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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.96 no.9 Madrid sep. 2004



Diverse clinical presentations of celiac disease in the same family

L. Rodrigo, S. Riestra1, D. Fuentes, S. González, A. López-Vázquez and C. López-Larrea

Service of Digestive Diseases and Immunology. Hospital Central de Asturias. 1Hospital Valle del Nalón. Oviedo. Spain



We performed a family study to evaluate a total of 34 extended family members (8 siblings, 23 children and nephews, and 3 grandchildren) of an adult patient with celiac disease (CD), a 58- year-old male with severe neurologic involvement manifested as myoclonias.
We found 3 other members affected with CD (a 44-year old sister, a 39-year old niece, and a 26-year old nephew). Two of them were completely asymptomatic and all had hypertransaminasemia. All exhibited a villous atrophy pattern of the duodenal mucosa (1 mild, 1 moderate, 1 severe). Overall family involvement was 11.8% (4/14).
We wish to emphasize the need to perform extended family studies when diagnosing a case of CD, since risk is not restricted to only first-degree relatives.

Key words: Clinical forms. Celiac disease. Familial study.

Rodrigo L, Riestra S, Fuentes D, González S, López-Vázquez A, López-Larrea C. Diverse clinical presentations of celiac disease in the same family. Rev Esp Enferm Dig 2004; 96: 612-619.

Recibido: 31-10-03.
Aceptado: 10-02-04.

Correspondencia: Luis Rodrigo. Servicio de Aparato Digestivo. Hospital Central de Asturias. C/ Celestino Villamil, s/n. 33006 Oviedo. Telf.: 985 108 058. Fax: 985 273 614. e-mail:



Celiac disease (CD) is an enteropathy due to hypersensitivity to gluten that is characterized by a considerable heterogeneity of clinical presentations (1). Screening studies for CD in the general population have shown a high prevalence (1 of 100-300 people), and also a low rate of diagnosis worldwide (2,3). CD does not present only in children, but its onset may be delayed until adolescence or adulthood; in our environment sixty percent of patients with CD, have been diagnosed in adulthood (4); some authors suggest that the majority of these cases are non-classical, or atypical forms of the disease (5). It is for this reason that, in order to increase the number of patients diagnosed, we should be aware of the non-classical clinical manifestations of the disease, and also perform serological screening in groups at higher risk (family of celiac patients, type 1 diabetes, etc.).

The families of celiac patients are one of the better characterized groups, as risk increases with relation to the genetic basis of the disease (6). Multiple studies have shown a high prevalence (2-18%) of CD among first-degree relatives (7-10). This wide variation in results may be related to the diagnostic methods used (serology, clinical symptoms, intestinal permeability or intestinal biopsy), and the criteria employed for its diagnosis (villous atrophy, latent forms). Currently, serological screening using tissue anti-transglutaminase antibodies (anti-tTG) is the method of choice in the search for new cases in risk groups.

We present here the results of an extended family study, carried out for a patient with CD and neurological manifestations; we emphasise the non-classical forms of presentation of this disease in affected relatives.


We assessed a total of 34 extended family members (8 siblings, 23 children and nephews, and 3 grandchildren) of an adult patient (a 58-year-old male) with CD and severe neurological symptoms (index case) (Fig. 1). A clinical history, and a complete physical exploration and laboratory study were performed to all family members, which included: hemogram, coagulation tests, general biochemistry, liver enzymes, serum iron, folic acid, and vitamin B-12 levels, TSH, and anti-thyroid antibodies. For the serological screening of CD, we determined antigliadin IgA (AGA), anti-endomysium IgA (EMA), and human-tissue anti-transglutaminase IgA (anti-tTG) antibodies, and HLA-II typing was performed in all cases.

In relatives in whom clinical and laboratory alterations were found, specific studies were carried out. When celiac disease was suspected, an upper digestive endoscopy with multiple duodenal biopsies, was performed.

We describe here the clinical characteristics of four patients with CD from the same family, which represents an overall familial involvement of 11.8% (4 of 34).

Case 1 (index case)

A 58-year-old male diagnosed with CD three years earlier underwent studies for a 1-year-standing clinical picture of diarrhea and abdominal pain. HLA-DQ2 heterodimer was positive, and an intestinal biopsy showed complete villous atrophy (Marsh grade 3c). Following two months on a gluten-free diet (GFD), digestive symptoms subsided.

Eighteen months ago the patient began to experience frequent, severe myoclonus. On neurological exploration an inexpressive face, peribucal fasciculations, generalized bradykinesia -more marked in the right half of the body, with preserved strength- and reflex myoclonus in the right lower limb were unveiled. Hematological and biochemical studies were normal. AGA was negative, while EMA and anti-tTG were positive with low titers; other antibodies detected were p-ANCA (1/80) and anti-smooth muscle (1/80). A second duodenal biopsy showed slight histological improvement with partial villous atrophy (Marsh grade 3a), and a considerable inflammatory infiltrate within the lamina propria.

A study of CSF cells and proteins was normal; CSF culture was negative. A brain magnetic resonance imaging (MRI) scan showed no significant anomalies. Electroencephalographic activity was normal. Electromyographic activity as recorded from the right tibial muscle showed sharp wave paroxysms of very low voltage in central cerebral regions, and myoclonic reflexes on the right leg. Neurological assessment showed a general alteration of cognitive functions, those of language and memory being better preserved, which suggested a predominant involvement of the right cerebral hemisphere at a parietal level, accompanied by subcortical dysfunction.

The patient was treated with clonazepan, pyracetam, azathioprine and two plasmapheresis sessions, but no positive response was elicited. Neurological involvement progressed, and the patient presented with disorientation, disarthria and myoclonus, and difficulty for walking unaided. Finally, the patient died from aspiration pneumonia two years after the onset of neurological involvement.

Case 2

A 44-year-old female, a sister of the index case, presented with a history of iron deficiency anemia and occasional diarrhea. Laboratory studies showed: Hb: 11.8 g/dl (MCV = 71.7), AST = 481 (N < 31 U/l), ALT = 754 (N < 31 U/l), FA = 722 (N < 280 U/l), and GGT = 134 (N < 32U/l). Anti-HCV and anti-HB core antibodies, and non-organ specific antibodies (ANA, SMA, AMA, LKM-1) were negative. In this patient EMA (1/40) and anti-tTG (30 U/mL) were detected, and HLA-DQ2 heterodimer was positive. A duodenal biopsy showed complete villous atrophy (Marsh grade 3c).

The patient was prescribed a GFD, and a remission of diarrhea and normalization of hemoglobin levels and liver enzymes, were observed at 3 months.

Case 3

A 39-year-old woman, a niece of the previous two cases, was completely asymptomatic, and exhibited normal biochemical tests, except for a minimal elevation of ALT = 65 (N < 31 U/l) and GGT = 146 (N < 39 U/l). Anti-HCV antibodies, anti-HB core, ANA, AMA, SMA and LKM1 were all negative. With respect to the serological study of CD, EMA (1/10) and anti-tTG (14 U/ml) were detected. HLA-DQ2 heterodimer was negative. A duodenal biopsy showed partial villous atrophy (Marsh grade 3a).

After 6 months on a GFD, liver function tests returned to normal and a serology of CD was negative.

Case 4

A 26-year-old male, a nephew of cases 1 and 2 above, and a cousin of case 3, was completely asymptomatic. Laboratory studies showed a slight elevation of AST = 42 (N < 31 U/l) and ALT = 72 (n < 31 U/l), and also a decrease in serum folic acid = 2 (N > 3 ng/ml), without anemia. EMA (1/320) and anti-tGT (> 200 U/ml) were positive, and the HLA-DQ2 heterodimer was positive. A duodenal biopsy showed mild villous atrophy (Marsh grade 3b).

Similarly to the other family members with CD, starting on a gluten-free diet was accompanied by a disappearance of laboratory alterations and a negativization of EMA and anti-tTG antibodies. A summary of these four cases is shown in table I.


The first report on a familial distribution of CD was made in 1935 (11); currently, it is known that a 70% concordance exists for CD in monozygotic twins, compared to 11% in dizygotic twins (12), which provides evidence for a strong genetic basis of this disease. The most powerful genetic association is with class II HLA alleles, which code for the DQ2 heterodimer (13). However, these are also present in 20% of the general population (10), for which reason other genetic or environmental factors, seem to be needed for the development of the disease. Moreover, our group observed that a class I HLA gene, the MICA 5.1 allele, is associated with non-classical forms of celiac disease, in subjects with the high-risk DQ2 heterodimer (14).

The first aspect we would like to highlight in the current study is the high prevalence of CD in this same family (11.8%). According to the degree of familial relationship, we have detected cases among brothers/sisters and nephews of the index case, which supports the need for carrying out extended familial studies, so that no cases are left undiagnosed within the same family. Another aspect we wish to emphasize is that two of the family members with CD were asymptomatic, which supports the need for serological studies in all extended family members, as we cannot rely on the presence of symptoms, in order to suspect the disease. The most efficient diagnostic approach should include a duodenal biopsy in all extended family members with positive anti-tTG antibodies, since it has been demonstrated that up to 92.3% of such family members can be diagnosed. However, the presence of mild forms of the disease among family members with a negative serology has been suggested by other authors (15), but with atypical symptoms and/or biochemical changes. Therefore we must bear in mind, that similarly to that which occurs in clinical practice, when faced with a clinical suspicion of CD, the "gold standard' is duodenal biopsy, regardless of serological results.

Up to 8% of CD cases can be associated with neurological symptoms, mainly cerebellar ataxia, epilepsy, and peripheral neuropathy. Patients with celiac disease who have neurological signs do not usually present with a picture of digestive disease, since the diagnosis of hypersensitivity to gluten is usually performed late in these cases. Knowledge of CD is important when neurological involvement coexists, because the introduction of a GFD during the first 6 months can lead to its improvement or disappearance. The pathogenesis of neurological involvement in CD is not well known, but it has been related to an autoimmune origin. In celiac patients with neurological symptoms the presence of anti-Purkinje cell and anti-CNS neurons antibodies has been shown (16,18).

An association between CD and myoclonus has been previously reported, and is characterized, as in our index case, by having its onset in adulthood and several years after the diagnosis of CD (19,20). Regarding the cause of myoclonus, it is known that, although of cortical origin, this condition is generally located in the cerebellum (19). In our patient the myoclonus appeared several years after the diagnosis of CD, and while the patient was on a GFD. However, the persistence of the enteropathy is indicative of lack of compliance with the diet, which could explain the appearance of complications. Similar to other cases, no response was seen to prescribed treatments, and the rapid evolution of the neurological picture toward an invalidating form in our patient was striking; its consequences eventually led to the patient's death.

In three of our family members with liver disease, the most common biochemical change was an increase in serum transaminase levels. On diagnosis, approximately 30% of celiac patients have altered liver function tests, their morphological substrate being a nonspecific reactive hepatitis (21,22). As in our cases, the initiation of a GFD was followed by a normalization of biochemical changes, for which reason the performance of aggressive diagnostic tests such as liver biopsy, is not necessary. Since hypersensitivity to gluten is the cause of 4.4-9% of cryptogenic hypertransaminasemias (23-25), we believe that, within the diagnostic protocol of this biochemical change, a serological study of CD should be included.

In conclusion, we wish to emphasize here the need to perform extended family studies when diagnosing a case of CD, since risk is not only limited to first-degree relatives. Furthermore, we would also like to draw attention to the frequent development of atypical or asymptomatic forms among family members of celiac patients. Thus, the importance of performing studies in relatives will increase the number of patients diagnosed with CD, within this well-characterized risk group.


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