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Year : 2022  |  Volume : 2  |  Issue : 2  |  Page : 98-101

Unexplained anasarca in type 1 diabetes mellitus: Breaking the hypoalbuminemia – Persistent diarrhea cycle

Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Date of Submission31-Jan-2022
Date of Decision01-May-2022
Date of Acceptance02-May-2022
Date of Web Publication30-May-2022

Correspondence Address:
Dr. Varuna Vyas
Department of Pediatrics, Academic Block, All India Institute of Medical Sciences, Jodhpur - 342 005, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_36_22

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Background: Undiagnosed Type 1 diabetes mellitus (T1DM) often presents as diabetic ketoacidosis (DKA). We report a child with newly diagnosed T1DM who developed anasarca and persistent diarrhea following resolution of DKA and was referred to us for the same. Clinical Description: We reviewed the clinical history, examination, and investigations that had been undertaken. Our clinical evaluation was in concurrence with the referring hospital-anasarca with probable partially treated spontaneous bacterial peritonitis (SBP). However, the cause of the subacute anasarca and persistent diarrhea was unclear. The child was empirically started on broad-spectrum antibiotics for the SBP, a high-protein diet to build up the protein, and continued the same subcutaneous insulin, on which he was euglycemic. After ruling out usual causes, i.e., renal, hepatic, and cardiac, we reviewed the possibility of celiac disease, tuberculosis, insulin edema, and hypothyroidism. Management: When he did not improve despite a good appetite, adherence to management, and all tests were inconclusive, we reviewed the etiopathogenesis. Untreated T1DM had led to chronic negative catabolism that had precipitated severe hypoproteinemia. A vicious cycle had set in which hypoalbuminemia was leading to bowel wall edema, resulting in protein malabsorption, perpetuation of diarrhea, and further hypoproteinemia. Our assumption proved to be correct when a single dose of parenteral albumin broke the cycle, and the child improved drastically with the resolution of diarrhea within 24 h and the edema in a few days. Conclusions: This case highlights the implications of severe catabolism in a patient with untreated diabetes and how this may be a self-perpetuating condition.

Keywords: Anasarca, diarrhea, hypoproteinemia, malabsorption, type 1 diabetes mellitus

How to cite this article:
Vyas V, Khera D, Mittal A, Singh K. Unexplained anasarca in type 1 diabetes mellitus: Breaking the hypoalbuminemia – Persistent diarrhea cycle. Indian Pediatr Case Rep 2022;2:98-101

How to cite this URL:
Vyas V, Khera D, Mittal A, Singh K. Unexplained anasarca in type 1 diabetes mellitus: Breaking the hypoalbuminemia – Persistent diarrhea cycle. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 Jul 4];2:98-101. Available from: http://www.ipcares.org/text.asp?2022/2/2/98/346255

Type 1 diabetes mellitus (T1DM) is a chronic disorder characterized by hyperglycemia that occurs due to autoimmune destruction of the beta islet cells of the pancreas. The characteristic symptoms are polyuria, polydipsia, polyphagia, and lethargy. In many cases of new-onset diabetes mellitus, these symptoms may not be noticed by the child, or the parents, and the child may present with diabetic ketoacidosis (DKA) at the time of diagnosis. Studies have described that the prevalence of DKA at first diagnosis of diabetes mellitus is as high as 59%.[1] Children with diabetes can have diarrhea due to infective causes or due to noninfective comorbidities such as celiac disease.

We hereby report this case of an adolescent boy who was referred to us in view of anasarca and persistent diarrhea following the resolution of DKA. We systematically investigated him for all the common causes of anasarca as well as diarrhea but could not find any cause. Finally, we reviewed the pathophysiology of anasarca and hypoproteinemia and speculated that a simple change in management might break a vicious cycle, that was otherwise not ending spontaneously. We report this case as we were unable to find similar cases on a literature search. We believe it may be under-reported due to nonrecognition of this phenomenon. Sharing our experience may help others in managing similar patients.

  Clinical Description Top

A 15-year-old boy with newly diagnosed T1DM with DKA at presentation was referred to us with a history of generalized swelling of the body, diarrhea, and pain abdomen that had started insidiously, a few days after resolution of DKA. The child was apparently well 2 months back when the parents noticed that he was becoming very tired by the end of the day, even by routine activities that he was normally accustomed to doing. There had not been increase in strenuous activities, or extra academic work that was causing him to sleep less. There was no history of fever, chronic cough, breathing difficulties, progressive pallor, diarrhea, or decreased oral intake due to illness or dieting. The child did not report any stress or depressed mood. The mother had not been worried initially, as his appetite had become voracious (he was always hungry, despite eating 5–6 meals a day with larger servings). However, the parents grew concerned when he started losing weight over a month, manifesting as looseness of clothes. He was taken to a local practitioner who made a diagnosis of enteric fever and started him on azithromycin and ofloxacin empirically for 2 weeks, despite no clinical evidence and inadequate workup. The child continued to lose weight. It was noticed that he would awaken multiple times at night to urinate, but there was no fever, pain, or burning sensation while passing urine, or urgency. Following 1 and half months of this illness, he developed difficulty in breathing that progressively worsened over 3 days and for which he was hospitalized. Although the lethargy increased, there was no history of loss of consciousness or seizures. At admission, the child was diagnosed with DKA based on clinical manifestations, tachypnea, and the presence of severe metabolic acidosis, hyperglycemia, and ketonuria. Antibiotics (details unavailable) were initiated in view of suspected sepsis. The DKA resolved within 3 days, and he was started on subcutaneous insulin, as his blood sugar levels started optimizing.

The child started developing generalized swelling within a week of hospitalization. Periorbital puffiness appeared first, followed by abdominal distension and subsequently swelling of the lower limbs over 3 days. There was no history of fever, breathlessness, awakening at night due to cough or respiratory discomfort, jaundice, decreased urine output, or frothy urine. There was no history of the appearance of reddish rashes associated with excessive itchiness. The child was not receiving any intravenous (IV) fluids during this period. The abdominal distension was accompanied by the development of loose stools within a day. These were watery without blood or mucous, and occurred 8–10 times a day. There was no history of vomiting. The child also started to experience diffuse abdominal pain, mild in intensity, and not localizing to any particular site. There was no identifiable aggravating (food intake or on moving around) or relieving (vomiting, intake of food or antacids) factor. Since the child had been consuming food from the hospital kitchen and there were no other similar cases in the ward, the possibility of food poisoning due to consumption of contaminated food or drink, and osmotic diarrhea were excluded. The treating team considered the possibility of spontaneous bacterial peritonitis and ordered a paracentesis. He was initially started on ceftriaxone at admission, which was changed to ofloxacin and metronidazole. We reviewed the documents from the referring hospital and noted normal reports, except leukocytosis with a total leucocyte count (TLC) of 35,000/mm3, and neutrophilia (77% neutrophils [N] and 10% lymphocytes [L]). Only the cytology reports of an ascitic fluid analysis were available, which revealed 640 cells/mm3 with 20% N, 80% L. The child was referred to us to determine the cause of anasarca that had developed following the resolution of DKA when there was no overt clinical indicator or test report to suggest an underlying renal, cardiac, or hepatic cause.

At the presentation to our hospital, the child appeared sick and had obvious anasarca. His heart rate was 90 beats/min (min), respiratory rate was 20 breaths per min, blood pressure 110/60 mmHg (all the vitals were normal for his age), and he was afebrile. His weight was 27.1 kg (Z score − 3.26), height 150 cm (Z score − 1.89), and body mass index 12 kg/m2 (Z score − 3.15). There was no pallor, icterus, cyanosis, clubbing, or stigmata of chronic liver disease. On per abdominal examination, the abdomen was distended, and the overlying skin was normal. There was mild generalized tenderness and shifting dullness but no palpable organomegaly. There was no renal angle tenderness. On chest auscultation, air entry was decreased with dullness on percussion – suggestive of bilateral pleural effusion. The cardiovascular and neurologic examinations were within the normal limits. There was thus no clinical evidence of a hepatic, cardiac, or renal cause of edema.

  Management and Outcome Top

Our clinical evaluation was in concurrence with the referring hospital. The clinical phenotype suggested anasarca with probable partially treated acute bacterial peritonitis, but the cause of anasarca was not clear. We decided to continue empirical treatment with broad-spectrum antibiotics while continuing the diagnostic work. There was no anemia (hemoglobin 14.7 g/dL). Although leukocytosis and neutrophilia persisted (TLC 20,100/mm3 with 74% N), the C-reactive protein was 5.31 mg/L (normal <6 mg/L), and the blood culture was sterile. Kidney function tests were normal; blood urea nitrogen 37 mg/dl and serum creatinine 0.47 mg/dl. The liver function tests showed normal bilirubin levels (0.36 mg/dl) and enzymes (serum glutamic-oxaloacetic transaminase 47 U/L, and serum glutamate pyruvate transaminase 10 U/L), but there was hypoproteinemia (total serum protein 2.99 g/dL), hypoalbuminemia (1.49 g/dl), and globulin levels of 1.5 g/dl. Proteinuria was absent on urine dipstick evaluation. Ascitic fluid cytology showed 150 cells with 95% L, biochemistry was normal (ascitic fluid sugar 133 mg/dL and protein 1.66 g/dL), there were neither acid-fast bacilli on Ziehl–Nelson staining nor bacteria on gram staining, and the culture was sterile. Although unlikely, workup for dengue fever was negative. An abdominal ultrasound revealed normal liver, spleen, and kidneys but mild-free fluid in the abdomen and pelvis. Long segment, circumferential wall thickening involving the ascending, transverse, and descending colon was seen. There was no abnormal luminal dilatation. These findings were suggestive of colitis, the most likely etiology being infective or inflammatory. However, the stool routine examination was normal. Hence, preliminary investigations remained inconclusive.

Since the child was allowed per orally, a high-protein diet was started. His blood sugar levels remained within the normal limits on the subcutaneous split-mix insulin regime. Although his abdominal pain resolved, the anasarca and diarrhea did not improve. Repeat serum albumin values did not increase despite the high-protein intake (2 g/kg/day), and no source of protein loss except for diarrhea, which continued for the next 10 days in the hospital, despite the adequate antibiotic cover. Since, by definition, the child had persistent diarrhea, we decided to look for evidence of malabsorption and common causes of malabsorption by revisiting history, examination, and planning relevant investigations.

The stool was neither explosive nor associated with gaseous distention, nor was it greasy. Stool pH was normal and reducing substance negative. As celiac disease is known to occur with Type 1 DM, serum anti-tissue transglutaminase antibodies were checked for and found to be negative. Total serum immunoglobulin A was also normal. There was the absence of evidence of abdominal tuberculosis (TB) on the computerized tomography (CT) scan. However, the CT abdomen showed gross ascites, moderate bilateral pleural effusion, and edematous colonic loops with thickening of jejunal folds. Nonetheless, a pleural tap was performed to rule out TB. Microscopy showed 200 cells/mm3 with 95% L; the pleural fluid sugar was 129 mg/dl and protein 1.74 g/dl; Ziehl–Neelsen staining and gram staining were negative; and culture was sterile. The thyroid function test was also normal, excluding hypothyroidism, though the edema was pitting. We also kept the possibility of insulin, edema a rare complication of insulin therapy.[2] Insulin edema can also occur within the 1st week of initiating insulin therapy. However, it has a female preponderance and may be associated with pulmonary edema. In our patient, the edema was not self-limiting, and there was no pulmonary edema. Moreover, our patient had persistent diarrhea and bowel edema, which are not described with insulin edema.

Finally, the possibility of a vicious cycle of hypoproteinemia, leading to bowel wall edema, and causing further protein malabsorption that was resulting in persistent diarrhea and refractory hypoproteinemia was considered. The only way to confirm this theory was to break the cycle by administration of parenteral albumin. The child was transfused IV 20 g of albumin. This led to a dramatic resolution of diarrhea and a decrease in anasarca within 24 h, and complete resolution over the next 2 days. He did not require any more doses of albumin. Oral protein ingestion was restarted, and the child has been under follow-up for his T1DM for the last 3 years. Though the blood sugar control is variable due to waxing and waning of compliance, a similar phenomenon has not recurred.

  Discussion Top

The main action of insulin on protein metabolism in T1DM is to decrease the breakdown of protein.[3] Untreated T1DM is associated with severe catabolism with loss of both protein and energy due to the complete lack of insulin. Insulin deprivation in untreated diabetes leads to a net increase in protein breakdown, mostly in the skeletal muscles. The initial hypoalbuminemia resulting from the unrecognized T1DM led to anasarca and bowel wall edema, which perpetuated protein malabsorption, manifested as diarrhea, and resulted in a vicious cycle despite insulin and though a high amount of protein was being ingested [Figure 1]. The boy had a complete and speedy recovery once parenteral albumin was administered. Since albumin is a biological product with its own inherent safety concerns, there was no concrete indication in giving it for anasarca, especially since the child's appetite was good.
Figure 1: Vicious cycle of hypoproteinemia, diarrhea, and edema in the patient

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The effect of insulin on protein metabolism varies depending on the tissue or the type of protein. Fractional synthesis rates of albumin are decreased in T1DM due to insulin deficiency, while the fractional synthesis rates of fibrinogen are increased. In adults, the level of serum albumin is inversely associated with the risk of ketosis in hospitalized individuals with T2DM.[4] Hypoalbuminemia is associated with increased complications and reduced short-term and long-term survival in critically ill patients.[5] We could not find any similar data in children on a literature search.

In the context of DM, albumin synthesis is dependent on adequate insulin reserve. Studies have demonstrated an inverse relationship between serum albumin and hemoglobin A1c levels, the pathophysiology being insulin deficiency causing both hyperglycemia and decreased albumin due to different mechanisms.[6],[7] In patients who have been recently started on insulin, insulin edema is also an important and under-reported cause of edema.[2] It is associated with transaminitis and occurs due to increased sodium and fluid retention after starting insulin. It is a self-limiting condition and has to be managed symptomatically, primarily by salt and fluid restriction.

To conclude, the management of this case reiterated that it is always worthwhile to go back to the basics. Once we understood the etiopathogenesis of the manifestations beyond the common pathophysiological causes, we were able to arrive at the appropriate reason for the anasarca and diarrhea and find an effective solution.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Nagl K, Waldhör T, Hofer SE, et al. Alarming increase of ketoacidosis prevalence at type 1 diabetes-onset in Austria-results from a Nationwide Registry. Front Pediatr 2022;10:820156.  Back to cited text no. 1
Krishnan R, Bindu S, Riaz I, et al. Insulin edema in an adolescent girl with newly diagnosed Type 1 diabetes mellitus. Indian Pediatr Case Rep 2022;2:25-8.  Back to cited text no. 2
  [Full text]  
Hebert SL, Nair KS. Protein and energy metabolism in type 1 diabetes. Clin Nutr 2010;29:13-7.  Back to cited text no. 3
Cheng PC, Hsu SR, Cheng YC. Association between serum albumin concentration and ketosis risk in hospitalized individuals with type 2 diabetes mellitus. J Diabetes Res 2016;2016:1269706.  Back to cited text no. 4
Vincent JL, Russell JA, Jacob M, et al. Albumin administration in the acutely ill: what is new and where next? Crit Care 2014;18:231.  Back to cited text no. 5
Rodríguez-Segade S, Rodríguez J, Mayan D, et al. Plasma albumin concentration is a predictor of HbA1c among type 2 diabetic patients, independently of fasting plasma glucose and fructosamine. Diabetes Care 2005;28:437-9.  Back to cited text no. 6
Tiwari S, Bothale M, Hasan I, et al. Association between serum albumin and glycated hemoglobin in Asian Indian subjects. Indian J Endocrinol Metab 2015;19:52-5.  Back to cited text no. 7


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