The pancreas is an organ which lies in the abdomen, behind the stomach. It plays an important role in the digestive system by producing enzymes which break down protein in food. These enzymes enter the small intestine through a tube which is also the route by which another digestive fluid, bile, passes from the gall bladder into the intestine. The pancreas also produces insulin, an enzyme that enables the body tissues to deal with glucose from the blood.

Diseases of the pancreas or gall bladder can give rise to pancreatitis. This is a syndrome in which the pancreas becomes inflamed and the digestive enzymes leak into the abdominal cavity. There, the enzymes can start to cause severe inflammation and damage to the surrounding tissues.

Causes

There are several possible causes of pancreatitis, including:

• Alcohol. Heavy drinkers are particularly at risk from attacks of pancreatitis.

• Drugs. Certain anti-HIV treatments used by people with HIV can cause pancreatitis, including ddI (didanosine, Videx / VidexEC) and d4T (stavudine, Zerit). Other drugs, such as the antibiotic pentamidine (Pentacarinat), which may be used to treat HIV-related illnesses, may also cause pancreatitis.

• Very high levels of triglycerides associated with protease inhibitor treatment.

• Infections that affect the gall bladder or pancreas may also cause pancreatitis. The infections linked to pancreatitis in people with HIV are cytomegalovirus (CMV), Cryptosporidium, Mycobacterium avium intracellulare (MAI), Salmonella and, less commonly, Cryptococcus, giardiasis, Kaposi's sarcoma and toxoplasmosis.

Some researchers believe that HIV infection itself can cause pancreatitis without other risk factors. Any physical blocks to the flow of pancreatic enzymes or of bile from the gall bladder can also cause the syndrome.

Pancreatitis is a relatively rare condition in people with HIV or AIDS: a recent Italian study has found that less than 1% of 976 HIV-positive patients taking HAART had pancreatitis, with risk factors being duration of HIV infection, an AIDS diagnosis, low CD4 cell count, long-term protease inhibitor-based highly active antiretroviral therapy (HAART), high triglyceride levels and long-term liver or gall bladder problems (Manfredi 2004). However, when pancreatitis does occur it is most often due to non-HIV-related reasons such as heavy alcohol use.

If the cause of the pancreatitis is removed, the individual may recover completely. This means that it is important to investigate thoroughly the range of possible causes so they can be eliminated. Pancreatitis may persist or recur if the cause is not removed, or if the structure of the organ has been irreparably damaged by scar tissue, known as fibrosis. This long-term problem is called chronic pancreatitis.

A recent analysis of data from the Swiss HIV Cohort Study has suggested that genetics may play a role in increasing susceptibility to pancreatitis. Among patients with high levels of amylase in the blood, a marker of pancreatitis, possession of certain variants, or alleles, of the CFTR and SPINK-1 genes was found to be associated with acute pancreatitis and higher amylase levels than the patients without these alleles (Felley 2004).

ddI and pancreatitis

One of the causes of pancreatitis among people with HIV is as a side-effect of ddI, although it only occurs in a small proportion of people taking the drug.

The effect of ddI on the pancreas may be mild, causing an increase in the levels of pancreatic enzymes in the blood, called hyperamylasaemia, but no physical symptoms. Hyperamylasaemia needs to be properly investigated since it can also be caused by an increase in the secretion of enzymes by salivary glands, which does not necessarily indicate any problem with the pancreas. Mild hyperamylasaemia caused by a ddI-induced increase in pancreatic enzymes can be perfectly harmless, but the condition becomes a cause for concern if the levels rise beyond a certain point. At the other end of the spectrum, there have been a number of deaths caused directly by ddI-related pancreatitis.

The risk of developing pancreatitis from ddI seems to be related to several factors. Individuals are at increased risk if they have other risk factors for pancreatitis apart from taking ddI, if they have a CD4 cell count below 50 cells/mm³ or if they are exposed to high levels of ddI. The Alpha trial found no difference in efficacy between doses of 200 and 750mg per day, but 5% of people taking the higher dose developed pancreatitis, compared with only 1% of the lower dose group.

Drugs which increase the amount of ddI in the blood also boost the risk of pancreatitis. Recent evidence has shown that the drug interaction between ddI and tenofovir (Viread) may be associated with an increased risk of pancreatitis (Milinkovic 2003). Fatal pancreatitis has occurred in a man who took ddI, d4T and tenofovir (Davies 2002).

Of 2613 HIV-infected people attending the Johns Hopkins HIV Clinic who were taking at least one nucleoside analogue reverse transcriptase inhibitor (NRTI), 33 developed pancreatitis. The incidence of pancreatitis was highest among people taking ddI with hydroxycarbamide (Hydrea) at 6.25 cases per 100 person-years. For the other NRTIs, the incidence rates per 100 person years were: 0.18 for AZT (zidovudine, Retrovir); 0.80 for ddI; 1.13 for d4T; 1.50 for ddI with d4T, and 2.17 for ddI, d4T and hydroxycarbamide. Interestingly, the ddI/d4T combination did not produce a significantly greater risk of pancreatitis relative to didanosine alone, an observation that was confirmed in another study (Dragovic 2003).

Other risk factors which increase a person's risk of ddI-related pancreatitis include:

• History of pancreatitis.

• High alcohol consumption.

• Obesity.

• High triglycerides.

• Gallstones.

• Co-administration of certain medications including pentamidine, ganciclovir (Cymevene) or hydroxycarbamide.

Several deaths from ddI-related pancreatitis have occurred among people with high CD4 cell counts and low viral loads who had a number of the above risk factors.

Multivariate analysis showed that a CD4 cell count below 200 cells/mm³, a history of pancreatitis and female sex were associated with pancreatitis. Other factors such as duration of NRTI therapy and use of other antiretrovirals were not associated with risk of pancreatitis. Hung (2004) found that the incidence of acute pancreatitis did not significantly increase with elevated triglyceride levels, which is relatively common after initiation of highly active antiretroviral therapy (HAART).

Pancreatitis also seems to be a greater risk among people with HIV / hepatitis C virus (HCV) co-infection, who are receiving concurrent treatment with ribavirin and interferon alfa for HCV and ddI and d4T for HIV infection, according to a study of 25 patients beginning HCV treatment. The median time to development of pancreatitis was 84 days after the start of HCV therapy, and in half of the cases pancreatitis was diagnosed by means of elevated lipase levels rather than clinical symptoms (Hester 2001).

Symptoms and diagnosis

The physical symptoms of pancreatitis include nausea, vomiting and pain, which can be very severe, in the 'epigastric' region below the breastbone. The abdomen may be very tender and painful to the touch.

Tests which are used to confirm the diagnosis blood tests which detect the presence of pancreatic enzymes in the blood, and X-rays or ultrasound or computerised tomography scans to see if there is an enlargement of the pancreas and gall bladder.

In cases of chronic pancreatitis where further tests are needed to identify physical damage to the pancreas, a procedure called endoscopic retrograde cholangiopancreatography (ERCP) may be used. A fibre-optic endoscope is passed into the intestine through the mouth and then hooked into the bile duct so that the changes in the pancreas and gall bladder can be seen. This procedure needs a highly skilled operator and carries some risk of damaging the pancreas and of introducing infections. In the course of ERCP, it is also possible to take samples of tissue to examine in the laboratory to check for infections or cancer.

Treatment

Pancreatitis is usually treated by removal of the causative agent, such as ddI. This has two main goals:

• To minimise the disruption caused by the failure of the pancreas to work properly.

• To minimise the damage caused by the release of pancreatic enzymes into areas where they are not normally found.

One complication of pancreatitis is that the released enzymes can damage the cells that produce insulin. This effectively makes the individual temporarily diabetic and causes swings in glucose levels in the blood which in themselves can cause coma and death. A patient with pancreatitis may also become dehydrated because of vomiting and the leaking of fluids out of body tissues. This may have to be corrected by giving fluid intravenously, since often nothing can be given by mouth.

Enzyme inhibitors such as aprotinin (Trasylol) may be given to stop the released enzymes damaging the pancreatic gland and surrounding tissue, but their value is debatable. Other experimental treatments in HIV-positive people incude gabexate and octreotide (Sandostatin / Sandostatin LAR), with a recent study showing that the combination of both drugs having a more rapid and effective response in terms of reducing pancreatic enzyme levels in the blood than either drug taken alone (Manfredi 2004).

Pain control

The pain caused by pancreatitis may be severe and is difficult to relieve. Some commonly-used opiate painkillers such as morphine and codeine are not recommended as they may worsen the problem. Pethidine is a safe alternative. A pain control regime may include anti-inflammatory drugs such as naproxen (Naprosyn / Synflex) or aspirin in high dose. In cases of severe pain a technique which destroys the nerves to the pancreas may be useful.

It may be helpful for people with chronic relapsing or recurrent pancreatitis to be in regular contact with their doctor so that adequate pain relief can be given quickly during an attack. Casualty departments, which may not have access to medical notes can be wary of people demanding strong painkillers, often labelling them as addicts working the system, and may only give them minimal pain relief.

Chronic pancreatitis

In some people, the initial attack of pancreatitis may cause physical damage to the pancreas that results in long-term problems and relapses. This is called chronic pancreatitis, and is a problem that is not confined to people with HIV. At present, medical treatment is limited to treating the symptoms. However, there are lifestyle changes that may help to reduce the number and severity of recurrences.

Ideally, all alcoholic drinks should be avoided. Any drugs which cause pancreatitis should be avoided. In chronic pancreatitis the reduction in pancreatic enzymes can cause difficulties with digesting food, especially fat. Doctors may prescribe digestive enzyme supplements, such as pancreatin (Creon), which may help. In severe cases where there is extensive damage to the pancreas, it may help to reduce dietary fat as meals rich in fat may cause an attack.

As certain opportunistic infections can cause pancreatitis, it is worth having thorough and exhaustive tests for any that are present so that they can be treated and prophylaxis taken afterwards to prevent recurrence.

Rarely, surgery may also be undertaken in cases of chronic pancreatitis. It is usually limited to cases when there are readily identifiable physical problems that can be corrected.

Doctors at Manchester Royal Infirmary have been studying the use of anti-oxidant vitamins to treat pancreatitis. In 1991 they reported the results of a small, 28 person placebo-controlled trial which concluded that sufferers of recurrent pancreatitis who took high doses of anti-oxidants were less likely to suffer a relapse. The level of discomfort and pain they suffered was also reduced when compared with a group receiving a placebo. Six participants had an attack whilst on placebo, compared with only one recipient of anti-oxidants. Most of the participants in this trial had pancreatitis caused by heavy use of alcohol.

Past studies at the hospital suggested that the optimum daily doses were 600µg selenium, 9000IU β-carotene, 540mg vitamin C and 270IU vitamin E (produced in a single tablet marketed as Selenium BCE) plus 2g methionine. After six months on this regime, the dose could be cut in half with no recurrence of symptoms (Uden 1990). A German study has also found that selenium and vitamin E were protective against the recurrence of future pancreatitis attacks (Kulinski 1992).

References

Davies L et al. Fatal acute pancreatitis in an HIV-positive man the result of an interaction between tenofovir disproxil fumarate (TDF) and didanosine (ddI). Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P124, 2002.

Dragovic C et al. Incidence of pancreatitis in HIV/AIDS - patients receiving nucleoside reverse transcriptase inhibitor drugs. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 920, 2003.

Felley C et al. The role of CFTR and SPINK-1 mutations in pancreatic disorders in HIV-positive patients: a case-control study. AIDS 18: 1521-1527, 2004.

Hester J et al. Pancreatitis: an emerging complication of HCV treatment in HIV co-infected patients treated with didanosine/stavudine containing regimens. 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract 739, 2001.

Hung C-C et al. Risk of acute pancreatitis among HIV-infected patients who developed marked hypertriglyceridemia after receiving antiretroviral therapy. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 746, 2004.

Kuklinski B et al. Anti-oxidative therapy of pancreatitis--an 18-month interim evaluation. Z Gesamte Inn Med 47(6): 239-245, 1992.

Manfredi R et al. Pancreatic involvement in HIV-infected patients undergoing antiretroviral therapy: What about a specific treatment? Fifteenth International AIDS Conference, Bangkok, abstract WePeB5854, 2004.

Milinkovic A et al. Pancreatic toxicity associated with the co-administration of didanosine and tenofovir. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 742, 2003.

Moore RD. Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 15(5): 617-620, 2001.

Uden S et al. Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 4(4): 357-371, 1990.