An unexpected cause of macroscopic haematuria

1 Angular cheilitis

This image is similar to but is not of the patient described in this article.

At the time of his hospital presentation, our patient had a body mass index (BMI) of 20 kg/m2 and appeared pale, but had no sign of bruising. He was apyrexial and well hydrated, with unremarkable cardiovascular and respiratory findings. Gastrointestinal examination revealed a red swollen tongue and angular cheilitis (Box 1). There was some mild left renal angle tenderness.

Urinalysis revealed > 500 ×106 non-glomerular red blood cells per litre (normal range < 13 ×106/L) but no pyuria. Abdominal ultrasound performed on the day of review was unremarkable. Peripheral blood tests revealed normal electrolyte levels and renal function, with a coagulopathy reflected by an international normalised ratio (INR) of > 10 (reference range, < 1.4) and activated partial thromboplastin time (APTT) of 115 seconds (reference range, 25–38 seconds) (Box 2). These results were verified with repeat testing. Clotting factor studies revealed severe deficiencies in factors II, VII, IX and X. There were also deficiencies in iron, vitamin B12, and serum folate, vitamin A and vitamin E concentrations (Box 2). Vitamin D levels were normal, but the serum alkaline phosphatase level was twice the upper limit of normal. Results of other liver function tests were normal. Endomysial antibody test results were positive, and tissue transglutaminase antibody (IgA) levels were more than five times the upper limit of normal.

A preliminary diagnosis of vitamin K deficiency, leading to a profound coagulopathy, secondary to a malabsorption syndrome from coeliac disease was made. Duodenal biopsies confirmed the diagnosis of coeliac disease (Box 3). Gastroscopy showed no gastritis or peptic ulcer disease. The duodenal mucosa appeared abnormal and was consistent with villous atrophy. No conclusion could be reached regarding the nonspecific abdominal pain the patient experienced on presentation. Inflammatory bowel disease was a differential diagnosis, but inflammatory markers were only marginally elevated (Box 2).

Parenteral vitamin K was administered, and the prothrombin time reduced to 15 seconds (INR, 1.3) and APTT became normal within 24 hours. The macroscopic haematuria resolved.

The patient was also given parenteral iron and vitamin B12 and oral multivitamin replacement. He was reviewed by the dietetic services and educated about coeliac disease. He also started a gluten-free diet. On clinical review 2 months later, he was feeling well and had put on 15 kg in weight (BMI, 26 kg/m2).

Duodenal biopsies 6 months after the initial presentation revealed variable villous abnormality, consistent with partially treated coeliac disease. The vitamin deficiencies had all resolved, and clotting factor studies were normal. Endomysial antibodies had become negative, and tissue transglutaminase antibody levels (IgA) were within the normal reference range. Bone mineral density at this time was normal.

Genotyping revealed the presence of the HLA DQ2 allele.

The most common presentation of coeliac disease is diarrhoea (43%); other reasons for presentation include anaemia (8%), bone disease (6%), weight loss (6%), and abdominal pain (5%).1 The remaining 32% of patients are asymptomatic or present with vague symptoms. Delay in the diagnosis of coeliac disease is common (mean, 11 years).2 About 47% of patients will have been misdiagnosed, and of those with classical symptoms of coeliac disease, 59% have been misdiagnosed as having irritable bowel syndrome.3 The clinical diversity of coeliac disease is recognised, and disorders involving nearly every organ system have been described with this condition.4

Haematuria is an unusual presenting symptom of coeliac disease.5 The haematuria in our patient indicated a systemic bleeding diathesis due to malabsorption of vitamin K, with subsequent prolongation of the prothrombin time and APTT.6 In patients with untreated coeliac disease, the prothrombin time is prolonged (INR, ≥ 1.4) in about 20%,7 and the coagulopathy is usually asymptomatic,8,9 but corrects quickly with administration of vitamin K.10

In the long-term treatment of coeliac disease, a gluten-free diet is paramount and leads to resolution of the underlying small bowel villous abnormality. A partial histological response to a gluten-free diet may reflect poor compliance, accidental exposure to gluten-containing food products, or slow recovery. Our patient claimed close adherence to the diet and was provided with adequate education and dietetic review. Histological recovery can be delayed, with 35% of patients still showing features of coeliac disease up to 2 years after commencing a gluten-free diet.11,12 Failure to achieve histological recovery can occur in the absence of gluten.13 The use of serology tests as surrogate markers for histological resolution is controversial.14-16 Some coeliac patients with negative results for endomysial and tissue transglutaminase antibodies have persistent villous abnormalities, necessitating the use of biopsies to monitor the response to a gluten-free diet (as in our patient).

On HLA genotyping, our patient possessed the HLA DQ2 allele, which is present in more than 90% of patients with coeliac disease, but in only 20% of the general population.17 Endomysial IgA antibodies have a sensitivity of 90% and specificity of 100%, tissue transglutaminase IgA has a sensitivity and specificity of 98%. Sensitivities for the IgG class endomysial and tissue transglutaminase antibodies are around 40%.18 Deficiency of IgA occurs in 1.7%–2.6% of coeliac patients, and these patients have negative results on IgA antibody testing. Total serum IgA levels should be tested together with IgG (endomysial, tissue transglutaminase) to improve the overall sensitivity of antibody testing.19

Our patient demonstrates the need to be aware of the various presenting features of coeliac disease, and reminds us that coeliac disease is often misdiagnosed.