Serial lipase measurements in pancreatic panniculitis

Abstract

Pancreatic panniculitis is a rare cutaneous manifestation of pancreatic disease with only scant case reports available to guide management. In this report, a woman in her 60s developed a painful, erythematous and indurated, nodular rash after an episode of acute pancreatitis postendoscopic retrograde cholangiopancreatography (ERCP). While clinically and radiologically the pancreatitis improved with standard conservative management, the panniculitis remained severely debilitating. Repeat testing of serum pancreatic enzymes revealed persistent and marked elevation. Octreotide was started to inhibit pancreatic enzyme release, and the lesions improved, with resolution of the panniculitis correlating with falling serum pancreatic enzyme levels. Hence, serial pancreatic enzyme testing may have utility in monitoring and management of pancreatic panniculitis.

Background

Pancreatic panniculitis is a rare cutaneous manifestation of pancreatic disease, presenting as a painful, indurated and erythematous nodular rash, most commonly affecting the lower limbs but may also involve the buttocks, trunk and upper limbs.^{1 2} The lesions are often exquisitely tender and may spontaneously ulcerate, releasing a brown viscous exudate. The incidence is estimated between 0.3% and 3% of patients with pancreatic disease, of which it has been associated with both acute and chronic pancreatitis, pancreas divisum, pancreatic pseudocyst and pancreatic carcinoma.^2–6

The pathophysiology of the condition is poorly understood; however, a popular theory implicates systemically circulating pancreatic enzymes as drivers of the panniculitis, entering subcutaneous tissue and inducing fat necrosis. Indeed, evidence of lipase in biopsy specimens of the skin lesions, along with antilipase monoclonal antibodies, supports this theory.⁶ Furthermore, a handful of case reports describe improvement of the panniculitis with the administration of octreotide, a somatostatin analogue that inhibits pancreatic exocrine enzyme release.4 5 7–9

Fat necrosis as a complication from pancreatic disease may not only affect the skin but can also occur within periarticular and intramedullary adipose tissue, manifesting clinically as arthritis. The triad of pancreatitis, panniculitis and polyarthritis is known collectively as PPP syndrome—a rare syndrome with higher morbidity and mortality than pancreatic panniculitis alone.¹⁰

Due to its rarity and with less than 150 published cases, the diagnosis of pancreatic panniculitis is often missed or significantly delayed.¹¹ As such, this case report aims to highlight the features of the condition and equip clinicians with strategies to recognise and manage this debilitating rash.

Case presentation

An active woman in her 60s presented to the emergency department complaining of severe abdominal pain, nausea and subjective fevers, 3 days following endoscopic retrograde cholangiopancreatography (ERCP). Examination revealed a distressed febrile patient, with a tense and distended abdomen. Her medical history was remarkable for type 1 diabetes mellitus, which was well managed, and she was otherwise fit and well. There was no relevant family history.

Biochemical investigation on admission demonstrated raised inflammatory markers and an elevated lipase of 336 U/L (reference range 10–60 U/L). Blood cultures were taken due to concerns of intra-abdominal sepsis, with growth of both Klebsiella oxytoca and Streptococcus anginosus. A venous phase contrast-enhanced CT abdomen revealed a diffusely oedematous pancreas, complicated by a gas-containing and fluid-containing collection in the pancreatic head—findings suggestive of disconnected duct syndrome in the setting of ongoing pancreatitis. The patient was admitted to the general surgical team for the management of pancreatitis complicated by a pancreatic collection and intra-abdominal sepsis, receiving intravenous antibiotics and crystalloid fluid therapy.

One week into the admission, the patient developed bilateral nodular lesions in her legs—starting as simple red nodules and progressing to well-demarcated, indurated, and erythematous plaques (see figure 1). The nodules were painful and exquisitely tender; indeed nodules that developed on the sole of the foot made it near impossible for the patient to walk without significant pain. The lesions gradually spread up the buttocks and onto the trunk, with scant minor nodules eventually in the arms. Over time some lesions ulcerated, releasing a brown viscous exudate.

Figure 1.

Pancreatic panniculitis on lower limbs.

Dermatology specialists were consulted with the query of a drug-induced erythema nodosum, perhaps secondary to the recently started antibiotics, and they were the first to introduce the prospect of pancreatic panniculitis.

Investigations

The lesions were biopsied where histopathology revealed features of lobular panniculitis with fat necrosis within the subcutaneous tissue—findings compatible with pancreatic panniculitis (see figure 2). On H&E stain ‘Ghost cells’, consisting of anucleate necrotic adipocytes with shadowy walls, are observed and are pathognomonic on skin biopsy.^{6 12} The brown exudate from the lesions was consistently sterile when cultured.

Figure 2.

H&E stain from leg lesion biopsy ×40 (left) and ×100 (right).

Now 2 weeks into the admission, repeat lipase and amylase levels were requested and grossly elevated at 10 155 U/L (reference range 10–60 U/L) and 4535 U/L (reference range 27–100 U/L), respectively. Repeat CT abdomen was organised and reported the peripancreatic inflammation and original collection of the pancreatic head to be mostly resolved.

Differential diagnosis

Among the many differential diagnoses to consider for an erythematous, indurated and nodular rash are the panniculitides, vasculitis, atypical infection and neoplasia. Erythema nodosum is the the most common form of panniculitis, which itself has an extensive list of infective, medication-related, inflammatory and malignancy-related associations. Erythema induratum, lupus panniculitis, traumatic panniculitis, infectious panniculitis and α1-antitrypsin deficiency panniculitis are also conditions that can mimic pancreatic panniculitis. With a breadth of differentials as such, comprehensive clinical examination and skin biopsy of the lesions are imperative—and indeed was key to the diagnosis of pancreatic panniculitis.

Treatment

With no radiological evidence of ongoing pancreatitis or pancreatic collection, and clinically a soft, non-tender abdomen, management remained supportive and non-operative, with intravenous crystalloid fluid therapy, antibiotics and nutrition optimisation. The lesions did not improve and remained incredibly painful and tender. Betamethasone diproprionate 0.05% ointment was applied topically three times per day, which the patient reported provided minor relief; however, it did not appear to improve disease progression objectively.

After a further 5 days, pancreatic enzymes were tested again and as high as previously with a lipase of 11 039 U/L (reference range 10–60 U/L) and amylase of 4716 U/L (reference range 27–100 U/L).

To target the persistent lipasaemia, octreotide, a somatostatin analogue and potent inhibitor of pancreatic enzyme release, was administered subcutaneously, at a dose of 100 mg three times per day. Over the next week, the lesions began to improve with regard to the level of erythema, induration, pain and tenderness. Most notably, the improvement appeared to correlate with decreasing levels of serum pancreatic enzymes, lipase halving to 5760 U/L a week after starting octreotide (see figure 3). The lesions continued to improve both objectively on examination and subjectively in patient comfort, and lipase continues to drop, down to 838 U/L when retested again a week later (see figure 4).

Figure 3.

Left leg after 1 week of octreotide.

Figure 4.

Left leg after 2 weeks of octreotide.

Outcome and follow-up

The patient remained on octreotide until serum lipase levels were within normal limits, a total of 3 weeks. This coincided with the resolution of the skin lesions, and the patient was pain-free and able to mobilise comfortably. There was residual hyperpigmentation and minor scaring of skin in some affected areas; however, they were no longer painful, indurated or tender. The patient did not experience any adverse effects from octreotide administration. With the restoration of baseline levels of function and mobility, of which she was independent of both, the patient was discharged home with follow-up with primary care in a week and with general surgery after 4 weeks. There was no reoccurrence of pancreatic disease or pancreatic panniculitis.

Discussion

Pancreatic panniculitis is a rare cutaneous manifestation of pancreatic disease, presenting as a painful, indurated and erythematous nodular rash. Its rarity often means the diagnosis is missed or significantly delayed.¹¹ Indeed, for this case report, uncertainty in the diagnosis and optimal management strategy contributed to prolonged hospitalisation and increased morbidity—with painful lesions on the patient’s soles severely impacting mobility. The cornerstone of management involves directed treatment of the underlying pancreatic pathology, and indeed most case reports describe the resolution of the rash through this approach.² However, this case is unique for a persistent and debilitating rash, despite resolution of the pancreatitis clinically and radiologically, raising the discussion of how best to manage the condition if this arises, and extended to circumstances where the underlying cause is not entirely curable.

While the pathophysiology of the condition is poorly understood, our experience with this patient suggests systemically circulating pancreatic enzymes as drivers of the panniculitis. An important feature of the case was the direct correlation between serum pancreatic enzyme levels and regression of the panniculitis (see figure 5). Serial lipase and amylase levels were not initially part of the management plan, a conscious decision by the treating team guided by the paucity of evidence for serial testing of pancreatic enzymes in the management of pancreatitis—an unnecessary cost to the healthcare system with no appreciable impact on prognosis or outcome.^{13 14} However, for patients presenting with pancreatic panniculitis, serial testing of serum pancreatic enzymes appears useful in identifying potential drivers behind the ongoing panniculitis—levels which in this case remained elevated despite 2 weeks of standard acute pancreatitis management and both clinical and radiological resolution of the pancreatitis. Therefore, while the evidence for serial pancreatic enzyme testing in pancreatitis is scarce, we hope clinicians identify pancreatic panniculitis as a separate entity, where the monitoring of elevated pancreatic enzymes and recognising lipasaemia as a contributing factor may be useful in guiding management and reducing patient morbidity.

Figure 5.

Left leg progression against serum pancreatic enzyme levels.

There is growing evidence to support the use of octreotide in PPP syndrome.4 5 7–9 A published literature review including 112 case reports of pancreatic panniculitis found 98.2% of cases had elevated serum pancreatic enzymes.² While the exact mechanism driving the panniculitis remains unknown, this association alongside histological findings of lipase and antilipase monoclonal antibodies in biopsies of the lesions suggests its implication. Indeed, case reports of pancreatic panniculitis in the setting of unresectable or metastatic pancreatic cancer describe symptomatic relief and resolution of the panniculitis with octreotide administration, a potent inhibitor of exocrine pancreatic function.4 5 7–9 It is important to acknowledge, however, that the primary management strategy for pancreatic panniculitis is to treat the underlying pancreatic pathology. Resolution of the pancreatic disease in turn will reduce pancreatic enzyme release and most often facilitates resolution of the panniculitis. There may still be a role of octreotide in augmenting the reduction of circulating pancreatic enzymes for additional symptom relief, concurrent with management of the underlying pancreatic pathology—however, more research is required to determine whether this would produce a meaningful reduction in morbidity as an adjunct therapy.

Learning points.

• For patients presenting with a painful, erythematous and indurated nodular rash affecting the lower limbs, buttocks or trunk, consider pancreatic panniculitis and underlying pancreatic pathology.

• Serum pancreatic enzyme levels appear to correlate with disease severity and hence may have utility in the monitoring and management of pancreatic panniculitis.

• Management should be directed towards the underlying pancreatic pathology, which in turn will reduce pancreatic enzyme release and most often facilitates the resolution of the panniculitis.

• Octreotide may be useful in the management of pancreatic panniculitis via inhibition of pancreatic exocrine enzyme release, particularly in patients with persistently elevated serum enzymes.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).