Recurrence of Diabetes Mellitus Type I
Recurrence of Type I diabetes mellitus has been well documented in approximately a dozen cases. The diagnosis of recurrent disease is made with the combination of sudden or progressive lack of glycemic control associated with selective loss of beta cells in the graft and persistence of the other types of islet cells, particularly alpha cells. In few cases the active phase of beta cell destruction has been demonstrated; this consists of selective mononuclear cell infiltration (isletitis). The inflammation is centered in islets still containing beta cells. The isletitis resolves when beta cells disappear.
The majority of documented cases of recurrent diabetes mellitus occurred in transplants from identical twins or HLA-identical siblings. In some cases isletitis resolved after introduction or increase in immunosuppression. HLA-mismatched transplants from cadaveric donors are, however, also susceptible to selective beta cells destruction. The latter appears to result from insufficient immunosuppression. In addition to the clinical and histological findings, the diagnosis of recurrent autoimmune disease is aided by the demonstration of islet cell autoantibodies in serum (GAD 65 and IA-2). In a study comparing patients with chronic graft failure versus patients with well functioning grafts, islet cell autoantibodies before transplantation and at the time of graft failure were significantly higher in the former group. Also, patients with failed grafts showed an increase in autoantibodies at the time of loss of graft function.
Recurrent autoimmunity appears to operate also in the case of allogeneic islet transplantation.
The rarity of recurrent Type I diabetes mellitus in whole pancreas transplantation has been attributed to the inclusion of donor lymphoid tissue with the transplanted pancreas. This would lead to recipient chimerism for a donor T cell subset (RT6.2).
We have not observed isletitis or selective beta cell loss after routinely evaluating immunoperoxidase stains for insulin and glucagon in over 600 pancreas transplant biopsies and over a hundred pancreatectomies. We have not been able to demonstrate islet cell autoantibodies in a small number with clinical presentation suspicious for recurrent diabetes mellitus.
It is important to emphasize that non-specific inflammation of islets and with no associated selective loss of beta cells can be seen in acute allograft rejection. Islet inflammation is proportional to the degree of inflammation in the neighboring exocrine parenchyma and usually consists of a mixture of inflammatory cells that may include eosinophils.
(Pictures: isletitis, inflammation in rejection normal pattern of beta and alpha cells in islets)
Histological correlation of possible causes of hyperglycemia in pancreas transplant patients:
Severe acute rejection: extensive parenchymal inflammation and or necrosis that affects both exocrine and endocrine component.
Thrombosis of large vessels: extensive parenchymal inflammation and or necrosis that affects both exocrine and endocrine component.
Chronic rejection: Progressive graft fibrosis is associated with loss of glycemic control. The graft looks sclerotic and there is extensive acinar loss. Residual islets contain beta cells.
Drug toxicity: The islet cells show vacuolization and swelling. The acinar component is normal (both acinar and endocrine components are vacuolized in ischemic injury).
Recurrence of autoimmune diabetes: Active destructive phase shows isletitis with progressive and selective loss of beta cells. The acinar component is not affected. In the inactive phase (after the disappearance of beta cells) the pancreas will look superficially normal. In these cases the loss of beta cells can be demonstrated by the lack of insulin stain in islets. After a prolonged period of time the islets as a whole can disappear.
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