Acute painless pancreatitis as an unusual presentation of leptospirosis in a low-incidence country

Abstract

A healthy, urban-dwelling man presented with lassitude, jaundice without increased liver enzymes or obstructive features on imaging, brief acute kidney injury, leucocytosis with near-normal C reactive protein and markedly increased serum amylase and lipase. Leptospirosis was not considered for 10 days because of the low incidence of the disease in the country, absent animal contact and physicians’ low index of suspicion. Presentation without fever and without the commonly associated abdominal pain, myalgia, headache, thrombocytopaenia or elevated serum creatine kinase added to the diagnostic challenge. Once an infectious cause of acute pancreatitis was contemplated, leptospirosis was immediately sought and diagnosed by PCR of urine and microscopic agglutination test, and he fully recovered on ceftriaxone. Physicians in countries with a low incidence of leptospirosis should be more aware of the possibility of the disease even when several key features such as fever or pain are missing and the patient has a rare infectious acute pancreatitis.

Background

Leptospirosis is caused by spirochete of the Leptospira genus, infecting many animals such as rodents, cattle and dogs that secrete the micro-organisms in their urine and transmit them to humans by direct contact or contact with contaminated water through abrasions of the skin or mucous membranes.¹ Leptospirosis is the most important zoonosis worldwide, being endemic in many tropical areas such as South East Asia, India or Brazil where a considerable burden of disease is being reported each year, and physicians are well aware of the disease and its protean manifestations. However, patients with leptospirosis can be encountered anywhere,^2–4 but the relative rarity of leptospirosis in highly developed temperate areas and its highly heterogeneous presentation increase the risk of a potentially dangerous delay in diagnosis. Thus, in low-incident countries, most cases are diagnosed in patients with travels to endemic areas. An especially high index of suspicion is required, and this is particularly true when a patient presents without travel and with few symptoms (eg, afebrile and painless) or a prominent unusual presenting manifestation (eg, acute pancreatitis) as we report to enhance the likelihood of a timely diagnosis in an atypical setting.

Case presentation

A healthy 63-year-old man was admitted with lassitude and jaundice. He presented to his primary physician 2 days prior complaining of extreme lassitude and fatigue without fever or pain of any kind and was referred when noted to be jaundiced.

He had always been healthy, lived in an urban environment on the second floor, worked as a caregiver for elderly people and did not take medications, smoke or abuse alcohol. There was no history of travel or animal contact of any kind. Sexual history was unremarkable.

On admission, he was comfortable, and vital signs were normal. Over the next week in hospital, out of 28 recordings, very few occasional temperatures of 37.6°C–37.7°C were noted. Examination revealed deep jaundice and nothing more. Chest X-ray and ECG were normal. In contrast, laboratory tests demonstrated a mild microcytic anaemia of inflammatory disease: Haemoglobin 12.6 g/dL (N 13.8–17.2), mean corpuscular volume (MCV) 73 fL (N 80–98), ferritin 515 mg/dL (N 20–323); marked neutrophilic leucocytosis (white cell count (WCC) 23.3×10⁹/L, N 3.8–9.8), and normal platelets (201×10⁹/L, N 140–440). C-reactive protein (CRP) was 43.4 mg/dL (N 0–5), fasting glucose 128 mg/dL (N 65–100), total/direct bilirubin 21.9/13.1 mg/dL (N total 0.3–1.1), with hepatocellular and cholestatic enzymes barely exceeding the upper limit of normal (transaminases 42–61 IU/L, N<41; alkaline phosphatase 138, N<130; GGT 31, N<61). Serum amylase was 428 IU/L (N<100) associated with lipase 373 IU/L (N<60), hypocalcaemia of 7.0 mg/dL (corrected for albumin, N 8.8–10.2 mg/dL), hypoalbuminaemia 2.6 g/dL (N 3.6–5.0), polyclonal hyperglobulinaemia 4.5 g/dL (N 2.9–3.5) and normal prothrombin time (13 sec, 100%). Serum creatine kinase was normal throughout (≤58 IU/L). In addition, non-oliguric acute kidney injury (AKI) was found: Blood urea nitrogen (BUN) 102 mg/dL (N≤23), creatinine 3.8 mg/dL (N≤1.2), phosphorus 3.4 mg/dL (N 2.5–4.5), potassium 3.3 mEq/L (N 3.5–5.3) and urinalysis showing just trace protein, trace red blood cells (rbc), no white blood cells (WBC) and positive bilirubin and urobilinogen.

Investigations

Serology tests for acute hepatitis viruses, herpesviruses, HIV, brucella, ricketsiae and Q fever were negative as were blood and urine cultures. Abdominal ultrasound showed no hepatomegaly or splenomegaly, no pancreatico-biliary abnormality and no ascites or lymphadenopathy. Fatty liver was noted. Abdominal CT confirmed absence of biliary duct dilatation and revealed mild fat standing in the lesser omentum and pancreas (figures 1 and 2) with no other pathology.

Figure 1.

Axial image from a contrast-enhanced abdominal CT study scanned during the portal phase, showing non-enlarged, homogeneously enhancing liver and spleen. The intrahepatic and extrahepatic bile ducts (the latter not shown) are not dilated. A mild fat stranding in the lesser omentum was demonstrated (long arrow) supporting acute interstitial oedematous pancreatitis without tissue necrosis.

Figure 2.

Coronal oblique reformation from the same study showing the uncinate process, head and part of the body of a normal-appearing pancreas (stars) with very mild peripancreatic fat stranding. D, duodenum.

Differential diagnosis

The differential diagnosis of combined jaundice and an AKI is presented in box 1.

Box 1. The differential diagnosis of combined jaundice and an acute kidney injury.

• Sepsis syndrome and hypoperfusion states.

• Drug-induced hepato-nephrotoxicity, adverse drug event (including herb intoxication).

• Acute haemolytic crisis (increased bilirubin production: unconjugated hyperbilirubinaemia).

• Obstructive jaundice, severe.

• Acute pancreatitis.

• Cirrhosis of the liver, advanced (‘hepatorenal syndrome’).

• Heart failure, severe.

• Tuberculosis, extrapulmonary (uncommon; eg, constrictive pericarditis, hepatobiliary and urogenital disease).

• Sarcoidosis (rare).

• Brucellosis (hepatic+genitourinary involvement).

• Ricketsial infection (azotemia common and jaundice rare).

• Q fever (both jaundice and associated glomerulonephritis are rare).

• Leptospirosis.

Sepsis is arguably the most common aetiology for the combination of jaundice and AKI. As many as a third of the patients develop jaundice (often later in the course than hypoxic hepatitis),⁵ and prerenal AKI is of course exceedingly common in sepsis. However, our patient never had hypotension, all cultures were negative and he was afebrile with low CRP values and no support for specific infections or infiltrative diseases mentioned above (Box 1, nos. 8–12). Drug-induced toxicity can also account for hepato-nephrotoxicity,^{6 7} but our patient was previously healthy with no drug exposure. The bilirubinaemia was primarily direct, and Hb was stable ruling out haemolysis. Severe obstructive jaundice can impair tubular function due to bile casts, but our patient had no obstruction on imaging, and his bilirubin levels were lower than usually encountered in the so-called ‘cholemic nephropathy’ syndrome.⁸ Likewise, there was no evidence of either cirrhosis or heart failure. He did have laboratory features of an acute pancreatitis (hyperamylasaemia, hyperlipasaemia and hypocalcaemia), but this was hardly severe enough to account for the combined jaundice and AKI.

While further imaging (magnetic resonance cholangiopancreatography - MRCP) of the pancreas was being planned, two remarkable things happened. First, the patient felt completely healthy, and on hospital day 8, WCC was down to 12.1×10⁹/L, creatinine 1.3 mg/dL (later 0.9) and CRP 11.2 (later 2.4). Only pancreatic enzymes persisted with associated hypocalcaemia and globulinaemia, and reactive thrombocytosis developed (platelets 536×10⁹/L). Second, a consultant (EN), who saw him briefly in the department of surgery where he was first admitted, remembered that he had been treated empirically with ceftriaxone for 4 days when jaundice was still felt to be due to pancreatico-biliary obstruction/infection. He was then transferred (untreated) to our department of medicine. The possibility of an ‘antibiotic-responsive disease’ and a review of the infectious causes of acute pancreatitis (Box 2) in the context of the patient’s jaundice and AKI strongly suggested leptospirosis (synonym, Weil’s disease), even in the absence of the characteristic bleeding manifestations ranging from conjunctival suffusion to haematuria, gastrointestinal bleed and ominous pulmonary haemorrhage.^{3 9}

Box 2. Infectious causes of acute pancreatitis**.

Viral (most common infectious aetiology).

Mumps virus.

Hepatitis B virus.

Hepatitis A virus.

Hepatitis C virus (rare without treatment).

Hepatitis E virus.

Coxackie virus, type B.

Cytomegalovirus.

Epstein-Barr virus (rare).

Herpes simplex virus.

Varicella-Zoster virus.

Influenza virus (H1N1) (rare).

HIV.

Enterovirus 71 (E71) (rare).

Covid-19.

Bacterial.

Mycoplasma.

Legionella.

Leptospira.

Salmonella.

Campylobacter (rare).

Nocardia (rare).

Parasitic.

Toxoplasma.

Cryptosporidium.

Ascaris.

Fungal.

Aspergillus.

Candida albicans (rare).

**Infections are considered among the relatively rare causes of acute pancreatitis.²⁷

The urine tested positive for leptospira in PCR and microscopic agglutination test (MAT) at the national reference laboratory was strongly positive as well (titre 6400 for L. Sejreo Bratislava).^{10 11}

Treatment

Treatment with intravenous ceftriaxone was continued for 7 days.¹¹

Outcome and follow-up

The patient was discharged asymptomatic, with near-normal blood tests that entirely normalised on a follow-up visit 1 month later.

Discussion

Leptospirosis in many low-incidence countries is seldom encountered, and physicians’ personal experience and index of suspicion may therefore be low. For example, in Israel, no more than 5–10 cases of leptospirosis are diagnosed each year per a population of 9 million people,¹² and in Scotland, a mere 14 patients were found in one institution over a 10-year period.¹³ Even in tropical climate countries where the disease is endemic (eg, India and Thailand), early diagnosis remains a challenge due to the highly variable and non-specific symptoms of leptospirosis.¹⁴ In non-endemic, low-incidence countries in particular, a significant diagnostic delay may occur, endangering the patient, since mortality had been reported.¹⁵ Our report aims to increase physician awareness of atypical features in the presentation of leptospirosis, many of them existed in our patient, mandating an ‘out of the box’ approach: when there are clinical, laboratory and imaging discrepancies in the patient’s presenting features, other competing aetiologies or pathologies that can explain the whole picture should be researched, preferably by study of the medical literature

In leptospirosis, fever and pain are the sine qua non of diagnosis. When we combined two large retrospective series of patients (n=387), 99.2% had fever which was very often >39°C. In addition, myalgia (88%), headache (87%), abdominal pain (51%) and arthralgia (57%) were highly prevalent, so that their combined absence seems to very significantly lower the probability of leptospirosis.^{15 16} When the atypical laboratory features of our patient are added (no thrombocytopaenia, no abnormal liver enzymes, bland urinalysis without significant haematuria or proteinuria, reported to occur in 69%, 76% and 70%, of the patients, respectively), the delay of >1 week in establishing the diagnosis can be better understood. To this must be added the low incidence in Israel (≤1 case per million, similar to the data from the US of 0.7 hospitalisations/1 000 000 adults)^{12 17} and the urban dwelling of the patient with absence of any occupational, household or recreational exposure to animals or their urine. Thus, our patient demonstrates the potential of leptospirosis to present with a striking paucisymptomatic and atypical form. It is the combined jaundice and AKI on admission that could have led to a more timely diagnosis, even if the AKI resolved almost at once, since the differential is quite narrow (Box 1).

Gastrointestinal symptoms are very common in leptospirosis on presentation, including anorexia, nausea, vomiting, diarrhoea and abdominal pain, often associated with hepatomegaly (~33%) and splenomegaly (~10%).¹⁵ Our patient had none of those, and in fact, we were all amazed to watch him eating heartily despite marked jaundice. However, notwithstanding his benign look, he was suffering from acute pancreatitis, a reported but rare manifestation of leptospirosis,¹⁸ not mentioned in the study of 353 cases.¹⁵ Nevertheless, after discounting hyperamylasaemia reflecting decreased renal clearance of amylase as part of the AKI (severe and requiring dialysis in 8% of the icterohaemorrhagic cases),¹⁵ acute pancreatitis had been reported in approximately 30 patients with leptospirosis, mostly in isolated case reports.^19–21 The clinical features of these patients were essentially similar to those without pancreatitis, though several features recur. First, most patients have significant abdominal pain, even acute abdomen on presentation.¹⁹ Associated high fever, myalgia often signifying rhabdomyolysis²⁰ and frequent conjunctival suffusion (hyperaemia) can be useful clues to the possible diagnosis of leptospirosis, as is the concurrent hypokalaemia often detected even in the presence of AKI.²² Second, although fatalities do occur, the pancreatitis is oedematous and self-limited in most patients. Third, in many reports (and in our patient), the course of pancreatitis may be prolonged, persisting even after AKI and jaundice resolved.²¹ Fourth, acalculous cholecystitis may be associated, though uncommonly.²³

Our patient’s pancreatitis was afebrile, painless and asymptomatic, an exceedingly rare feature. Yet he had markedly elevated pancreatic enzymes (up to six times the upper limit of normal) but neither organ failure (excluding the associated AKI which in this case has an alternative explanation) nor complications. Thus, according to the revised Atlanta classification system, he had interstitial oedematous acute pancreatitis of mild severity.²⁴ The pathogenesis of pancreatitis in leptospirosis remains largely unknown. In infected dogs, where as many as 50% develop pancreatitis associated with liver or kidney involvement, or both, the major histological finding is the striking divergence between the severity of clinical illness and the subtlety of histological changes.²⁵ In humans, this is reflected by the typical discrepancy between the high plasma bilirubin concentration and the almost normal transaminase levels, also seen in our patient. Renal injury is complex and multifactorial,²² with leptospira-triggered interstitial nephritis and a varying degree of acute tubular necrosis mediated by hypotension and rhabdomyolysis.²² A single study of the histology of pancreatic involvement in several cases of fatal human leptospirosis reported pancreatic alterations that ranged from a mild inflammatory infiltrate to moderate fat necrosis with haemorrhagic findings.²⁶ Pancreatic oedema with mild lymphocytic infiltrate were the most common finding.²⁴ Toll-like receptor 2 activation by leptospiral antigens may have a central role in the inflammation.^{9 27 28} Vasculitis of small vessels, endothelial damage and ischaemiae, similar to observations in other tissues of patients with leptospirosis,²⁰ can initiate the release of intracellular proteolytic enzymes and trigger acute pancreatitis.

In conclusion, a few sporadic cases of leptospirosis do occur even in countries of low incidence of the disease and are either locally acquired or imported by travellers.¹⁴ Physicians who may never have encountered such a patient need to consider this diagnosis, particularly in the context of patients with otherwise unexplained jaundice, AKI and pancreatitis (in any combination) regardless of the presence of fever or associated pain.

Patient’s perspective.

Thank G-d and thanks to you I am well and home again. I soon felt so much better. I could not understand why they were taking so much blood and keeping me in hospital when all I wanted is to go home. Then I felt like I was disappointing them, but I never touched an animal, did not travel and have had no skin cuts or wounds to speak of…

Learning points.

• When there are clinical, laboratory and imaging discrepancies in the patient’s presenting features, other competing aetiologies or pathologies that can explain the whole picture should be researched.

• Physicians in low-incidence countries should become more cognizant of leptospirosis, an emerging zoonotic disease that may present in many variable forms.

• Acute (infectious) pancreatitis may constitute a rare presentation of leptospirosis, usually in combination with jaundice, or an acute kidney injury, or both, in patients who may be afebrile and painless.

• Detection of leptospira in the urine by PCR is a rapid, sensitive diagnostic test, and 1 week of parenteral ceftriaxone constitutes an effective treatment.