Acute pancreatitis during interferon-alpha and ribavirin treatment for hepatitis C

Abstract

A patient treated with interferon-alpha and ribavirin for hepatitis C, who developed acute pancreatitis, is presented here along with a literature review. A 45-year-old Caucasian man was admitted to the intensive care unit because of an acute pancreatitis. According to the adverse drug reaction probability scale, it is probable that pancreatitis was induced by treatment (interferon and ribavirin) for chronic hepatitis C (CHC) commenced 2 months ago. We performed a literature search of all available English-language articles published on MEDLINE between January 1966 and July 2008 using the key terms “acute pancreatitis”, “interferon” and “ribavirin”; only four papers were found with a total of 13 reported cases demonstrating acute pancreatitis developed during treatment for CHC. Looking out for the minimal clinical signs and symptoms of acute pancreatitis in patients with CHC using interferon and ribavirin can help to detect this relevant and rare adverse drug reaction early.

BACKGROUND

Acute pancreatitis occurrence during the treatment of chronic hepatitis C (CHC) is a rare event; interferon (IFN), standard or pegylated, and ribavirin (RBV) are considered drugs that can induce pancreatitis.¹ Complications are often severe enough to warrant hospital admission, although symptoms can resolve promptly after discontinuation of antiviral treatment. There are few cases reported in the literature about pancreatitis induced by IFN and/or RBV. More studies to determine which of those two medications are associated with drug-induced pancreatitis and to investigate the mechanisms of pancreatic injury are requested.

CASE PRESENTATION

A 45-year-old Caucasian man was admitted on May 2007 to the intensive care unit of the São Jose Hospital in Criciuma, a city located at Santa Catarina, which is a southern state of Brazil. He was presenting with strong abdominal pain associated with nausea and vomiting, mental confusion, sleepily, epistaxis and haemoptysis. He acquired hepatitis C virus (HCV), probably in a blood transfusion 7 years ago when he suffered an automobile accident and he had a pelvic fracture. He had a history of social alcoholism and he was recommended to stop alcohol use since the diagnosis of CHC in 2003; however, he only stopped drinking alcohol 3 years ago. He had no others co-morbid medical diseases and he was not taking any medications except for 3 million units of IFN-alpha subcutaneously three times weekly and 1000 mg RBV daily that he started 2 months before admission to treat genotype 1a HCV.

INVESTIGATIONS

Blood analysis was performed (see table 1 for laboratory results).

Table 1.

Blood analysis on admission and after 48 hours

Variable (normal range/unit)	Values on admission	Variable (normal range/unit)	Values after 48 h
Glycaemia (70–110 mg/dl)	185	Calcium (8.5–10 mg/dL)	7,5
Haematocrit (39–53%)	28.1	Haematocrit	28
White blood cells (3.6 to 11×103)	4.22	Albumin (3.5–5.5 g/dL)	1,8
Platelets (100–450×103)	16	Total bilirubin (0–1.00 mg/dL)	0,79
Amylase (25–115 IU/L)	452	Prothrombin time (70 –100%)	76,3
Lipase (2 –IU/L)	412	Activated partial thromboplastin time (up to 43 s)	32,2
Lactate dehydrogenase (100–190 IU/L)	200	Triglycerides (<150–199 mg/dL)	145
Sodium (140–148 mEq/L)	125	PaO2 (80–100 mmHg)	78
Potassium (3.6–5.2 mEq/L)	6,2	SaO2 (>95%)	93,2
Urea nitrogen (15–39 mg/dL)	118	Urea nitrogen	122
Alanine aminotransferase (30–65 IU/L)	41	Creatinine (0.6–1.3 mg/dL)	5,0
Glutamic oxaloacetic transaminase (15–37 IU/L)	37	HIV	No reagent

*Normal ranges used by the São José Hospital, Criciuma-SC, Brazil.

Radiographs of chest and abdomen were normal. Cranial CT scan was normal and abdominal CT scan revealed a hepatosplenomegaly and mild steatosis. Although the images did not prove pancreatitis, pancreatitis diagnosis was established on the clinical criteria the patient presented with (intense abdominal pain and increased amylase and lipase serum levels); thus, fasting, venous hydration, antibiotic and analgesic treatment was established. The treatment with IFN and RBV was suspended. The patient received 14 units of platelets and 2 units of red blood cell concentrate.

OUTCOME AND FOLLOW-UP

On day 2 of hospital admission, amylasemia reduced to 250 IU/L and on day 3 the hyperlipasemia fell to 87 IU/L. A new CT abdomen scan was performed to evaluate pancreatitis and it highlighted aspects compatible with mild acute pancreatitis (diffuse pancreatic oedema). On day 6, the patient showed clinical improvement and his levels of serum amylase returned to normal (65 IU/L). A low fat diet was introduced and the patient stayed for 2 days in the intensive care unit. After that, he was transferred to the infirmary section of gastroenterology where he stayed for 5 days. Before his hospital discharge, an US abdomen ultrasonography showed discrete splenomegaly and non-tumoural chronic hepatopathy; however, his last dosage of amylase had remained at normal level (57 IU/L).

Rapid resolution of symptoms after discontinuation of treatment with IFN and RBV and the absence of recurrent pancreatitis suggests this treatment for CHC was the most likely cause of acute pancreatitis. Also, no reoccurrence of pancreatitis was observed at 6 months follow-up; nevertheless, the patient continued to have CHC.

DISCUSSION

Acute pancreatitis was established on the basis of clinical data such as intense abdominal pain, hyperamilasaemia and hyperlipasaemia. Days after admission, the findings of the abdominal CT scan showed a diffuse pancreatic oedema, which is compatible with mild pancreatitis. We have searched the common risk factors for acute pancreatitis to explain this case. Demonstration of cholelithiasis, long-term or recent alcohol consumption, hypercalcaemia and hyperlipidaemia were excluded. The patient had never been submitted to an endoscopic retrograde cholangiopancreatography.

The treatment of acute pancreatitis invariably includes making the patient nil per mouth and discontinuing the offending medication, such as the drugs to treat CHC. Although ribavirin use is not present in the list of drugs associated with pancreatitis, other nucleoside analogues and IFN are described as “class II drugs associated with pancreatitis” (>10 but <20 reported cases of acute pancreatitis with or without positive rechallenge).¹

There are some difficulties in assessing the probabilities of a drug-related adverse reaction; however, the use of a scoring system can help to determine it. The Naranjo adverse drug reaction probability scale is one of the most valid and widely used techniques in clinical practice.² Using this scale to verify if IFN and RBV were associated with acute pancreatitis, a score of 6 was obtained (table 2) indicating a probable adverse drug reaction association. A higher score would have been impossible to achieve because some of the questions from the Naranjo scale could not be considered (that is, placebo was not given to verify a reaction; it is not ethical to repeat administration or increase the dose).

Table 2.

Adverse drug reaction probability scale in a case of acute pancreatitis in a patient with hepatitis C treated with interferon and ribavirin

Question	Yes	No	Do not know	Score
1. Are there previous conclusive reports on this reaction?	x			+1
2. Did the adverse event appear after the suspected drug was administered?	x			+2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	x			+1
4. Did the adverse reaction reappear when the drug was readministered?			x	0
5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?		x		+2
6. Did the reaction reappear when a placebo was given?			x	0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?			x	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?			x	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?			x	0
10. Was the adverse event confirmed by any objective evidence?			x	0
Total score				6
Adverse drug reaction probability categories: definite 9; probable 5–8; possible 1–4; doubtful ⩽0.

We performed a literature search of all available English-language articles published on MEDLINE between January 1966 and July 2008 using the key terms “acute pancreatitis”, “interferon” and “ribavirin” (all words in text and indexed terms). The search showed 4 articles where there were a total of 13 report cases demonstrating acute pancreatitis developed during treatment for CHC^3–6 Acute pancreatitis developed within 5 months (1–21 weeks) after the initiation of the treatment. All of them (except one that used IFN isolated) reported IFN and RBV combination treatment as the potential cause of drug-induced pancreatitis in these patients.

The mechanism of IFN and/or RBV-induced acute pancreatitis is still unknown. Despite that nucleoside analogues have been associated with the induction of pancreatitis, there are no references about isolated RBV use as a cause of acute pancreatitis; however, RBV raises the risk of pancreatitis by producing mitochondrial toxicity when co-administered with other drugs such as antiretrovirals.⁷ Our patient was HIV negative and had never taken antiretroviral drugs.

However, some potential mechanisms by which IFN can cause pancreatitis are suggested. IFN is known to precipitate or exacerbate autoimmune disorders, such as thyroid disease, diabetes and others^8,9 This cytokine stimulates cells to express class I major histocompatibility complex presenting auto-antigens and, although the autoimmune pancreatitis is described as a chronic disease, IFN could induce an autoimmune acute inflammation leading to pancreatic damage. We have not searched for the presence of auto-antibodies in our patient; thus, this explanation is only speculative.

An elevated level of triglycerides is associated with IFN use. This disorder is a documented cause of acute pancreatitis in patients treated for CHC;¹⁰ however, the hypertriglyceridemia does not explain the occurrence of acute pancreatitis in our patient because his level of triglycerides was normal.

From the published literature, IFN seems more likely than RBV to be the cause of acute pancreatitis. New studies about the interactions and toxic effect of these drugs are needed to clarify this point.

It is important that physicians are alerted to the possibility of drugs as a cause of pancreatitis, which is often ignored because of the difficulty in implicating a drug as its cause. Particularly in CHC, the minimal clinical signs and symptoms in patients taking IFN and RBV should be followed closely for an acute pancreatitis to be detected early.

LEARNING POINTS

• Among adverse drug reactions, pancreatitis is often ignored because of the difficulty in implicating a drug as its cause.

• Interferon and ribavirin are considered in the list of drugs associated with pancreatitis.

• To treat drug-induced pancreatitis, it is necessary to discontinue the offending medication.

• It is important to pay attention to the clinical signs and symptoms of acute pancreatitis in patients with chronic hepatitis C treated with interferon and ribavirin.