A 70-year-old woman was referred for assessment of loss of appetite, nausea, and weight loss of 12kg over the preceding 12 months. She had an iron-deficient, microcytic anaemia.
Her past medical history included pernicious anaemia, common variable immune deficiency, and bronchiectasis. On examination she had crackles generally heard across her lung fields, together with hepatomegaly.
30a) What is pernicious anaemia?
30b) What other diseases are associated with pernicious anaemia?
30c) Discuss the differential diagnosis and appropriate investigations
30d) Discuss the causes and features of the diagnosis.
30e) How is pernicious anaemia treated?
30a) What is pernicious anaemia?
Pernicious anaemia is the consequence of vitamin B12 deficiency resulting from autoimmune destruction of the gastric parietal cell mass and consequent absence of intrinsic factor. The type of gastritis is termed chronic atrophic gastritis Type A (as opposed to type B, due to Helicobacter pylori). Type A gastritis predominantly affects the gastric corpus, causing mucosal atrophy, achlorhydria, and secondary hypergastrinaemia. Gastrin concentrations may approach those seen in Zollinger–Ellison syndrome (ZES) from gastrin-secreting tumours. In contrast to ZES, hypergastrinaemia is secondary to achlorhydria, with a high antral pH; it is therefore not associated with excessive gastric acid production or gastroduodenal ulceration. Destruction of chief cells leads to low serum levels of pepsinogen I.
Pernicious anaemia is more common in people of northern European decent, and the prevalence in the UK is estimated at 120 per 100,000. It is slightly more prevalent in women, with a ratio of 1.6:1. Ninety percent of cases develop >40 years of age, with a peak at 60 years of age.
Patients are generally asymptomatic before severe corpus atrophy has occurred. Once the disease is advanced and vitamin B12 (cobalamin) concentrations are reduced, patients often develop non-specific symptoms of fatigue, nausea, or weight loss. Mucosal consequences of B12 deficiency manifest with a sore tongue which is beefy red. A megaloblastic anaemia with marked macrocytosis is characteristic, but neurological symptoms are the most worrying. A myelopathy affecting the posterior columns of the spinal cord manifests as loss of proprioception, and a peripheral neuropathy develops. A useful clinical clue is an extensor plantar response in the absence of ankle tendon reflexes. Psychiatric disturbances with paranoia (‘megaloblastic madness’) may occur, but advanced cases are now uncommon. Without cobalamin replacement the course is fatal.
Advanced gastric atrophy is visible at endoscopy, with loss of rugal folds and visible submucosal vessels. Biopsies should be taken to confirm severe atrophy of the corpus, with sparing of the antral mucosa. Intestinal metaplasia may be present. An earlier stage of type A gastritis has been described (a so-called ‘proliferative stage’), with hyperplasic polyps secondary to the hypergastrinaemia. Type A autoimmune gastritis should be suspected in people who have multiple gastric polyps in the absence of long-term therapy with a proton pump inhibitor.
Pernicious anaemia is associated with other autoimmune diseases, including adrenal insufficiency, hypothyroidism, Grave’s disease, type 1 diabetes, myasthenia gravis, vitiligo, alopaecia, and coeliac disease. This association is sometimes referred to as polyglandular autoimmune syndrome type II. Polyglandular autoimmune syndrome type II is inherited in a polygenic fashion, with an onset in adulthood, and is more common in females. The autosomal recessive polyglandular autoimmune syndrome type I has its onset in childhood and may also include pernicious anaemia. Pernicious anaemia is also associated with premature greying of hair, blue eyes, blood group A, HLA B8 and DR3, and common variable immunodeficiency (as in our patient).
Pernicious anaemia is a well documented risk factor for gastric adenocarcinoma. It is possible that common variable immunodeficiency increases this risk. Nevertheless, there is no recommended protocol for endoscopic screening of these patients. It is unclear whether the risk is related to a combination of autoimmune (type A) gastritis and Helicobacter pylori-associated (type B) gastritis. An increased incidence of gastric mucosal carcinoid tumours has been reported, due to hypergastrinaemia. Carcinoid syndrome is not associated more often than by chance. Pancreatic and oesophageal malignancies may occur more frequently.
30c) Discuss the differential diagnosis and appropriate investigations.
Before considering the specific clinical circumstances in the current patient, a brief comment about uncomplicated pernicious anaemia is appropriate. The condition is so common in older people that treatment of B12 deficiency is generally started without further investigation. Investigation of a low serum vitamin B12 in younger patients includes measurement of gastric parietal cell and intrinsic factor antibodies. False-negative results are common in older people. Thyroid function should be checked, because of the association with autoimmune thyroid disease. Addison’s disease should be considered as a potential cause of persistent fatigue in a patient with pernicious anaemia. Folate concentrations should be measured to exclude concomitant folate deficiency as a cause of a macrocytic anaemia. Terminal ileal disease (such as Crohn’s) should be considered, but rarely causes B12 deficiency unless a long segment (>100cm) is affected or resected. Upper gastrointestinal endoscopy is appropriate if there is doubt about the diagnosis, to obtain biopsies from the body and antrum of the stomach; it is wise to take distal duodenal biopsies to exclude small intestinal villous atrophy at the same time. The Schilling test uses isotopes of cobalamin to test absorption of an oral dose with and without intrinsic factor; it is now obsolete. Measurement of serum gastrin or serum pepsinogen is unnecessary.
For this particular patient, nausea and loss of appetite are non-specific, but our patient had hepatomegaly, which makes malignancy more likely. Metabolic disturbance (hyponatraemia, hypercalcaemia), drugs and intracranial pathology should also be considered. The weight loss and iron deficiency call for urgent assessment, although achlorhydria can decrease iron absorption.
Weight loss should not simply be ascribed to a loss of appetite and reduced food intake. Underlying malignancy and gastric carcinoma in association with pernicious anaemia tops the list, with hepatomegaly from metastases. Malabsorption, from coeliac disease associated with pernicious anaemia, or villous atrophy associated with common variable immunodeficiency is possible, but would not explain the hepatomegaly. Endomysial or tissue transglutaminase antibodies are of no diagnostic value in immunodeficiency, owing to low IgA and IgG concentrations. Non-Hodgkin lymphoma associated with common variable immunodeficiency could account for the systemic symptoms and hepatomegaly. Finally, bronchiectasis with chronic airways infection may cause weight loss. Hepatomegaly might conceivably be due to amyloidosis of the AA type, although this usually presents with renal disease before organomegaly is evident.
An upper gastrointestinal endoscopy is the investigation of choice to identify a gastric carcinoma, or obtain small intestinal biopsies. This patient had a gastroscopy which revealed a large gastric tumour involving the posterior wall of the stomach, extending from the upper body to the pre-pyloric antrum. Histopathology revealed a gastric adenocarcinoma. A staging CT scan of the abdomen and pelvis was requested (Fig. 30.1) and this revealed a large gastric tumour with locally advanced disease extending through the wall of the stomach into the lesser omentum, lymph node enlargement at the porta hepatis and coeliac axis, and multiple focal liver lesions suggestive of metastases. Stage T3N2M1.
30d) Discuss the causes and features of the diagnosis.
Gastric adenocarcinoma has declined worldwide since the 1930s. Even so, gastric cancer remained the second most common cause of cancer-related death worldwide in 2002. The decline only applies to antral (non-cardia) gastric tumours, probably from better food preservation following the advent of refrigeration, and a reduction in H. Pylori infection. H. pylori is classified as a class I carcinogen by the WHO. The incidence of gastric cancer remains high in the Far East (Japan and China), thought to be due to the consumption of high volumes of raw and preserved fish with a high nitrate content. Bacteria convert nitrates to carcinogenic nitrites. H. pylori-associated (type B) chronic gastritis may lead to gastric atrophy, intestinal metaplasia, dysplasia, and cancer. Chronic autoimmune gastritis (type A) may cause gastric cancer via the same sequence of events, and the common factor appears to be the chronic inflammation. Both type A and B gastritis are associated with intestinal type tumours, as opposed to the diffuse type responsible for linitis plastica.
Gastric cancers typically present late. Tumours localized to the mucosa, which have the best chance of cure when completely resected, are usually asymptomatic, and found incidentally or in association with a screening programme. These ‘early gastric cancers’ are more commonly encountered in Japan than in the UK, although it is difficult to demonstrate that this is because of ready access to endoscopy. Symptoms usually herald spread of the tumour. Direct transmural extension involves adjacent organs. Lymphatic spread occurs relatively early. Distant metastases most commonly involve the liver. Metastatic involvement of the supraclavicular nodes on the left (Virchow–Trossier), a periumbilical nodule (Sister Mary Joseph nodule), or transperitoneal spread with malignant ascites, all imply advanced disease.
As for all cancers, a histopathological diagnosis is essential and tissue is readily obtained through endoscopic biopsies. Gastric cancer is generally staged according to the TNM classification, and may also be categorized into stages I–IV. Our patient already had distant metastases (M1), which made her disease stage IV, regardless of the depth of tumour invasion into the gastric wall (T3) or lymph node involvement (N2).
30e) How is this condition treated?
Once distant metastases are present, gastric cancer is unresectable, and median survival is <1 year. Large tumours that adhere to adjacent organs and involve regional lymph nodes without distant metastases, although potentially resectable, carry a 5-year survival of <10%. Non-adherent invasive gastric cancer, with or without lymph node involvement, carries a 5-year survival of <30% after resection. Tumours that invade the sub-mucosa and do not affect nodes have a 60% 5-year survival after resection.
Resection of distal gastric cancer involves a subtotal gastrectomy. Diffuse or proximal tumours require total gastrectomy. There has been much debate between Japan and the West about the extent of lymph node clearance. Lymph node resection involves removal of nodes along the lesser curve, the greater curve (N1/D1), the left gastric artery, the hepatic artery, the coeliac artery, and the splenic artery (N2/D2). D1 resection involves removal of the affected part of the stomach or the whole stomach along with the lesser and greater omentum. D2 resection includes the omental sac, part of the transverse mesocolon, clearance of nodes surrounding the above mentioned arteries, and partial resection of adjacent organs (spleen and pancreatic tail). Extended (D2) lymphadenectomy adds to the surgical complications without a significant survival benefit, so D1 resection is usually recommended.
Adjuvant chemotherapy adds no clinically significant survival benefit, but perioperative chemotherapy with platinum-based regimens, seems to improve survival. One trial has shown that 3 cycles of preoperative and 3 cycles of postoperative combination therapy with epirubicin, cisplatin and 5-fluorouracil (ECF regimen) was associated with a 5-year survival of 36%, compared with 23% for those having surgery alone; this was confirmed in a subsequent study.
Two-thirds of gastric cancers diagnosed in the West are unresectable or have metastasized at the time of diagnosis. Depending on the patient’s health, palliative chemotherapy may be given. The choice of chemotherapy is large, which suggests that none show particular advantage, so specialist advice is appropriate. Post-operative chemoradiation is practised in the USA. The standard of care in the UK is ECF, which offers a small survival benefit. Oxaliplatin and capcytabine may be substituted for cisplatin and 5-fluorouracil (EOX regimen). Docetaxel may be substituted for epirubicin, and may have some benefit over ECF at the cost of more frequent neutropenia. Irinotecan with 5-fluorouracil (IFL regimen) has also been tested and may be better than cisplatin and 5-fluorouracil, the latter being a commonly used regimen in the USA. Targeted therapies with monoclonal antibodies to the epidermal growth factor receptor (cetuximab), and vascular endothelial growth factor (bevacizumab) and tyrosine kinase inhibitors (erlotinib and gefitinib) are under investigation. The matrix metalloproteinase inhibitor marimastat did not fulfil early promise.
It needs to be remembered that the current chemotherapeutic regimens are toxic and offer a small survival benefit. Our patient opted for palliative radiotherapy for symptom control.
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