Neurological Features and Enzyme Therapy in Patients With Endocrine and Exocrine Pancreas Dysfunction Due to CEL Mutations

The patients were recruited from Family 1 in the study by Raeder et al. (1). Nine patients having diabetes and severely reduced fecal elastase level were studied. Six additional patients were included for studies of the neurological features. The patients were given standard PEST and followed for 30 months. An online appendix describes the study design, protocol, determination of exocrine dysfunction, and statistical analysis (available at http://dx.doi.org/10.2337/dc07-2217).

Baseline characteristics of the nine patients are given in supplementary Table 1, and the results after treatment are shown in Fig. 1 and supplementary Table 3. Two patients dropped out of the study after 1 and 6 months, respectively, because of side effects.

Six patients identified loose stools as a major complaint. Seven patients reported immediate improvement of abdominal symptoms with treatment; however, the treatment was unsatisfactory for the majority, and doses were subsequently increased.

Baseline fecal elastase values were <10 μg/g in all patients (compatible with severe exocrine deficiency) and did not change with treatment. A1C was moderately high at baseline and did not change. Pretreatment BMI was normal (median [range] 24.0 [18–32] kg/m²). Mean body weight increased by 3 kg after 12 months of treatment (P = 0.01).

Seven patients had steathorrea at baseline. At 30 months, fat excretion was reduced in all four patients studied (from 35 [25–43] to 22 [12–37] g/day; P = 0.01). Vitamin E levels were low in all patients but increased with treatment (from 7.6 [2.8–10.1] to 13.2 [5.5–14.1] μmol/l; P = 0.03) and normalized in five of seven subjects after 12 months. Levels of vitamins D and A were in the lower normal range; vitamin D levels remained unchanged, whereas vitamin A values increased with PEST (from 1.1 [0.5–1.4] to 1.6 [1.3–1.7] μmol/l; P = 0.03). There was a small but significant increase in total, HDL, and LDL cholesterol but no change in triglycerides. Osteoporosis was diagnosed in three and osteopenia in two patients at baseline. Bone mass density did not change.

The neurological findings are described in supplementary Table 2. Electrophysiological studies revealed peripheral neuropathy with slowing of nerve conduction consistent with a demyelinating etiology in 10 of 15 subjects. Four had additional electromyogram pathology suggesting axonal damage. There was no correlation between diabetes duration and symptom severity. Five subjects had symptoms and electrophysiological signs of carpal tunnel syndrome.

Magnetic resonance imaging showed multiple high-signal lesions in the cerebral periventricular white matter in one patient (IV-11) consistent with her multiple sclerosis diagnosis. Another subject (III-9) had scattered high-signal lesions in the supratentorial white matter, and his daughter had one periventricular high-signal lesion. They showed no clinical evidence of central nervous system disease. There was no effect on neurological symptoms after 12 months of treatment.

PEST constitutes the main treatment of maldigestion due to exocrine pancreatic insufficiency. Symptomatic effect in our patients was immediate, probably due to improved absorption, as indicated by decreased fecal fat excretion and normalization of serum vitamin E. It is well recognized that fat excretion is seldom normalized by PEST. Exocrine function, as assessed by fecal elastase, did not improve. This was anticipated; the very low elastase values probably reflect end-stage pancreatic disease. Glycemic control remained unchanged, confirming recent results from a study examining enzyme replacement in type 1 diabetes with exocrine dysfunction (3).

A high prevalence of exocrine insufficiency has been reported in both type 1 and type 2 diabetes (4) and in HNF1A and HNF1B maturity-onset diabetes of the young (5,6). Claims that this deficiency is moderate, nonprogressive, and therefore clinically irrelevant (7) are contradicted by the finding of pathologically high fat excretion in diabetic patients with fecal elastase deficiency (4). An independent correlation between fecal elastase levels and, respectively, glycemic control and residual β-cell function has been reported (8).

A predominantly demyelinating neuropathy was present in 10 of 15 patients. Only four patients had evidence of axonal damage. Neuropathy is common in diabetes, particularly in the presence of chronically poor glycemic control, but it is typically in the form of axonopathy (9), although demyelinating changes are described (10). Our patients exhibited few signs of long-standing hyperglycemia (supplemenary Table 1). No correlation between disease duration and presence of neuropathy was seen. Five patients had carpal tunnel syndrome, confirming the association between diabetes and compression neuropathy.

Vitamin E deficiency affects both the central and peripheral nervous systems (11). The associated peripheral neuropathy is most often axonal (11), although demyelinating neuropathy also occurs (12). Vitamin E levels improved following treatment, but the electrophysiological findings and patients’ sensory symptoms did not improve. This result is consistent with that in primary vitamin E deficiency, in which supplementation, at best, stabilizes the condition. Fat malabsorption and/or chronic vitamin E deficiency may contribute to the neurological manifestations seen in Family 1.

In conclusion, demyelinating peripheral neuropathy appears to be a consistent feature of the CEL syndrome. Whether this is directly connected to the mutation or secondary to malabsorption and/or diabetes is unclear and warrants further study. PEST alleviated symptoms, reduced fecal fat excretion, and improved vitamin A and E status but did not improve glycemic control. Vitamin status should be checked in patients with diabetes and fecal elastase deficiency because it may indicate treatable malabsorption.

This study was supported in part by funds from Haukeland University Hospital, Innovest, University of Bergen (Bergen Translational Research Grant Program) and the Norwegian Research Council (Functional Genomics [FUGE] Program).

We thank Liv Aasmul for practical assistance.