This Month in Gastroenterology

Article Outline

• Antibiotic Therapy for Whipple's Disease
• Gastric Cancer in Lynch Syndrome
• Inhibition of Hepatitis C Virus–Infected T-Cell Activation by the Herb Silymarin
• A Bile Acid Receptor in Pancreatic Acini That Is Triggered to Initiate Acute Pancreatitis
• Copyright

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Antibiotic Therapy for Whipple's Disease 

Whipple's disease is a rare inflammatory disorder caused by infection of different organ systems with Tropheryma whipplei. In the gastrointestinal tract, jejunal infection with T whipplei causes diarrhea or steatorrhea with weight loss. Treatment with a combination of doxycycline, hydroxychloroquine, and sulfamethoxazole or sulfadiazine is usually recommended, but prospective data assessing the efficacy of these antibiotics are lacking. Moreover, retrospective case series report failure rates of up to 30% using these antibiotic regimens.

In this issue of Gastroenterology, Feurle et al report the results of a randomized, controlled trial to evaluate the efficacy of 2 intravenously applied bactericidal antimicrobials in Whipple's disease. Consecutive patients with untreated Whipple's disease from central Europe who reported to the trial center in Germany were treated with 2 g ceftriaxone infused intravenously once daily for 14 days or with meropenem 1 g infused intravenously 3 times daily for 14 days in an open-label, prospective, randomized fashion. In both arms, the initial intravenous treatment was followed by oral trimethoprim–sulfamethoxazole at a dosage of 160/800 mg twice daily for 12 months. Follow-up examinations with endoscopy and biopsies were scheduled for a period of 3 years. At diagnosis, routine laboratory tests were performed on blood samples, and polymerase chain reaction (PCR) of cerebrospinal fluid obtained by lumbar puncture was performed to detect T whipplei. If positive, this was repeated after 6 and 36 months. Small-bowel mucosal biopsies, examined for periodic acid-Schiff–positive macrophages, and clinical and laboratory reevaluations were required at 6, 12, 24, and 36 months. The primary outcome variable was maintenance of remission for 3 years, determined by a composite index of clinical and laboratory data as well as histology.

A total of 42 patients were randomized over a 6-year period, and the baseline characteristics of both groups were comparable. Both regimens provided signs of initial clinical, laboratory, and histopathologic remission after 3 months, and remission was obtained in all patients by the end of the treatment period. Remission was maintained in all patients during the time of observation, except for 2 who died from unrelated causes (Figure 1). In a prolonged follow-up of on average 89 months, no clinical recurrences occurred. Cerebrospinal fluid PCR was initially positive in 10 patients and became negative at the end of the treatment period in all. Recurrent positive PCR was found in 1 patient after 36 months. This patient did not respond to ceftriaxone or meropenem, but responded to chloroquine and minocycline.

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• Figure 1. 

  Kaplan–Meier estimate of the time course to remission in tissue samples in the 2 groups of the randomized, controlled trial.

This study, the first randomized, controlled trial in Whipple's disease, shows that intravenous treatment with ceftriaxone and with meropenem, each followed by 12 months of oral trimethoprim–sulfamethoxazole, induced remission in all patients. Based on cost and administration frequency, ceftriaxone can be considered the initial preferred treatment for this rare condition.

See page 478.

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Gastric Cancer in Lynch Syndrome 

The Lynch syndrome is a dominantly inherited condition, caused by a germline mutation in 1 of the DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The condition is associated with a highly elevated risk of colorectal cancer (hereditary nonpolyposis colorectal cancer) and endometrial cancer, and Lynch syndrome families undergo systematic screening for these types of cancer. The Lynch syndrome is also associated with an increased risk of gastric cancer, but the actual risk is poorly defined and whether this merits surveillance for gastric cancer in the Lynch syndrome has not been established.

In this issue of Gastroenterology, Capelle et al report incidence trends and gastric cancer risks in Lynch syndrome mutation carriers. In The Netherlands, families with Lynch syndrome are registered in a national Hereditary Cancer Registry. Through the registry, family members are offered diagnostic confirmation and cancer surveillance, and adherence to surveillance is registered. A total of 2014 mutation carriers in 236 families were identified. During follow-up, gastric cancer was diagnosed in 32 (1.6%; 12 with MLH1 mutation and 20 with MSH2 mutation) of them, below the age of 45 in only 12.5%. the majority of cases with gastric cancer had a negative family history of gastric cancer. In approximately half of the patients, gastric cancer was the first and only malignancy, whereas the others presented as metachronous tumors.

The gastric cancer incidence in the Lynch syndrome patients was compared with the overall incidence of gastric cancer in the general Dutch population from 1970 to 2003. The standarized incidence ratio of gastric cancer in Lynch syndrome was 3.4 (95% confidence interval, 2.1–5.2). A Kaplan–Meier analysis demonstrated a lifetime risk of developing gastric cancer of 8.0% for males and 5.3% for females (P = .02; Figure 2). The risk did not differ between MLH1 and MSH2 mutation carriers, but was not elevated in MSH6 carriers. Time-trend analysis showed no evidence for a declining gastric cancer incidence in Lynch syndrome subjects, although the overall incidence of gastric cancer in The Netherlands was rapidly declining over the study period.

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• Figure 2. 

  Cumulative incidence of gastric cancer in male and female Lynch syndrome carriers.

This study confirms the high risk of gastric cancer development in Lynch syndrome subjects with a MLH1 or MSH2 mutation. Surveillance of these Lynch syndrome mutation carriers, for instance starting at the age of 45, may lead to a decline in gastric cancer incidence, but this requires confirmation in large, prospective studies.

See page 487.

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Inhibition of Hepatitis C Virus–Infected T-Cell Activation by the Herb Silymarin 

Patients infected with hepatitis C virus (HCV) have only 1 option for treatment, pegylated interferon and ribavirin, with a sustained viral response in those that complete treatment around 55%. Many patients utilize alternative complementary medicines and herbs, either as an adjunct to their treatment, or as sole therapy for the infection. Silymarin, extract from the seeds of the milk thistle plant, is 1 of the more common herb preparations used to treat liver disease, but its effects on HCV infection are not known.

In the study by Morishima et al, a standard preparation of silymarin, MK001, was utilized to examine its effects on immune cell proliferation and cytokine production, because these are typically activated during immune-mediated liver injury triggered by HCV. MK001 dose-dependently inhibited the proliferation of freshly isolated peripheral blood mononuclear cells stimulated with anti-CD3 (or phytohemaglutinin) by an average of 70% between 3 HCV-infected and 2 uninfected individuals. MK001 also inhibited proliferation of isolated HCV-antigen-specific T cells. Cytokine responses from anti-CD3 stimulated T cells by measuring tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 levels were also decreased by a mean of 70%, 68%, and 71%, respectively, with MK001. A nearly pure isolation anti-CD3 stimulated T cells treated with MK001 showed almost no production of TNF-α, IFN-γ, or IL-2 in culture (Figure 3). MK001 also inhibited proliferation and cytokine production of spontaneously proliferating Jurkat T cells, and blocked T-cell receptor-induced nuclear factor-κB activation.

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• Figure 3. 

  T-cell secretion of TNF-α, IFN-γ, and IL-2 is inhibited by MK001 (silymarin). Peripheral blood mononuclear cells from an HCV-infected subject were enriched for T cells and cultured with 0.5% DMSO or media (not shown), or plate-bound anti-CD3 (10 μg/ml) in the presence of MK001 (20 μg/mL) or vehicle (DMSO) for 24 hours. TNF-α, IFN-γ, and IL-2 levels in culture supernatants were evaluated using multiplex enzyme-linked immunosorbent assay. Detection limits were 2, 2, and 4 pg/mL, respectively.

This study indicates that silymarin (MK001) can dose-dependently inhibit HCV and non–HCV-infected activated T-cell proliferation and cytokine production, and thus may prove useful in control of hepatic inflammation in chronic liver disease. The clinical benefit of this should be evaluated.

See page 671.

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A Bile Acid Receptor in Pancreatic Acini That Is Triggered to Initiate Acute Pancreatitis 

Acute pancreatitis can be triggered under several clinical circumstances, including obstruction of the pancreatic duct by a gallstone, and with refluxate of biliary contents during endoscopic retrograde cholangiopancreatography. These processes are believed to trigger the release and activation of pancreatic proteases that begin to autodigest tissue. However, it has never been clear what might commence the process—pancreatic ductal hypertension, for instance, or specific substances within bile that might interact with protease-rich pancreatic acini.

In the study by Perides et al, mice genetically deficient in G-protein–coupled bile acid receptor 1 (Gpbar1) were studied along with wild-type mice after initiating pancreatitis with retrograde infusion of the naturally occurring murine and human bile acid taurolithocholic acid 3-sulfate sodium salt (TLCS) or hyperstimulation with cerulein. Gpbar1 is normally expressed at the acinar cell apical pole, and is absent in Gpbar1^−/− mice. Whereas both TLCS and cerulein induced pancreatic edema, hyperamylasemia, inflammation, and acinar cell injury at 24 hours after treatment in wild-type mice, these parameters for pancreatic injury were markedly reduced in Gpbar1^−/− mice after TLCS (Figure 4), but not cerulein, indicating specific direct protection against bile salts. Physiologic calcium transients, zymogen activation, and leakage of lactate dehydrogenase induced by TLCS in acini were reduced or absent in Gpbar1^−/− mice. There was no difference in amylase secretion between wild-type and Gpbar1^−/− mice.

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• Figure 4. 

  Genetic deletion of Gpbar1 reduces the severity of TLCS-induced pancreatitis. Acute pancreatitis was induced in wild-type and Gpbar1^−/− mice by retrograde ductal infusion with 3 mM TLCS. Twenty-four hours after the start of pancreatitis induction, animals were humanely killed and pancreatitis severity was evaluated. Solid bars report results obtained using wild-type mice and open bars report results from Gpbar1^−/− animals. *Significant differences in bracketed groups in which results from wild-type and Gpbar1^−/− mice are compared. NS, not significant.

The study indicates that biliary acute pancreatitis may be triggered by a receptor-mediated event, namely, bile acids interacting with acinar-expressing Gpbar1. Blocking pancreatic Gpbar1 might prevent or reduce severity of acute pancreatitis.

See page 715.