Acute Pancreatitis (AP) is a common gastrointestinal disorder with increasing health burden ^[1]. Physicians concern not to miss the diagnosis of AP when a patient presents with abdominal pain, for the reason that early aggressive management plays a significant role in outcome ^[2]. Ultrasonography and pancreatic enzymes, amylase and lipase combinedly are widely available tools in the diagnosis of AP; furthermore, to diagnose any acute abdominal conditions. Although Diabetic Keto Acidosis (DKA) is known to cause abdominal pain, the priority to consider it a foremost diagnosis becomes less, when no past history of diabetes, no osmotic symptoms, presence of guarding, tenderness, mildly elevated blood glucose levels and elevated amylase and lipase levels. Elevation of amylase and lipase less than/equal to three times normal may be nonspecific and represent other abdominal and systemic causes, but elevation more than three times the normal is reported to be diagnostic of AP. This increase may also be related to pancreatic metabolic diseases and extra pancreatic abnormalities of the pancreatic ducts like recurrence of chronic pancreatitis and nonpancreatic causes like chronic viral liver disease, ectopic pregnancy, mumps, HIV infection, macroamylasemia, macrolipasemia, head trauma and diabetic ketoacidosis ^[3].  This paper aims to report three cases of DKA which presented as abdominal pain and found to have marked hyperamylasemia and hyperlipasemia and to focus the possibility of DKA in the differential diagnosis of marked hyperamylasemia and hyperlipasemia.

This is a case series carried out over a period of one year (December 2022-November 2023) in the department of medical gastroenterology and hepatology, Chettinad hospital and research institute, Chengalpattu, a tertiary care hospital of south India with limited resources. Patients of DKA, who were admitted with abdominal pain and found to have elevated amylase lipase levels more than 1000 U/L are studied in detail. Institutional ethical committee approval was sought and obtained before the conduct of the study.

CASES:

CASE -1:

A 57-year-old female, who is known diabetic and hypertensive presented with sudden onset epigastric pain and vomiting for 2days. The pain was dull aching with no radiation. It was associated with non-projectile, non-bilious vomiting containing food particles. She did not report fever, loose stools, constipation, jaundice, or headache. She has not experienced any such previous episodes before. The patient denied use of drugs other than diabetes and hypertension and/or alcohol. Her antidiabetic medication did not contain DDP-4 inhibitors. She added her life is stressful in the recent days due to personal reasons. On general examination she had tachycardia (P.R-120/min) and signs of mild dehydration. On abdominal examination, epigastric tenderness was elicited, and bowel sounds were preserved. Rest systemic examination was unremarkable. On admission baseline laboratory tests were requested, the significant inferences were, mild hyperglycemia, microcytic hypochromic anemia, strikingly raised amylase and lipase. Rest of the parameters such as Liver Function Test, Renal Function Test, Serum Electrolytes were within normal limits. ABG was suggestive of metabolic acidosis. The abdominal ultrasonography was suggestive of cholelithiasis. In view of markedly elevated pancreatic enzymes and persisting abdominal pain patient was taken up for CT abdomen which did not add any over ultrasonography. Over next one hour capillary blood glucose shot to 531mg/dl. Patient was initiated of Intravenous fluids and Insulin infusion. Blood glucose was controlled over 12hrs. Insulin infusion along with dextrose was continued for 36hrs, i.e., till metabolic acidosis correction. Patient symptoms improved gradually.

CASE-2:

A 36year old female with no known comorbidities presented to emergency department with chief complaints of abdominal pain since 2days. The pain was peri-umbilical, dull-aching with doubtful radiation. It was associated with multiple bouts of non-projectile vomiting containing food particles. She also noticed fatigue and weight loss of 2kgs over last one month. No other significant GI complaints. Her mother is a diabetic of Insulin therapy. She works as a manager in a corporate office and lives a sedentary life style. On general examination, BP-100/66mmHg, patient was tachypneic (RR-25/min) and tachycardic (H.R-110/min). Per-abdomen, guarding and diffuse tenderness elicited; Bowel sounds heard. Other systems were normal on examination. Laboratory investigations revealed metabolic acidosis, hyperglycemia, leukocytosis, hyponatremia, urinary ketonemia and significantly elevated pancreatic enzymes. (Table-1) CT abdomen showed fatty liver and tiny microliths in both kidneys. She improved gradually with correction of acidosis and hyperglycemia.

 CASE-3:

A 56year old male who is a known diabetic, hypertensive, coronary artery disease, chronic kidney disease on regular follow up was brought to the emergency department with history of sudden onset breathlessness since 3hours. Patient also gave history of orthopnea. On general examination, BP-160/10mmHg, PR-100/min, RR-34/min, SPO2-82% in room air; pallor and pedal edema noted, No raised JVP. Respiratory system examination revealed bilateral crepitations. Cardiac and other system examination were unremarkable. X ray chest carried out showed bilateral non-homogenous infiltrations suggestive of pulmonary edema. Requested baseline investigations was suggestive of normocytic-normochromic anemia, leukocytosis, hyperuricemia, hypocalcemia, hyperkalemia, uremia, elevated creatinine levels and mild hyperglycemia. ABG was showing a mixed acidosis with high anion gap. Echocardiography demonstrated a preserved ejection fraction with normal chambers. Patient was treated in the line of flash pulmonary edema secondary to acute on chronic kidney disease (ACKD) with regular monitoring of electrolytes, renal function tests and blood glucose. However, the acidosis did not revert completely, but was on improving trend; clinically attributed to ACKD. Day-3 following admission, patient complained of severe periumbilical pain with guarding. CT abdomen showed bilateral small kidneys and prostratomegaly. Labs repeated including amylase and lipase showed a marked elevation of pancreatic enzymes. Blood sugars which were under controlled before, on the same day, gradually rose more than 300mg/dl in spite of adequate insulin administration; ketones turned positive. Insulin therapy was geared up and patient responded to therapy.

Table 1. Complementary exams.

DKA is a state of absolute insulinopenia and impaired glucose utilization leading to hyperglycemia and ketonemia ^[4]. DKA is triggered by multiple factors such as, poor compliance, infections, class of drugs class such as corticosteroids, DPP-4 inhibitors, antipsychotic agents, thiazide diuretics, Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, etc. and medical conditions such as Myocardial infarction, cerebrovascular disease and pulmonary embolism ^[5]. The probable precipitation factor in our case is probably non-compliant to antidiabetic drugs (case-1) and stress (case-3). In a setting of epigastric pain with significantly elevated pancreatic enzymes and high blood sugars, DKA and AP shall not be excluded, unless proved with necessary investigations and therewithal both can coexist. When both exist together, the question of causation and association emerge. AP perse, precipitating DKA is not that frequently reported in the literature ^[6]. Several hormonal derangements are attributed: 1. Drop in insulin production and increase in glucagon release secondary to acinar cell damage ^[7], 2. Neuroendocrine stress response to critical illness, that lead to increase in counterregulatory hormones such as cortisol, catecholamines, and growth hormone, 3. State of ketosis induced by acute pancreatitis and nutritional deficits ^[8].

Rather, several observations have been made on DKA leading to AP, whilst, among them the majority had the triad of DKA, hypertriglyceridemia (HTG) leading to AP ^[9]. In a study by Nair, et al. among 100 patients with DKA, 11% had AP; amongst 70% had some identifiable cause of AP, especially hypertriglyceridemia (35%) and the rest 30% did not have any known cause of AP, which shall be attributed to DKA by its very nature. Hypertriglyceridemia as a whole including the ones provoked by DKA accounts 10% of all AP ^[10]. DKA stimulating AP without HTG is rarely reported in the literature ^{[11, 12]}. Yadav D, et al among 150 DKA episodes found that 16 (11%) had radiological evidences of AP without HTG. The probable mechanism is considered to be acidosis that give raise to acinar injury ^[13]. This is supported by the study done by Nair, et al. and reports by Yadav, Hansraj. P, et al. and Slyper. A., Wyatt. D, et al. where AP occurred more among ones with low PH and high anion gap ^{[10, 11, 12]}.

Notwithstanding, whether DKA leads to AP or AP precipitates DKA or just coexist, the deadly combination is associated with poor outcomes. Yuan, et al. in his research on 48 patients with concomitant AP and DKA showed increase in AKI, severity of AP and length of hospital stay ^[14]. Similar results have been demonstrated by Wang, et al and Fu, et al in their respective studies ^{[15, 16]}. Hence, it is essential to diagnose the side-by-side existence early, so that aggressive fluid resuscitation, insulin supplementation and other management shall be initiated from the very beginning judiciously ^[2]. Unlike the characteristic pain in AP, the one of DKA is usually a subacute onset, dull, diffuse, without radiation; but may radiate and localize as like in AP. This may be because the pain in DKA is multifactorial and it does have pancreatic involvement. Hyperglycemia induced delayed gastric emptying, gallbladder hypomotility and Hepatic capsule expansion, hydrogen ions induced gastrointestinal mucosal inflammation, pancreatic acinar injury, hypoperfusion induced organ damages including pancreas and are found to be the cause of pain ^[17]. A study on 48 south China patients demonstrated that patients with comorbidities such as diabetes and hypertension, who are not alert on presentation are likely to have concomitant DKA and AP ^[14].

Physical examination features including guarding may be elicited in either of the conditions. Similarly, there is no specific laboratory parameter till date that point the co-occurrence. Several studies were undertaken to bring into light the same. Yan Fu, et al., in his study among 136 DKA patients found 19.9% to have a concomitant disease; they were obese with higher levels of serum triglycerides, blood glucose and hemoglobin A1c (HbA1C). however multivariate analysis showed, blood glucose solely with a cutoff of 391.89mg/dl, predicted concomitant DKA with a sensitivity and specificity of 81.5% and 94.5%, respectively ^[16]. A retrospective study by Khan AA, et al., showed elder age group and high cholesterol levels predicted concomitant DKA and AP ^[18]. A study done at Institute Foundation G. Giglio, Italy, among 170 diabetic patients illustrates serum triglyceride at a cutoff of 10.52mmol/l (Sensitivity- 80%, Specificity-93.2%), total cholesterol at a cutoff of 9.03mmol/l (Sensitvity-72%, Specificity-91.7%) and low PH, more likely to have AP and DKA together ^[19]. When laboratory evidences fail to differentiate whether it’s an isolated disease or mixed disease, radiological modalities are the feasible resort.  CT is considered gold standard for the diagnosis of AP with a sensitivity of 90%. In our observation all of the three cases have a normal CT picture, that ruled out AP in our cases. However, CT has its own drawbacks; It may be normal within initial 48hrs and may not show any radiological evidence in mild pancreatitis ^[20]. Several studies especially one lead by Yadav, et al. observed that 12 among the DKA study participants, who did not have clinical or radiological features of AP, were found to have significant hyperenzymemia ^[13]. Although, this may be attributed to the proportion of cases that have microscopic pancreatitis and normal CT scan, it may not be considered as per the criteria of AP. As a whole, all significant hyperenzymemia in DKA need not be solely pancreatitis and the cause of hyperenzymemia is still to be explored.

Serum amylases are majorly of two types, divided based upon the origin of production, they are S-Amylase (salivary gland) and P-Amylase (pancreas). Unlike P-Amylase which is exclusively from pancreas, s-amylase although signifies salivary glands, is identified in various tissues like testes, ovary, fallopian tube, lungs, adipose tissue, etc. ^[21]. Similarly, lipases are sourced more than 95% only from pancreas, placing a strong role in pancreatic diseases, even though are also produced in various organs like tongue, stomach, intestines, liver and heart ^{[22, 23]}. Among the pancreatic enzymes synthesized in the acini, less than 1% diffuses via the basilar membrane into the circulation, that represents the utmost percentage of serum levels ^[24]. Nearly 25% of the serum amylases and small proportion of serum lipases are filtered and deactivated by kidneys, while a major proportion is reabsorbed. The reabsorbed enzymes and the circulating enzymes are removed by liver and reticuloendothelial system, although no clear evidences exist ^[22]. Salivary amylases are elevated in disease conditions involving specified organs, where they are synthesized. Various pancreatic and extra-pancreatic causes of hyperenzymeia and the underlying mechanisms are here by ^[22]. 1. Alcohol, drugs, toxins, immediate post ERCP, trauma to pancreas and pancreatitis perse and its related complications such as pancreatic pseudocysts, pancreatic ascites; the mechanism underlying is immoderate release as a result of altered exocytosis or damage to pancreatic acini. 2. Viral hepatitis, cholecystitis, colitis, wherein its additionally secreted in reaction to inflammation involving adjacent organs/structures, 3. Anatomical abnormalities such as choledocholithiasis, choledochocele, pancreaticobiliary junction anomalies, para duodenal diverticula, sphincter of Oddi dysfunction and periampullary tumors, where obstruction of the ductal flow leads to shift of zymogen granules from apical membrane to basilar membrane thereby into systemic circulation, 4. Impaired clearance in renal/hepatic dysfunction/failure ^{[24, 25]}.              

In the diagnosis of AP, the sensitivity of significant elevation of amylase and lipase ranges between 45% to 87% and 64% to 100% respectively, while the specificity in the range of 92% to 99% for both. Besides diagnosis, amylase and lipase do not have any advantage in predicting severity, etiology or mortality ^[23]. When the diagnosis of AP is concerned in a patient of DKA, none of the studies could bring out a strong correlation with pancreatic enzymes ^{[14, 16, 19]}. The reason is probably because both the pathologies are associated with hyperenzymemia independently. Very limited conditions have been reported to cause significant elevation of amylases and lipases. In a systematic review by Ahmer M et al., MEDLINE and EMBASE databases published from 1985 to August 2013 were searched using keywords ‘pancreatitis’, ‘lipase’ ‘amylase’ and ‘diagnoses’ and data of non-pancreatitis causes of significant (>3X) hyperenzymemia were included from 58 studies for analysis. The causes were categorized based on probable pathogenesis such as impaired renal clearance, abdominal, critical illness, drugs, toxins and miscellaneous ^[26]. Amongst, only a very few studies have shown marked elevation (>1000) of both the enzymes similar to our study; 1. Afferent loop obstruction in a patient with status post subtotal gastrectomy and Roux-en Y gastrojejunostomy for post-vagotomy syndrome by brooks. S, et al. ^[27], 2. Macrolipasemia and probable macroamylasemia in a 16year old girl with chronic diarrhea ^[28], 3. Pancreatic type hyperamylasemia, hyperlipasemia in a young female with ruptured ovarian cyst, a case report by Sidhartha Sinha, et al. ^[29], 4. Case of ruptured ectopic pregnancy in a nulliparous woman ^[30], 5. 1^st reported case of simultaneous macrolipasemia and macroamylasemia in a patient with gluten enteropathy by Zaman Z, et al ^[31].

On literature search, only we could find very limited studies of marked hyperenzymemia in DKA without radiological evidences of AP. Rizvi AA, et al. in his series of cases has demonstrated amylase level of 1,024 units/l and lipase of 3,455 units/l in a 72year old female with DKA without AP ^[32]. Similarly, Rathindranath sarkar, et al. in a case of DKA has shown a maximum level of amylase and lipase elevation as 1169IU/dl and 4128IU/dl respectively ^[33]. E.E Nsien, et al. in his case series of three patients with DKA brought out enzymes in thousands, the maximum values recorded was 1026IU/L for amylase and >4000IU/L for lipase ^[34]. A study done between January 1998 and September 1999 at Our Lady of Mercy University Medical Center in 150 DKA episodes had shown 11% to have significant amylase elevation and 10% to have significant lipase elevations. The overall incidence of nonspecific elevation was 24.6% for lipase and 16.6% for amylase. The maximum elevation of lipase observed in the study was 529IU/dl ^[13].  Similar study from the same institute revealed, 21% to have nonspecific hyperamylasemia in DKA and 13% to have significant hyperamylasemia; while, nonspecific hyperlipasemia in 29% and significant hyperlipasemia in 17%. The positive predictive value of amylase and lipase in predicting coexisting AP in the same study was 69% and 52% respectively. The study also showed that enzyme elevation does not correlate with severity; other than predicting severity, indices like RANSONS and CTSI ^[10]. AH Knight in his article on hyperamylasemia and DKA, pointed no increase in mortality ^[35]. M.C. Vantyghem et al. in his case control study with three subsets of cases i.e., DKA, poorly controlled diabetes mellitus and well-controlled diabetes mellitus revealed, hyperenzymemia correlates positively with hyperglycemia and negatively with arterial PH ^[36]. This is in according with Nair, et al (PH: p=0.0001, Glucose: p=0.02).  A study on 31 insulin dependent DKA patients by Fontaine p, et al., exhibited a significant correlation between serum osmolality and hyperamylasemia ^[37]. Similar findings are also observed by Yadav, et al ^[13]. Based on the above correlations, probable mechanisms are put forth: 1. Acidosis induced acinar injury, 2. Covert renal insufficiency leading to poor reabsorption, 3. Release from non-pancreatic sources especially liver and stomach which are much related to DKA.

Abdominal pain is commonly seen in DKA. Co-occurrence of DKA and AP without hypertriglyceridemia is infrequent. Marked hyperenzymemia is rarely found in DKA. Abdominal imaging may be considered in cases with severe, persisting abdominal pain.