An Unexpected Cause of Raised Procalcitonin

Procalcitonin is well known as a relatively specific biomarker for bacterial sepsis. Therefore, when its level is elevated, the immediate response by the treating team is to initiate antibiotics and look for possible sources of infection. Our patient was admitted with acetaminophen overdose and had no signs and symptoms of infection but had an extremely high level of procalcitonin usually seen in cases of overwhelming sepsis. This led us to consider other rare causes that may cause such high levels of procalcitonin and we found that acetaminophen overdose was one of them.

This is only the sixth reported case till date of acetaminophen overdose with high procalcitonin levels. The level of procalcitonin of 97 ng/mL is the highest among all the cases reported so far. The postulated mechanisms behind this rise of procalcitonin and its relation to the dose of acetaminophen and the degree of liver injury is worth examining. It is also worthwhile to note that a noninfectious etiology can cause such a significant increase in a biomarker considered to be specific for bacterial sepsis.

A 28-year-old previously healthy female was admitted as a case of acetaminophen overdose. She gave a history of consuming 36 tablets of 500 mg acetaminophen (total 18 g) after an altercation with her husband, 2 days prior to presentation to hospital. The patient denied alcohol consumption or co-ingestion of any other drug and had no other symptoms except nausea and abdominal pain. She visited the hospital emergency as these symptoms did not improve over the next 2 days.

The patient had no history of fever, loose stools, genitourinary, or other systemic symptoms. There was no history of recent travel or sick contact.

She had no prior history of psychiatric illness and had no similar past history. The patient was not on any chronic medications, had no history of liver disease, or other medical illness in the past. Her surgical history was significant for 2 uneventful lower sections C-sections. She did not smoke or consumed alcohol.

In the emergency room, the patient looked fatigued. She was afebrile with a blood pressure of 110/70 and pulse rate of 72/min. Abdomen was soft and non-tender and other systemic examination was normal. Her baseline investigations revealed raised transaminases and low acetaminophen levels.

She was started on symptomatic treatment and on intravenous N-acetylcysteine infusion as per hospital toxicology guidelines. Liver function tests were monitored. Her laboratory workup at admission and during her stay is detailed in Table 1 laboratory profile.

The patient was found to have a very high serum procalcitonin level, neutrophilic leukocytosis with normal C-reactive protein. To look for a source of infection, further investigations including routine urinalysis, blood and urine cultures, chest X-ray, and an ultrasound abdomen were performed. The workup, however, turned out to be negative for any active infection. Leukocytosis was attributed to dehydration as it resolved after re-hydration. Her procalcitonin level was monitored along with liver enzymes. It showed a downtrend with improvement in her liver functions and clinical condition.

The main differential diagnosis for raised procalcitonin levels is bacterial infection which was practically ruled out by absence of clinical features, no fever, low CRP, negative cultures and normal chest and abdominal imaging. The other rare possibility of malignancy was also effectively ruled out as the procalcitonin values showed a downward trend.

The patient was started on N-acetylcysteine as per protocol. She was also empirically started on IV antibiotic ceftriaxone in view of raised procalcitonin, but it was discontinued after 3 days as there was no evidence of bacterial infection.

Her symptoms of nausea and mild abdominal pain resolved within 24 h. She was otherwise well and was discharged in a stable condition. Her procalcitonin levels decreased significantly from 97 ng/mL to 2 ng/mL by day 5 when she was discharged home.

Procalcitonin is widely used as a biomarker of bacterial infection. This is because its synthesis is triggered by bacterial endotoxins and inflammatory cytokines, mainly interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha [1]. It is primarily synthesized by the thyroid C cells during normal homeostasis. However, during bacterial sepsis, its synthesis in extrathyroidal tissues notably liver, pancreas, kidneys, intestines, and other cells including leukocytes, immune cells, and endothelial cells is significantly enhanced (100–1,000 fold) [2].

However, it can also be raised in several non-infectious conditions though it is not as common. Among the noninfectious causes of raised procalcitonin are mechanical trauma, burns (more in inhalational burns), pancreatitis, extensive surgery, and heat stroke, and the levels are more or less similar to levels seen in bacterial sepsis (Table 2 causes of raised procalcitonin levels).

In bacterial sepsis, procalcitonin kinetics shows an initial increase after 6–12 hours of onset of infection, followed by a steady rise for the next 2–4 hours. The half-life of pct is 20–24 hours. Therefore with effective antibiotic therapy, it is expected to decrease by half over the following 24 hours [3].

One of the postulated mechanisms for raised procalcitonin levels is that these conditions are often accompanied by translocation of lipopolysaccharide or other bacterial products from the gut to the systemic circulation stimulating procalcitonin release [4]. Thus conditions which compromise the intestinal epithelial barrier and increase gut permeability can cause significantly raised procalcitonin levels. The extent to which procalcitonin raises may be proportional to the extent of compromise of gut epithelial barrier. Human exposure to lipopolysaccharide was shown to increase procalcitonin levels to much higher levels as compared to tumor necrosis factor and IL-8 [5, 6].

The raised levels of procalcitonin in noninfectious cases were first observed in carcinomas, specifically medullary C cell, small cell lung, and bronchial carcinoid. It has also been found to be elevated in cirrhotic patients and in those with chronic liver disease among other conditions [7].

Paracetamol overdose is among the rare noninfectious causes of high procalcitonin levels and there have been transaminitis (3–5 times) and no increase in INR. However, she had the maximum level of procalcitonin among all the cases reported.

Among the postulated mechanisms of high procalcitonin levels in those with paracetamol overdose, the foremost is procalcitonin induction by inflammatory cytokines released by injured hepatocytes [8].

Only 5 cases have been reported previously. We will further examine the correlation between paracetamol overdose and procalcitonin levels, and its relation to liver injury in the ensuing discussion.

In all of the 5 cases reported previously no definite pattern is evident, between the level of procalcitonin and either the dose of paracetamol ingested or the degree of liver injury as reflected in the level of transaminase or prothrombin levels. Our patient had no pre-existing liver disease and she had only mild transaminitis (3–5 times) and no increase in INR. However, she had the maximum level of procalcitonin among all the cases reported.

There are several studies examining the relation between procalcitonin and liver disease including acute liver failure, chronic liver failure, and liver metastases (26–30) which show that levels of procalcitonin do correlate with the severity of liver injury. However, in the subset of patients with acute liver injury due to paracetamol overdose, the procalcitonin levels have been found to be typically much more elevated (3–6.6 times) [9].

The fact that paracetamol-induced liver injury causes much higher values of procalcitonin as compared to other etiologies causing the same severity of liver injury, implies that paracetamol acts via other mechanisms releasing procalcitonin – in the liver or from other tissues.

The liver injury induced by paracetamol is via an inflammatory response with macrophage activation and release of cytokines and pro-inflammatory regulators. This, however, does not explain the high procalcitonin levels in patients with normal or only mildly elevated liver enzymes. The other postulated mechanism by Tscheidel et al. [10] is by involvement of other tissues such as the endothelium suggesting the involvement of other damaged tissues, including immune cells in the release of procalcitonin.

However, this fails to explain the other observable fact. That the amount of paracetamol ingestion and paracetamol levels do not correlate with the procalcitonin levels. This points to a possible underlying predisposing host and genetic factor that determines the procalcitonin response of an individual.

There have been only 5 cases reported previously in literature of high procalcitonin levels related to paracetamol overdose [11] (Table 3 laboratory values of all reported cases).

The oldest patient was 65 years old and the youngest was 24 years old. Our patient was 28 years old and she had the maximum level of procalcitonin level of 97 ng/mL and she presented 48 h after ingestion 18 g of acetaminophen. Though the number of cases is too few to draw any conclusion, we observed that there was no correlation between the level of procalcitonin with the patient’s age, ingested dose of acetaminophen and level of liver enzyme elevation. The procalcitonin levels showed a downtrend by day 3 to day 5, but the data are not complete in some of the cases.

Based on this review of previously published cases, the underlying mechanism of procalcitonin elevation remains unclear and is only partially explained by existing theories. If the alternate explanation that paracetamol causes raised procalcitonin via release from other tissue is true, then the levels should be higher in those with higher dose of paracetamol ingestion.

Again, this review points to other host dependent factors, possibly genetically mediated that influence the extent of procalcitonin rise. Further research in this area may help elucidate other important pathways and improve understanding of procalcitonin physiology and its clinical and practical significance.

Raised procalcitonin levels do not always indicate a bacterial infection. Acetaminophen overdose is a rare cause of raised procalcitonin levels. Procalcitonin level can reach as high as 100 plus without evidence of significant liver injury. Further studies are needed to elucidate the mechanisms behind this substantial rise of procalcitonin in this subset of patients.

The case report study complies with the guidelines for human studies and was conducted ethically in accordance with “World Medical Association Declaration Of Helsinki.” The ethics approval for this case report was not required as per DHA Ethical Committee policy. A written informed consent was obtained from the patient) for publication of the details of their medical case and any accompanying images.

There is no conflict of interest for this study.

This study was not funded.

Dr. Uzma Sabahat designed the study plan, wrote the abstract and manuscript. Dr. Liza Thomas contributed to writing and finalizing the discussion and conclusion. Dr. Niaz Shaikh reviewed the final manuscript, and Dr. Nageen Murad contributed compiling tables of investigations. All authors approved the final manuscript.