Abstract
Many etiologies of acute liver injury (ALI) include drug-induced liver injury (DILI), viral illness, and autoimmune disease. Acute pancreatitis is an uncommon though significant etiology of ALI caused by inflammation, fluid shifts, and ischemia secondary to microthrombi formation that can progress to liver failure if left untreated. We present a case of hypertriglyceridemia-induced pancreatitis resulting in liver injury-associated acute pancreatitis (LIAAP) and a concurrent consumptive coagulopathy consistent with an ischemic hepatopathy. Through treatment of her pancreatitis with intravenous insulin and plasmapheresis and subsequent transition to an oral regimen for her hypertriglyceridemia upon hospital discharge, the patient demonstrated full resolution of her ALI and coagulopathy. Through this case, we hope to highlight the importance of recognizing LIAAP and its underlying pathogenesis.
Keywords: disseminated intravascular coagulation (dic), ischemic hepatopathy, drug-induced liver injury, acute pancreatitis, acute liver injury
Introduction
Acute pancreatitis is an uncommon etiology of acute liver injury (ALI), resulting from excessive activation of a systemic inflammatory response cascade that can result in multi-organ dysfunction [1]. We present a case of a 37-year-old female admitted for hypertriglyceridemia-induced pancreatitis and diabetic ketoacidosis (DKA) in the setting of medication nonadherence. Early into the patient’s admission, she developed a consumptive coagulopathy with markedly elevated transaminases consistent with an ischemic hepatopathy. With proper management of her pancreatitis and DKA, her coagulopathy resolved, and the transaminases normalized rapidly with clinical resolution.
Case presentation
A 37-year-old female with insulin-dependent diabetes mellitus, hypertriglyceridemia, and recurrent pancreatitis presented to the emergency room with several days of mid-epigastric abdominal pain in the setting of medication nonadherence over the previous three weeks (to include her regimen of atorvastatin, fenofibrate, and icosapent ethyl for her hypertriglyceridemia). Following fluid resuscitation, laboratory evaluation confirmed hypertriglyceridemia-induced pancreatitis and DKA. Her initial laboratory evaluation on day 1 of her hospital admission is listed in Table 1 (of note, liver function testing was not obtained on the day of her hospital admission).
Table 1. Laboratory evaluation on day 1 of hospital admission.
cells/mm3 - cells per cubic millimeters; g/dL - grams per deciliter; cells/µL - cells per microliter; mmol/L - millimoles per liter; mg/dL - milligrams per deciliter; mmHg - millimeters of mercury
PT - prothrombin time, PTT - partial thromboplastin time, INR - international normalized ratio
| Parameter | Observed value | Reference range |
| White blood cells | 4.0 cells/mm3 | 3,200-10,800 cells/mm3 |
| Hemoglobin | 14.5 g/dL | 13.1-18.6 g/dL |
| Platelets | 314 cells/µL | 150,000-350,000 cells/µL |
| PT | 13.2 seconds | 12-15 seconds |
| PTT | 26.9 seconds | 25-35 seconds |
| INR | 1.0 | 0.8-1.2 |
| Fibrinogen | 571 mg/dL | 219-482 mg/dL |
| Serum sodium | 130 mmol/L | 136-145 mmol/L |
| Serum potassium | 3.7 mmol/L | 3.5-5.1 mmol/L |
| Serum chloride | 108 mmol/L | 98-107 mmol/L |
| Serum bicarbonate | 6 mmol/L | 21-32 mmol/L |
| Serum urea | 7 mg/dL | 7-18 mg/dL |
| Serum creatinine | 0.4 mg/dL | 0.7-1.3 mg/dL |
| Random blood glucose | 214 mg/dL | 70-100 mg/dL |
| Serum calcium | 7.6 mg/dL | 8.5-10.1 mg/dL |
| Serum phosphorus | <0.7 mg/dL | 2.5-4.9 mg/dL |
| Serum magnesium | 1.3 mg/dL | 1.6-2.6 mg/dL |
| Serum triglycerides | 3,952 mg/dL | 50-199 mg/dL |
| Hemoglobin A1C | 11.6% | 4.8-5.6% |
| Venous blood gas lactic acid | 1.48 mmol/L | 0.9-1.7 mmol/L |
| Venous blood gas pH | 7.24 | 7.31-7.41 |
| Venous blood gas pCO2 | 22.0 mmHg | 41-51 mmHg |
She was subsequently treated with intravenous insulin and plasmapheresis, with rapid symptomatic improvement and resolution of her DKA. However, on day 3 of her admission, she demonstrated a marked ALI and coagulopathy without mental status changes. Her laboratory evaluation obtained on day 3 of her hospital admission is listed in Table 2.
Table 2. Laboratory evaluation on day 3 of hospital admission.
cells/mm3 - cells per cubic millimeters; g/dL - grams per deciliter; cells/µL - cells per microliter; mmol/L - millimoles per liter; mg/dL - milligrams per deciliter; IU/L - international units per liter; mmHg - millimeters of mercury
PT - prothrombin time, PTT - partial thromboplastin time, INR - international normalized ratio
| Parameter | Observed value | Reference range |
| White blood cells | 3.4 cells/mm3 | 3200-10,800 cells/mm3 |
| Hemoglobin | 9.1 g/dL | 13.1-18.6 g/dL |
| Platelets | 32 cells/µL | 150,000-350,000 cells/µL |
| PT | 29.9 seconds | 12-15 seconds |
| PTT | 46.7 seconds | 25-35 seconds |
| INR | 2.9 | 0.8-1.2 |
| Fibrinogen | 166 mg/dL | 219-482 mg/dL |
| Serum sodium | 137 mmol/L | 136-145 mmol/L |
| Serum potassium | 4.1 mmol/L | 3.5-5.1 mmol/L |
| Serum chloride | 109 mmol/L | 98-107 mmol/L |
| Serum bicarbonate | 18 mmol/L | 21-32 mmol/L |
| Serum urea | 3 mg/dL | 7-18 mg/dL |
| Serum creatinine | 0.5 mg/dL | 0.7-1.3 mg/dL |
| Random blood glucose | 178 mg/dL | 70-100 mg/dL |
| Serum calcium | 7.4 mg/dL | 8.5-10.1 mg/dL |
| Serum phosphorus | 2.8 mg/dL | 2.5-4.9 mg/dL |
| Serum magnesium | 2.3 mg/dL | 1.6-2.6 mg/dL |
| Serum total bilirubin | 2.4 mg/dL | 0.15-1.00 mg/dL |
| Serum direct bilirubin | 1.6 mg/dL | 0.2-0.3 mg/dL |
| Serum alkaline phosphatase | 101 IU/L | 40-129 IU/L |
| Serum alanine aminotransferase | 5,308 IU/L | 17-63 IU/L |
| Serum aspartate aminotransferase | >8404 IU/L | 12-39 IU/L |
| Venous blood gas pH | 7.36 | 7.31-7.41 |
| Venous blood gas pCO2 | 34.1 mmHg | 41-51 mmHg |
A thorough workup of her ALI, including abdominal computed tomography (CT), ultrasound imaging, and an autoimmune and infectious laboratory evaluation, were ultimately unremarkable. Outside hospital records from her last hospitalization for pancreatitis approximately six months prior were obtained, and it was noted that a liver biopsy was taken at the time with evidence of lobular hepatocyte injury without fibrosis. Because of this, a decision was made to forego a subsequent liver biopsy, and no direct interventions for the ALI were performed.
After this exhaustive workup, drug-induced liver injury (DILI) and ischemic hepatopathy remained the most likely etiologies. With these possibilities came a clinical dilemma related to the management of her recurrent pancreatitis: how should the lipid-lowering therapy which could at least in rare cases cause liver damage be handled? During her previous episodes, she was presumed to have DILI secondary to her hypertriglyceridemia medication regimen of atorvastatin, fenofibrate, and icosapent ethyl, and discontinued this regimen for a short duration. However, she had intermittent periods of medication compliance over the next several months, with full discontinuation of all her home medications three weeks prior due to gastrointestinal distress.
With continued treatment of her DKA and pancreatitis while inpatient, her transaminases downtrended considerably with near resolution of her coagulopathy by the date of her hospital discharge (day 8). Her laboratory evaluation obtained on day 8 of her hospital admission is listed in Table 3.
Table 3. Laboratory evaluation on day 8 of hospital admission and date of discharge.
cells/mm3 - cells per cubic millimeters; g/dL - grams per deciliter; cells/µL - cells per microliter; mmol/L - millimoles per liter; mg/dL - milligrams per deciliter; IU/L - international units per liter
PT - prothrombin time, PTT - partial thromboplastin time, INR - international normalized ratio
| Parameter | Observed value | Reference range |
| White blood cells | 5.8 cells/mm3 | 3,200-10,800 cells/mm3 |
| Hemoglobin | 9.9 g/dL | 13.1-18.6 g/dL |
| Platelets | 147 cells/µL | 150,000-350,000 cells/µL |
| PT | 13.8 seconds | 12-15 seconds |
| PTT | 32.1 seconds | 25-35 seconds |
| INR | 1.0 | 0.8-1.2 |
| Fibrinogen | 501 mg/dL | 219-482 mg/dL |
| Serum sodium | 138 mmol/L | 136-145 mmol/L |
| Serum potassium | 3.5 mmol/L | 3.5-5.1 mmol/L |
| Serum chloride | 101 mmol/L | 98-107 mmol/L |
| Serum bicarbonate | 28 mmol/L | 21-32 mmol/L |
| Serum urea | 5 mg/dL | 7-18 mg/dL |
| Serum creatinine | 0.4 mg/dL | 0.7-1.3 mg/dL |
| Random blood glucose | 180 mg/dL | 70-100 mg/dL |
| Serum calcium | 9.5 mg/dL | 8.5-10.1 mg/dL |
| Serum phosphorus | 4.0 mg/dL | 2.5-4.9 mg/dL |
| Serum magnesium | 2.0 mg/dL | 1.6-2.6 mg/dL |
| Serum total bilirubin | 1.18 mg/dL | 0.15-1.00 mg/dL |
| Serum alkaline phosphatase | 172 IU/L | 40-129 IU/L |
| Serum alanine aminotransferase | 1,630 IU/L | 17-63 IU/L |
| Serum aspartate aminotransferase | 70 IU/L | 12-39 IU/L |
| Serum triglycerides | 264 mg/dL | 50-199 mg/dL |
She was subsequently discharged to home with her previous home regimen of atorvastatin, fenofibrate, and icosapent ethyl for her hypertriglyceridemia, along with her previous home insulin regimen and close follow-up with an endocrinologist. At her gastroenterology outpatient follow-up appointment two weeks later, repeat complete blood count and liver function testing demonstrated near total resolution of her ALI and coagulopathy, with her laboratory evaluation listed in Table 4.
Table 4. Laboratory evaluation two weeks after hospital discharge.
cells/mm3 - cells per cubic millimeters; g/dL - grams per deciliter; cells/µL - cells per microliter; mmol/L - millimoles per liter; mg/dL - milligrams per deciliter; IU/L - international units per liter
PT - prothrombin time, INR - international normalized ratio
| Parameter | Observed value | Reference range |
| White blood cells | 6.3 cells/mm3 | 3,200-10,800 cells/mm3 |
| Hemoglobin | 11.3 g/dL | 13.1-18.6 g/dL |
| Platelets | 411 cells/µL | 150,000-350,000 cells/µL |
| PT | 13.4 seconds | 12-15 seconds |
| INR | 1.0 | 0.8-1.2 |
| Serum sodium | 140 mmol/L | 136-145 mmol/L |
| Serum potassium | 3.7 mmol/L | 3.5-5.1 mmol/L |
| Serum chloride | 103 mmol/L | 98-107 mmol/L |
| Serum bicarbonate | 27 mmol/L | 21-32 mmol/L |
| Serum urea | 16 mg/dL | 7-18 mg/dL |
| Serum creatinine | 0.5 mg/dL | 0.7-1.3 mg/dL |
| Random blood glucose | 207 mg/dL | 70-100 mg/dL |
| Serum calcium | 10.3 mg/dL | 8.5-10.1 mg/dL |
| Serum phosphorus | 3.3 mg/dL | 2.5-4.9 mg/dL |
| Serum magnesium | 1.6 mg/dL | 1.6-2.6 mg/dL |
| Serum total bilirubin | 0.63 mg/dL | 0.15-1.00 mg/dL |
| Serum direct bilirubin | 0.3 mg/dL | 0.2-0.3 mg/dL |
| Serum alkaline phosphatase | 78 IU/L | 40-129 IU/L |
| Serum alanine aminotransferase | 97 IU/L | 17-63 IU/L |
| Serum aspartate aminotransferase | 36 IU/L | 12-39 IU/L |
| Serum triglycerides | 158 mg/dL | 50-199 mg/dL |
Given the clinical and near total laboratory resolution with continued medication compliance, her initial presentation ultimately suggested an ALI secondary to a transient ischemic hepatopathy caused by her acute pancreatitis.
Discussion
Acute pancreatitis is a common medical condition often requiring hospitalization with simple fluid resuscitation, pain control, and bowel rest. However, delayed or inadequate treatment can result in severe acute pancreatitis, which can result in multiple organ failures, including liver injury-associated acute pancreatitis (LIAAP) and subsequent liver failure [2].
Though the exact mechanism of LIAAP is not clearly defined, it is theorized that excessive activation of a systemic inflammatory response cascade leads to liver ischemia due to an acute decrease in liver perfusion [1,3]. In the pathophysiology of acute pancreatitis, activated digestive enzymes induce neutrophils to release inflammatory factors which can result in multiple organ dysfunction [4]. It is believed that increased activation of tumor necrosis factor-α results in the activation of neutrophils and subsequent release of IL-1, IL-6, IL-8, and other cytokines contributing to the inflammatory state leading to hepatocellular injury [5]. Given its proximity to the pancreas, the liver is often the first extrapancreatic organ attacked by these inflammatory mediators.
In addition, acute pancreatitis can result in low blood volume caused by this proinflammatory state [6]. In acute pancreatitis, there is typically a 50% decrease in portal venous blood flow [7]. This marked drop in volume results in subsequent poor liver perfusion, clinically manifesting in ALI and possible progression to acute liver failure [8].
The treatment of LIAAP is the first and foremost treatment of the underlying acute pancreatitis. Typical treatment includes fluid resuscitation, which helps to further increase portal venous blood flow that was previously reduced due to inflammatory mediators [9]. In addition, it is essential to provide adequate pain control and bowel rest, along with a slow addition of nutritional supplementation [10].
Several clinical features can assist in distinguishing LIAAP from DILI. As in our patient, the swift downtrend of her transaminases with the treatment of her pancreatitis, along with her laboratory values notable for hypophosphatemia, hyperglycemia, and a coagulopathy consistent with a mild disseminated intravascular coagulation presentation, all suggest an ischemic etiology [11].
Conclusions
Though acute pancreatitis is a common presentation in the inpatient hospital setting, it is important to recognize this disease process as a possible cause of ALI and acute liver failure. Additionally, one should consider an ischemic hepatopathy etiology in patients admitted for acute pancreatitis who demonstrate an ALI with consumptive coagulopathy. With this case, we hope to highlight the importance of monitoring for liver organ dysfunction in acute pancreatitis and its underlying pathogenesis.
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Logan Oliver, Chuchu Liu, Brett Sadowski
Acquisition, analysis, or interpretation of data: Logan Oliver, Chuchu Liu, Brett Sadowski
Drafting of the manuscript: Logan Oliver, Chuchu Liu, Brett Sadowski
Critical review of the manuscript for important intellectual content: Logan Oliver, Chuchu Liu, Brett Sadowski
References
- 1.Liver injury associated with acute pancreatitis: the current status of clinical evaluation and involved mechanisms. Liu W, Du JJ, Li ZH, Zhang XY, Zuo HD. World J Clin Cases. 2021;9:10418–10429. doi: 10.12998/wjcc.v9.i34.10418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Severe acute pancreatitis: surgical indications and treatment. Heckler M, Hackert T, Hu K, Halloran CM, Büchler MW, Neoptolemos JP. Langenbecks Arch Surg. 2021;406:521–535. doi: 10.1007/s00423-020-01944-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hepatic perfusion changes in an experimental model of acute pancreatitis: evaluation by perfusion CT. Tutcu S, Serter S, Kaya Y, Kara E, Neşe N, Pekindil G, Coşkun T. Eur J Radiol. 2010;75:203–206. doi: 10.1016/j.ejrad.2009.04.072. [DOI] [PubMed] [Google Scholar]
- 4.Central role of neutrophil in the pathogenesis of severe acute pancreatitis. Yang ZW, Meng XX, Xu P. J Cell Mol Med. 2015;19:2513–2520. doi: 10.1111/jcmm.12639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-Kappa B. Murr MM, Yang J, Fier A, Kaylor P, Mastorides S, Norman JG. J Gastrointest Surg. 2002;6:474–480. doi: 10.1016/s1091-255x(01)00071-3. [DOI] [PubMed] [Google Scholar]
- 6.Fluid resuscitation in acute pancreatitis. Gardner TB, Vege SS, Pearson RK, Chari ST. Clin Gastroenterol Hepatol. 2008;6:1070–1076. doi: 10.1016/j.cgh.2008.05.005. [DOI] [PubMed] [Google Scholar]
- 7.Splanchnic tissue perfusion in acute experimental pancreatitis. Juvonen PO, Tenhunen JJ, Heino AA, Merasto M, Paajanen HE, Alhava EM, Takala JA. Scand J Gastroenterol. 1999;34:308–314. doi: 10.1080/00365529950173744. [DOI] [PubMed] [Google Scholar]
- 8.Multiple organ dysfunction associated with severe acute pancreatitis. Halonen KI, Pettilä V, Leppäniemi AK, Kemppainen EA, Puolakkainen PA, Haapiainen RK. Crit Care Med. 2002;30:1274–1279. doi: 10.1097/00003246-200206000-00019. [DOI] [PubMed] [Google Scholar]
- 9.Management of severe acute pancreatitis. Lee PJ, Papachristou GI. Curr Treat Options Gastroenterol. 2020;18:670–681. doi: 10.1007/s11938-020-00322-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Nutrition management in acute pancreatitis: clinical practice consideration. Lakananurak N, Gramlich L. World J Clin Cases. 2020;8:1561–1573. doi: 10.12998/wjcc.v8.i9.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Levi M, Toh CH, Thachil J, Watson HG. Br J Haematol. 2009;145:24–33. doi: 10.1111/j.1365-2141.2009.07600.x. [DOI] [PubMed] [Google Scholar]