V. Sri Nagesh ( Department of Endocrinology, CARE Hospital, Hyderabad, India. )
Sanjay Kalra ( Department of Endocrinology, BRIDE Hospital, Karnal, India. )
Type 1 Diabetes is a complex disorder that is made more complex by the myriad of co-morbid conditions associated with it. Mauriac Syndrome is a well-known but nowadays uncommon condition that presents with growth retardation secondary to poor glycaemic control. Limited Joint Mobility is an often-missed association of diabetes. Its importance lies in the fact that it can cause significant impairment of fine movements in T1DM children. It also indicates poor glycaemic control over a long period of time and can be used as a surrogate marker for development of diabetic microvascular complications. Anaemia in T1DM is protean and can develop due to a combination of nutritional factors, chronic renal disease, coeliac disease and worm infestation. Management is etiological. Vitamin deficiencies are ubiquitous in T1DM and if left untreated, can lead to neurological, haematological and skeletal dysfunction.
The best-known co-morbid conditions are the local site reactions clubbed together under the moniker lipodystrophies. These can be either atrophic or hypertrophic and are usually due to repeated injections at the same site, improper technique and needle re-use. Management is often difficult and they are best prevented by appropriate diabetes education and emphasis on proper injection techniques at the time of T1DM diagnosis, with periodic reinforcement. Amyloidosis is a little known condition that shares a lot of features in common with the lipodystrophies and often needs to be differentiated from lipohypertrophy. T1DM is a disease which is often associated with a poor quality of life and these co-morbid conditions also need to be treated for effective general and psychological well-being.
Keywords: Type 1 diabetes, Mauriac, Limited Joint Mobility, Lipodystrophy, Lipoatrophy, Anaemia, Lipohypertrophy, Amyloidosis, Brink-Starkman.
Type 1 diabetes (T1DM) is a not uncommon condition encountered in the endocrine clinic. It is one of the more difficult conditions to manage because of the various factors involved in fluctuation of the blood glucose levels. While hypoglycaemia and diabetic ketoacidosis are the more common complications encountered in the management of this condition, there are a few other conditions which are observed less commonly, but nevertheless can have major implications for proper management of this disorder. This article will focus on some conditions which may occur in resource-challenged settings.
Mauriac Syndrome is one of the "quite often heard, but nowadays rarely seen" complications of Type 1 diabetes. With improved health care infrastructure and awareness, better monitoring, and more targeted management of blood sugars, this pernicious syndrome is becoming increasingly rare.
Mauriac first described this condition in 1930.1 Male to female ratio is equal and it is classically found in adolescent diabetics. Etiology for growth failure includes poor glycemic control, reduced Insulin like Growth Factor-1 (IGF-1), IGF Binding Protein 3(IGFBP-3) levels and Growth Hormone levels or production of bio-inactive forms of these hormones, insulin deficiency, insufficient tissue glucose availability and an imputed circulating IGF-1 inhibitor. While insufficient insulin use is the commonest cause of this syndrome, a variant of Mauriac Syndrome secondary to supra-physiological insulin doses, especially with rapid acting analogues has also been reported. Excessive use of insulin (up to 1.5 U/kg/day) in previously uncontrolled Type 1 diabetes can cause a rapid deposition of glycogen in liver and limited tissue availability of glucose, leading to onset of a Mauriac like picture. Rationalization of insulin dosage leads to improvement.
In its classical form, this syndrome is characterized by short stature, delayed puberty, hepatomegaly due to glycogen deposition, limited joint mobility, moon facies, stretched waxy skin, abdomen distension, and muscle weakness and wasting (predominantly proximal). Nephropathy and retinopathy are frequently co-morbid. Bone age and height age are often delayed. Some variants of Mauriac Syndrome can present with obesity and in these children, weight age, Waist Height Ratio and Waist Hip Ratio might be elevated; but usually all these parameters are low in a typical case of Mauriac Syndrome.
In Mauriac Syndrome, liver enzyme derangement is not always observed. When present, transaminases are more frequently elevated, than are alkaline phosphatase and bilirubin. Retinopathy and nephropathy are not uncommon associations of this syndrome.2 Special care should be taken in poorly controlled Type 1 diabetes with retinopathy, when hyperglycemia is being corrected. There can be rapid deterioration of retinopathy and even blindness can ensue if the glycemic correction is too aggressive.3
Syndrome of Limited Joint Mobility (SLJM)
Limited joint mobility is quite common in patients with diabetes mellitus, especially long standing T1DM. It is classically marked in the small joints of the hands. Skin can also be thickened and waxy, especially over the dorsum and these skin changes can precede limited joint mobility.4 Incidence is linked to duration of diabetes and possibly poor glycemic control. Cigarette smoking can also contribute to LJM. The incidence has been decreasing over the past 20-25 years, in concordance with improved management of diabetes. Increased collagen deposition, cross-linking, enzymatic and non-enzymatic glycosylation of collagen and abnormal cross linking of collagen have been implicated in the pathogenesis of LJM.
Early detection is difficult because this is a painless condition. Patients often present with complaints of poor grip, limited mobility and loss of fine movements of hands; often presenting to the orthopaedic surgeon or neurologist, rather than to the endocrinologist or diabetologist. This assumes importance, because LJM is reversible to some extent in early stages, while changes in later stages are irreversible. Tests which are used to diagnose this condition are the prayer sign and table top test. The Brink-Starkman classification system is often used to grade the severity of LJM (Table-1).5
Differential diagnoses include Stenosing flexor tenosynovitis (trigger finger) and Dupuytren\'s contracture. Both these conditions typically do not involve all the fingers and are more amenable to treatment.
LJM has often been associated with retinopathy and nephropathy, possibly due to poor glycemic control contributing to all the three problems. The association is stronger for men as opposed to women. While no study has conclusively proven this association, the importance of LJM lies in serving as a pointer for better evaluation of microvascular complications. A more direct association is with diabetic foot ulcers, with LJM in the metatarsophalangeal and the sub-talar joints causing high foot pressures, contributing to plantar ulceration. LJM is also found in Type 2 diabetes, albeit, less commonly. All these factors indicate that education about LJM should be integral to diabetes education and examination for this condition should be a part of regular diabetes evaluation.
Treatment of LJM is difficult and evidence about improvement with glycemic control is often controversial and anecdotal. Corticosteroids have been used with variable success and there has been one case report of improvement with pancreatic transplantation, and improvement in this case could also have been secondary to the concomitant use of steroids. Physiotherapy and occupational therapy can be quite helpful. Smoking should be discouraged.
Very few studies have looked at the prevalence of anaemia in Type 1 diabetes. This has been attributed to the heterogeneous nature of anaemia in diabetes. More often than not, anaemia is secondary to chronic disease. In addition to chronic disease, etiology has also been linked to Vitamin B12 deficiency, celiac disease, nutritional anaemia often due to inadequate dietary iron intake, functional erythropoietin deficiency in diabetic nephropathy, chronic blood loss, intravascular haemolysis due to associated ketoacidosis or associated parasitic or other infections and Autoimmune Polyglandular Syndrome with its associated coeliac disease and pernicious anaemia.6 Most studies which have looked at morphological classification of anaemia in Type 1 diabetes have found a microcytic hypochromic picture secondary to iron deficiency. This has been linked to low socioeconomic status and deficient intake of iron from animal sources and vitamin C deficiency.7 Thalassemia minor is one of the less common causes of anaemia.
The significance of anaemia in Type 1 diabetes is fourfold. Firstly, it is often an undiagnosed cause of growth failure and short stature. Second, anaemia has a bearing on the accuracy of HbA1C. Among type 1 DM patients with similar levels of glycemia, iron deficiency anaemia is associated with higher concentrations of HbA1c. Replacement of iron in these children leads to a reduction in HbA1c and hence iron status of the patient must be given credence while interpreting HbA1c concentrations in T1DM.8 Thirdly, persistent anaemia could be a subtle indicator of renal dysfunction and could indicate functional erythropoietin deficiency due to uncoupling of the haemoglobin-erythropoietin-feedback mechanism.9 Fourth, unexplained anaemia in T1DM could also indicate thyroid dysfunction, coeliac disease or other components of APS.
Evaluation of anaemia should be integral to the management of T1DM in children and should include a Complete Blood Picture, at least annually and in children found to have anaemia, and based on the blood picture, should be followed by iron studies, B12 levels, renal function tests, thyroid function tests and coeliac screen, as required. Coeliac disease often presents with a dimorphic blood picture. Management is Treatment of anaemia is directed to correction of the etiology, with iron, folic acid and B12 replacement. Erythropoietin therapy should be considered in T1DM with chronic renal disease. There is very little evidence that EPO therapy aggravates renal damage, but it does interfere with the reliability of HbA1C as an index of glycaemic control and HbA1C reports during EPO treatment should be interpreted with caution. Levothyroxine should be replaced as required. Anaemia due to coeliac disease might need parenteral iron and B12 replacement. Helminthic worm infestation, especially in tropical countries is an often-overlooked cause of anaemia. There is no clear data as to whether there is increased prevalence of parasitic infestations in Type 1 diabetes and neither are there any guidelines as to its prophylaxis and treatment. The best option would be to treat children with Type 1 diabetes as per the existing WHO guidelines for school age children with albendazole or mebendazole, as and when required, along with periodic deworming, as per school based programmes.
A few studies in recent years have correlated Vitamin D deficiency with the severity and frequency of T1DM. Studies indicating that T1DM patients have lower vitamin D levels than control groups have also been reported. It has also been reported that vitamin D is important in the prevention of islet cell death and there is an association of Hypovitaminosis D with insulin resistance and beta-cell dysfunction.10 A few studies have also reported improvement in glycaemic control after Vitamin D supplementation.11 Data about Vitamin D deficiency in T1DM have been conflicting. While theoretically, coeliac disease co-existing as part of APS in T1DM can contribute to Vitamin D deficiency, quite a few studies report prevalence of Vitamin D deficiency not much different from general population data. Appropriate supplementation should be done in all children with T1DM.
Similar data exists regarding Vitamin B12 deficiency. Vitamin B12 deficiency can be consequent to poor dietary intake, especially vegan diets, due to coeliac disease or pernicious anaemia as a component of APS. Prevalence of chronic autoimmune gastritis and pernicious anaemia can be increased up to 5 times in people with T1DM.Patients with T1DM can exhibit auto antibodies to intrinsic factor (AIF) type 1 and 2 and parietal cell antibodies (PCA) especially those with glutamate decarboxylase-65 (GAD-65) antibodies and HLA-DQA1*0501-B1*0301 haplotype.12 Depending on extent of deficiency, clinical manifestations can range from impaired memory, dementia, delirium, peripheral neuropathy, sub acute combined degeneration of the spinal cord, megaloblastic anaemia and pancytopenia. There are no guidelines for screening, but a pragmatic approach would suggest screening at diagnosis and then later yearly for 3 years, then five yearly thereafter or in presence of any clinical indication since vitamin B12 deficiency can develop at any point of time.13 Treatment includes oral or parenteral therapy with B12. The optimal supplementation dose of vitamin B12 is also unknown. Folate administration prior to correcting vitamin B12 deficiency should be avoided because it can cause worsening of the associated neurological manifestations.
Long-term insulin use in diabetes mellitus can be associated with local subcutaneous fat abnormalities known as lipodystrophies. They are characterized by either fat accumulation (lipohypertrophy) or fat loss (lipoatrophy). Insulin lipohypertrophy presents as benign swelling at the injection site and is a result of local anabolic effects of insulin with promotion of fat and protein synthesis.14 Initial changes are very discreet and can present as reddening or thickening of skin. Risk factors include longer duration of diabetes, repeated injection into same site and re-using needles.15 Type of insulin has very little bearing on incidence of lipohypertrophy. Also, patients tend to repeatedly inject into the hypertrophic sites because they are relatively painless, thus perpetuating the problem. It remains a frequent complication of insulin therapy irrespective of the insulin source (animal, recombinant, or analogue) and the mode of administration.
Histology reveals adipocyte proliferation, and collagenous scar tissue with hypo vascular collagen and bland looking fibroblasts.16 Management is important because insulin absorption is delayed and often erratic when injected into areas of hypertrophy and can cause fluctuating blood glucose levels. Treatment involves rotation of injection sites and avoiding injections into areas of hypertrophy. Often, there is a marked reduction in insulin requirement once the site is changed. Liposuction is another alternative in resistant cases, as is co-administration of dexamethasone along with insulin.16 Switching to rapid acting analogues can also help, as it minimizes the contact time the adipocytes have with insuli.
Lipoatrophy, on the other hand, is an entirely different entity. It is an immune mediated inflammatory response. Atrophy results from the local formation of complexes between injected antigen and circulating antibody with activation of complement and infiltration of inflammatory cells. Earlier it was assumed to be due to bovine and porcine insulins and with the advent of human insulins, it was expected that this condition would become almost non-existent. However, lipoatrophy continues to be reported and has been found to be associated with all types of insulins including rapid acting analogues, glargine, detemir and pump therapy.17-20
Treatment is difficult and also needs addressing of cosmetic issues. Priority should be given to changing or rotating the site of insulin injection. A change in the type of insulin can often have benefit. Cromolyn sodium21 and dexamethasone/prednisolone22 injections have been used for management. Dermal fillers can address cosmetic concerns. This condition often resolves in children, but can be persistent in adults. Self-examination by the patient and examination by the health care provider, ideally at every visit can help in early detection.
Amyloidosis is a disorder in which amyloid fibrils are deposited extracellularly and impair tissue function. It can either be local or systemic. Local amyloid deposition at the site of repeated insulin injection causing subcutaneous insulin resistance has been occasionally reported. In most of the case reports, the amyloid at the injected site is identified as amyloid insulin type (AIns).23 The nature of amyloid in the insulin injection site is considered to be insulin itself or insulin related substance. The earliest reported cases with this deposition were with animal insulins and were assumed to be due to deposition of these foreign proteins. But in the last decade, a few cases have also been reported with recombinant insulin and analogues. The type of insulin does not seem to be a major reason for the formation of amyloid. The commonest differential diagnosis is lipohypertrophy, which is also due to insulin injection. It can be differentiated clinically by palpation. Amyloid is solid and firm to touch, while lipohypertrophy is usually softer and lobular. Lipohypertrophy often regresses after cessation of insulin injection into affected site, while amyloid will not regress. However, it might not always be possible to differentiate these two entities by palpation and excision and biopsy might be required.24 It is clinically significant because poor penetration of insulin, can contribute to ineffective insulin treatment and once again underlines the importance of injection site rotation.
The entities discussed in this article are a few of the associated conditions that can occur in children with T1DM. All these complications tend to occur more frequently in resource-challenged settings, because of delayed, inadequate, or inappropriate treatment. Often, with the entire focus on glycaemic management, these conditions are missed. Delayed recognition can have major implications both for short-term glycaemic control and also long term complications of diabetes. They can also have a major impact on quality of life, and evaluation for these conditions should be mandatory in the periodic Type 1 diabetes health check-up. Attention to proper insulin prescription, insulin technique, and supportive management will help reduce the occurrence of these complications.
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