community prophylaxis against the disease--but homocysteine status would need monitoring.

Chronic pancreatitis.

Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local complications, and psychosocial issues associated with the disease are additional therapeutic challenges.

Micronutrient therapy for chronic pancreatitis: rationale and impact.

Micronutrient therapy, designed to buttress tissue methyl and thiol groups, curbs attacks and controls background pain in patients with chronic pancreatitis, irrespective of aetiology. This outcome and the premises upon which it is based facilitate an understanding of links with mutations in genes for hereditary pancreatitis and cystic fibrosis, demography, and predisposition to pancreatic cancer. Above all, there is an opportunity for prophylaxis in individuals at high risk of developing the disease.

'Not knowing something is normally a milestone on the way to knowledge'. An interview with Joan M. Braganza, DSc, FRCP, FRCPath, Reader Emeritus, University of Manchester, UK.

Dr. Joan Braganza, a world expert in the field of chronic pancreatitis, proposed a new template for its pathogenesis based on the role of free radical pathology, in particular the heightened but unmitigated oxidative detoxification reactions via cytochromes P450. Dr. Braganza has gone on to show how pancreatic damage in cystic fibrosis, acute pancreatitis and pancreatic cancer fit into the scheme, paving the way for new treatment modalities. In this interview, Dr. Braganza shares her life experience as an investigator and provides a perspective for young researchers entering the field of pancreatology.

Dietary antioxidant lack, impaired hepatic glutathione reserve, and cholesterol gallstones.

BACKGROUND: Theoretical considerations and experimental studies suggest a causal connection between micronutrient antioxidant insufficiency and the development of human gallstones. METHODS: Fasting plasma/serum samples from 24 patients with cholesterol gallstones-on unchanged lifestyles-were analysed for the four main micronutrient antioxidants, glutathione and factors that impact or report upon glutathione homeostasis. The results were assessed by comparison with laboratory referent ranges. RESULTS: The vitamin E:cholesterol ratio was lower in patients than controls (P=0.021) as also concentrations of beta-carotene (P=0.001) and vitamin C (P=0.001) but not selenium (P=0.280). A fall in plasma glutathione (P=0.001) was also accompanied by lower values of pyridoxyl-5-phosphate (the coenzyme that participates in vitamin B6-dependent enzyme reactions) which is involved in glutathione biosynthesis (P<0.001), and of folate (P=0.012) but not vitamin B12 (P=0.377) that participate in its regeneration via the methionine-homocysteine pathway. Despite these defects, values for plasma homocysteine were not significantly different from controls (P=0.092)-an anomaly rationalised by poor levels of precursor methionine (P=0.003) and cysteine (P=0.046). CONCLUSIONS: Micronutrient antioxidant-including sulphur amino acid-lack, with disturbed glutathione homeostasis, are features of cholesterol gallstone disease.

Acute pancreatitis in Soweto, South Africa: relationship between trypsinogen load, trypsinogen activation, and fibrinolysis.

OBJECTIVE: It is not known why acute pancreatitis in Soweto, South Africa, pursues an aggressive course. We sought clues from circulating trypsinogen load at admission as marker of initial acinar injury, trypsinogen activation using the carboxypeptidase B activation peptide as surrogate, proteinase inhibitors, the coagulation-fibrinolysis axis, indicators of inflammation, oxidative stress markers, and antioxidant status. This article reports on the first four aspects. METHODS: The study involved 24 consecutive patients with a first attack. All of them were admitted within 24 h, and 22 were alcoholic. Urine was analyzed for anionic trypsinogen and the carboxypeptidase B activation peptide. Serum was tested for anionic and cationic trypsinogen, alpha1 proteinase inhibitor and alpha2 macroglobulin. Plasma from a subset was assayed for soluble fibrin, cross-linked fibrin degradation products (surrogates for thrombin and plasmin activity, respectively), and tissue-type plasminogen activator and inhibitor. RESULTS: Soweto controls had higher serum anionic trypsinogen (p = 0.004) and plasminogen activator:inhibitor ratio (p = 0.047) than U.K. controls. The outcome of acute pancreatitis was mild in 17 but severe in seven with three deaths, two on day 2. In mild pancreatitis, intense plasmin activity (p < 0.001) accompanied the surge in trypsinogen, especially anionic (p < 0.001), but without increased thrombin activity and in five patients without trypsinogen activation. In severe pancreatitis, further significant increments in plasmin activity and trypsinogens were accompanied by increased thrombin activity (p = 0.013) and trypsinogen activation (p = 0.046). There was no correlation between surrogates of plasmin and thrombin activity, or between either and the carboxypeptidase B activation peptide, which showed a curvilinear relationship to total serum trypsinogen. CONCLUSIONS: The aggressive nature of alcoholic acute pancreatitis in Soweto seems to reflect early profound fibrinolysis, which precedes coagulation and is initially independent of trypsin. Subclinical acinar-cell injury and a profibrinolytic diathesis in outwardly healthy Sowetans may predispose to this problem.