The aetiology of LC is largely unknown. At present, LC is thought to be caused by an immunological reaction to different mucosal insults in predisposed individuals. Infectious agents, drugs, or food antigen such as gluten may be precipitating factors.
Infection with Campylobacter jejuni
has been associated with the onset of LC.19
Of special interest is the condition known as “Brainerd diarrhoea”. This is outbreaks of chronic watery diarrhoea characterised by acute onset and prolonged duration, and histopathological resemblance of LC.20
Epidemiological data suggest an infectious cause of “Brainerd diarrhoea”, but no causative organism has been identified. The theory of an infectious cause in some cases of LC is supported by a sudden onset in 25% of patients, and a clinical course with a single attack in 63% of cases. The non-significant tendency to seasonality of disease onset, and the response to metronidazole in some patients, may also support an infectious theory.
To date, at least 16 drugs have been reported with the onset of LC.8,14,21–33
Ticlopidine is most often reported with more than 30 cases8,21,34
followed by Cyclo 3 Fort.23,35
In most cases there has been an association with the introduction as well as with the withdrawal of the drug, and histopathological remission has in many cases followed clinical remission after drug withdrawal. In the present study, the onset of LC in three patients was associated with introduction of a drug followed by clinical remission after withdrawal. Carbamazepine was reported in two cases and paroxetine, a selective serotonin reuptake inhibitor, in one case. To our knowledge, this is the first report of paroxetine associated LC. A weaker association was seen in 16 LC patients where an association was found only to introduction of the drug. However, patients did not improve after withdrawal of the drug and required medical treatment. The suspected drug in seven of these patients was sertraline, another selective serotonin reuptake inhibitor. It may however be difficult to obtain a correct drug history, especially regarding the use of non-steroidal anti-inflammatory drugs or proton pump inhibitors which in Sweden have been available over the counter since 1985 and 2000, respectively. This may cause underestimation of our values for drug induced disease.
The importance of genetic factors in LC is largely unknown and there are only a few reports of familial occurrence of MC.36–39
The family history of bowel diseases in our cohort of LC patients is a new and intriguing observation. Ulcerative colitis, Crohn’s disease, coeliac disease, or CC was reported in 34 first or second degree relatives of 24 LC patients. A family history of ulcerative colitis or Crohn’s disease was seen in 14 (7%) LC patients compared with three of 170 (2%) LC patients reported by Pardi and colleagues.13
We do not have the number of relatives at risk and cannot assess family risk estimates. Familial aggregation is well known in patients with ulcerative colitis or Crohn’s disease, and in first degree relatives the risk of inflammatory bowel disease is increased 10–15-fold.40
In order to analyse the influence of genetic and/or environmental factors, or to identify an early stage of subclinical disease, a number of subclinical markers have been analysed. Studies of intestinal permeability, antineutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae
antibodies, and faecal calprotectin have suggested, although data are not consistent, subclinical abnormalities in healthy relatives of patients with inflammatory bowel disease.41–43
Hypothetically, an underlying common abnormality predisposing to both MC and inflammatory bowel disease may explain the association found by us.
Our patients were slightly younger at diagnosis than in most previous reports. The female:male ratio was within the previous reported ratios of 1.1:1 to 5.0:1.4,8,11,13,14
Contrary to earlier studies, we did not find a higher proportion of ex-smokers than current smokers8,13
but our smoking data were uncertain considering the large number of patients with unknown smoking habits. The clinical data were consistent with the two previous largest retrospective studies.8,13
Fernandez-Banares et al
reported a higher frequency of abdominal pain, faecal incontinence, and flatulence in their LC patients, which may reflect the prospective design of their study.14
In the present study, we included patients only on histopathological criteria without taking into account clinical criteria. This allowed us to analyse the whole spectrum of clinical symptoms in cases with histopathologically proven LC. We found a small number of patients (4%) without diarrhoea and some (9%) who had only mild diarrhoea whereas the remaining patients had pronounced diarrhoea. LC has previously been described in patients without diarrhoea7,9
and whether those patients will later develop diarrhoea is not known. Abdominal pain, weight loss that sometimes was substantial, and nocturnal diarrhoea were other common symptoms. The clinical course was similar to the results of Baert et al
and Fernandez-Banares et al
but differed from the data of Pardi et al
whose patients all had intermittent or constant diarrhoea.8,13,14
The frequency of associated diseases of the autoimmune or inflammatory type was similar to the study by Pardi and colleagues.13
Thyroid disorders dominated, followed by coeliac disease. The relation between LC and coeliac disease is complex. Fine et al
found a high prevalence of coeliac disease associated HLA-DQ genes in MC which may explain the coexistence of both coeliac disease and MC in the same individual.44
To date, no randomised controlled treatment trials have been carried out in LC, and only a few uncontrolled studies with a reasonable number of patients exist.13,14
Corticosteroids, prednisolone, as well as budesonide were the most effective therapies in our study and >80% of patients improved short term. However, the relapse risk was high after withdrawal of therapy. Budesonide, a topically acting corticosteroid with a high receptor binding affinity and with low systemic effects due to a high first pass metabolism in the liver, is a better alternative than prednisolone for long term treatment.45
However, controlled studies are required to address the efficacy and safety of budesonide in short term as well as in long term therapy in LC. The response rate to cholestyramine was 57%, which is within previously reported rates of 46–83%.13,14,46
A high frequency of patients with concomitant bile acid malabsorption in the Spanish study was probably the explanation for their high response rate of 83%.14
The outcome of 5-ASA or sulphasalazine therapy is inferior compared with the Spanish data14
but close to those of Pardi and colleagues.13
Side effects of sulphasalazine were common and similar to the occurrence in CC.47
Lymphocytic colitis and CC are considered related but separate diseases. They are clinically indistinguishable and can be differentiated only by histopathological assessment. The clinical course of LC in the present study differed from our previous study of CC where a single attack was seen in only 2% of patients, and 85% patients had a chronic intermittent course.47
Conversion of LC to CC has been reported previously and is considered to be uncommon.48
Our figures indicate that the conversion rate may be higher but a histopathological follow up of the whole material is necessary to assess this properly.
This is the largest cohort of patients with LC reported hitherto. The strength of the study is the size of the material and that all biopsy material was reassessed. Referral bias was limited as the majority of referred patients were from local hospitals and only 13% of these patients came from university hospitals. Furthermore, the severity or clinical course of the referred cases did not differ from the 79 patients from the catchment area of our own hospital (data not shown).
In summary, our data confirm previous reports regarding sex and age distribution, clinical features, associated diseases, and outcome of therapy. A single attack with clinical remission after limited disease duration was common. Drug induced disease was suspected in 10% of patients, and paroxetine causing LC has not been reported previously. The finding of a family history of other bowel disorders is new and deserves confirmation as well as the observation of a possible seasonal variation in disease onset.