Abstract
An 81-year-old gentleman, who had evidence of extrahepatic biliary obstruction, was found to have a serum ferritin concentration of 10,892 μg/L, which later increased to more than 40,000 μg/L when he developed sepsis. Endoscopic retrograde cholangiopancreatography was performed with stent insertion allowing drainage of the bile. The rising pattern of serum ferritin concentrations, bilirubin and alkaline phosphatase noted before the procedure was followed by a steep fall in these biochemical markers after the insertion of the stent.
Introduction
Plasma ferritin concentrations are increased in iron-overload conditions such as hereditary haemochromatosis, as well as in liver disease, infections, inflammatory conditions and malignancy. A literature review of patients with high concentrations of ferritin found that liver disease was the cause in 20% of cases, but no patients had biliary tract obstruction. 1 Very high concentrations (>10,000 μg/L) have only been described in adult Still's disease, multiple blood transfusions and in severe acute hepatocellular damage secondary to ischaemia, sepsis and paracetamol overdose. 2,3 However, information relating to the rise in ferritin concentrations in patients with biliary tract obstruction is sparse and no reports of ferritin concentrations >10,000 μg/L in patients with obstructive jaundice have been identified.
This case report draws attention to the link between very high ferritin concentrations and biliary tract obstruction.
Case report
An 81-year-old man presented with a three-month history of weight loss and anorexia, recent vague abdominal pain and a two-week history of pale stools and pruritis. Apart from minor urinary tract symptoms attributed to prostatism, he had no other problems. His medical history included recurrent vertigo, non-insulin-dependent diabetes mellitus and hypertension. His medication comprised beta-blockers, statins, angiotensin-converting enzyme inhibitors, diuretics and calcium channel blockers. He did not smoke and drank only one unit of alcohol per week.
On examination, he was deeply jaundiced. There were no stigmata of chronic liver disease and there was no cervical lymphadenopathy. There were no signs of sepsis and no abnormalities were detected in either the cardiovascular system or respiratory tract. There was hard irregular hepatomegaly and a palpable tender gallbladder on abdominal examination.
Initial laboratory tests on day one revealed marginally low sodium of 132 mmol/L (136–145 mmol/L), potassium 4.3 mmol/L (3.5–5.1 mmol/L), urea 18.5 mmol/L (3.5–7.2 mmol/L) and creatinine 251 μmol/L (53–115 μmol/L). The patient's liver function tests were suggestive of obstructive pathology with bilirubin 338 μmol/L (3–20 μmol/L), alanine transaminase 422 U/L (0–30 U/L), alkaline phosphatase 2723 U/L (50–200 U/L) and gamma glutamyl transferase 2621 U/L (9–36 U/L). The albumin was low at 25 g/L (34–48 g/L) with a prolonged prothrombin time of 29.8 s (10–15 s) and international normalized ratio of 2.4. Full blood count was normal and there was no increase in C-reactive protein (CRP). Ferritin was 10,892 μg/L (22–275 μg/L) and carbohydrate antigen 19.9 (CA 19.9) was 3458 kU/L (0–37 kU/L). All assays were run in an Abbott Architect biochemical/immunoassay analyser (Abbott Laboratories, Abbott Park, IL, USA), as per the manufacturer's recommendations.
A CT scan of the abdomen reported dilation of the intra- and extrahepatic biliary tracts with a common bile duct (CBD) diameter of 20 mm throughout its course. The gallbladder was grossly distended and the pancreatic duct was also dilated, while the liver and spleen were normal in size. However, because of renal impairment, intravenous contrast was not administered and, hence, it was difficult to ascertain whether there was a lesion in the head of the pancreas or liver.
The diagnosis of biliary tract obstruction was confirmed and endoscopic retrograde cholangiopancreatography (ERCP) was planned. However, two days prior to ERCP (day 7 after admission to hospital), the patient developed signs of sepsis with a temperature of 38.5°C and laboratory results revealed a high white cell count (WCC) of 26.9 × 109/L (neutrophils 25.6 × 109/L), although the CRP was only 14 mg/L. Ferritin concentrations increased further to >40,000 μg/L with continued worsening of liver function tests. CA 19.9 was 1867 KU/L. Blood cultures grew Yersinia enterocolitica. A diagnosis of cholangitis was made and the patient was commenced on tazocin intravenously.
Repeat blood tests two days later (day 9 after admission) showed similar values for ferritin (>40,000 μg/L) and worsening liver function tests. On the same day, ERCP was performed under general anaesthesia, and it showed that the biliary tract obstruction was due to an ampullary tumour (Figure 1) causing a tight stricture of the distal common bile duct with proximal biliary tract dilation (Figure 2). Following sphincterotomy, a pig-tail stent was inserted, which resulted in the rapid drainage of bile. Biopsy from the ampulla of Vater confirmed the presence of a villous adenoma with low-grade dysplasia. The patient's clinical condition improved within days. Renal function started to improve within a week. The raised liver function tests and ferritin concentrations began to fall and these trends continued until discharge on day 36. When he was reviewed one month later in the clinic (on day 70), he was well, his liver function tests had returned to normal, his CA 19.9 was 180 KU/L and ferritin was down to 853 μg/L. The iron studies were normal: serum iron of 8.9 μmol/L (5.5–25.8 μmol/L); total iron binding capacity 46 μmol/L (45–70 μmol/L); serum transferrin 1.84 g/L (1.63–3.44 g/L); and transferrin saturation 19% (20–55%).
Endoscopy picture of the ampullary tumour (marked by arrows) at the time of endoscopic retrograde cholangiopancreatography
Cholangiogram demonstrating a stricture in the distal common bile duct (CBD) causing dilation of the CBD, common hepatic duct (CHD), intrahepatic ducts (IHDs) and cystic duct (CD)
Discussion
Ferritin is the cellular storage protein for iron and has a molecular weight of 440 kDa. It consists of 24 subunits and contains both light (L-ferritin, 19 kDa, gene on chromosome 19) and heavy chains (H-ferritin, 21 kDa, gene on chromosome 11), which can store up to 4500 atoms of iron within its spherical cavity. Ferritin synthesis is subject to at least two levels of control, including DNA transcription via its promoter and mRNA translation through interactions with iron regulatory proteins. Ferritin, along with transferrin and the transferrin receptor, is a member of the protein family that coordinates cellular defence against oxidative stress and inflammation. 4 Ferritin measured in the plasma is usually apoferritin, a non-iron-containing molecule. The plasma level generally reflects overall iron storage, with 1 ng of ferritin per mL indicating 10 mg of total iron stores. Thus, a normal adult male with a plasma ferritin level of 50–100 ng/mL has iron stores of approximately 500–1000 mg.
Ferritin is also an acute phase reactant, with plasma levels increasing in liver disease, infection, inflammation and malignancy. The synthesis and release of ferritin by hepatic cells is directly enhanced by inflammatory cytokines such as interleukin-1 and tumour necrosis factor. 5 In extrahepatic biliary obstruction, hepatocyte damage secondary to cholestasis leads to increased cellular release of ferritin, as well as the release of cytokines in serum and, hence, raised plasma ferritin levels. However, it is worth noting that the effect of inflammation is usually to elevate serum ferritin approximately three-fold and a high CRP level is usually expected in this setting. 6
Ferritin is thought to be excreted into the bile canaliculi of patients with iron overload, probably by lysosomal exocytosis. It follows that obstruction of the biliary tract is likely to elevate serum concentrations. 7 The very high ferritin levels in the patient in this case report may be explained either by infection or biliary tract obstruction. However, we believe that the latter is more likely.
Cholangitis is a common complication of biliary tract obstruction and this might account for the raised ferritin levels in this case report. However, given that the patient only developed sepsis seven days after admission, infection could not explain the high ferritin of 10,892 μg/L on admission when the CRP and WCC were normal, and the patient had no clinical signs of sepsis. However, sepsis probably contributed to the peak ferritin observed later. Growth of the Gram-negative bacillus Y. enterocolitica is enhanced by the uptake of iron, a process that increases its virulence. Iron-overload conditions have been associated with increased risk of invasive yersiniosis. 8
Interestingly, the CRP was only marginally elevated in this patient and this has been reported to be a feature of Y. enterocolitica infections, although it may equally be related to impaired synthesis of CRP by the liver. 9
A literature search identified one case series describing the association between biliary tract obstruction and raised ferritin levels. Basso et al. 10 reported 16 patients with extrahepatic cholestasis due to CBD stones (n = 11), benign biliary tract stricture (n = 2) and cholangiocarcinoma (n = 3). The levels of CA 19.9 and ferritin were found to be increased and these returned towards normal after relief of the obstruction. Further analysis of their data demonstrated a correlation between the levels of ferritin and those of both bilirubin and alkaline phosphatase, but not between ferritin and CRP. Moreover, the authors concluded that the increase in ferritin may reflect impairment in metabolic hepatic clearance in the presence of cholestasis. It is worth noting that the highest ferritin level observed in this series was 2400 μg/L. In the present case report, the levels of ferritin were markedly raised beyond anything that has previously been reported in patients with biliary tract obstruction. The standard markers of obstruction – for example, alkaline phosphatase and bilirubin – continued to rise during admission and this trend was mirrored by the increasing level of ferritin. The patient was treated with intravenous antibiotics for two days, but it was only after biliary drainage had been achieved with a stent that the levels of all these three markers began to decline. This strong temporal correlation between these trends and the timing of ERCP (Figure 3) is not in keeping with the idea that inflammation or sepsis was the sole cause of the very high ferritin levels and would suggest, instead, that the impairment of ferritin clearance associated with biliary tract obstruction and cholestasis played an important role in this process leading to extremely high levels of ferritin in this patient.
Laboratory findings in relation to the timing of endoscopic retrograde cholangiopancreatography
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