Treatment of Hepatitis B related Polyarteritis Nodosa presenting with mononeuritis multiplex.

John M Reid and Richard J Coleman

Address for correspondence;  Dr John M Reid, Department of Neurology, Ward 40, Aberdeen Royal Infirmary, Forresterhill, Aberdeen, United Kingdom, AB25 2ZN

Email: johnshazreid@yahoo.co.uk

SMJ 2006 51(2): 54

Keywords: Hepatitis B, mononeuritis multiplex, Polyarteritis nodosa.

  

Abstract

We describe the case of a male patient who presented with mononeuritis multiplex due to polyarteritis nodosa following recent hepatitis B infection. Despite immunomodulatory treatment, the condition progressed with renal and small bowel involvement and the patient died. This case illustrates the difficulty in treating this multisystem disorder and we review the literature on its pathogenesis and treatment.

 

Case Report

A 58 year-old man presented to his GP with symptoms of tingling in his hands that resolved over 3 days.  Blood tests showed elevated liver enzymes and hepatitis screening that showed him to be hepatitis B virus (HBV) positive.  He was homosexual but denied unprotected sexual contact for several years.  There was no history of blood transfusion or injecting any drugs.  One month later he developed pins and needles initially in the toes of his left foot which then affected the right foot and progressed to the calves.  His ankles were weak and he tended to trip.  He had lost 2 stone in weight.  He did not drink alcohol and took no medications.  When seen for neurological assessment he was thin, had bilateral ankle oedema, and BP was 150/90.  He had left ankle dorsiflexion weakness and bilateral plantiflexion weakness.  Both ankle jerks were absent.  Pinprick sensation was reduced on the soles of both feet and the dorsum of the left foot.  He had absent vibration sense from the ankles distally.  These findings were consistent with a right common peroneal and bilateral tibial neuropathies.  Nerve conduction studies showed evidence of a lower limb neuropathy.  CSF examination was acellular, with normal protein and glucose; oligocloncal bands were absent.  An ESR was 48 and alanine aminotransferase 71 U/L (normal range 1-40), alkaline phosphatase 127 U/L (normal range 45-105), gamma glutaryl transferase 63 U/L (normal range 4-35) and bilirubin 12 U/L.  Full blood count and renal function were normal and urine dipstick negative for protein.  Hep B serology was positive for HBV surface (HBsAg) and early (HBeAg) antigens, and was positive for HBV core IgM antibody consistent with acute HBV infection.  The following tests were either normal or negative: Hepatitis C, HIV, cryoglobulins, complement, B12, folate, glucose, thyroid function, serum ACE, auto-immune profile including ANCA, syphyllis serology, Borrelia serology, urine protein/creatinine ratio and clotting screen.  His serum IgG level was 18.9 (normal range 8-14), with no paraprotein band visible and with Bence Jones fraction absent;  IgA and IgM levels were normal.  He was treated initially with a right ankle foot orthosis and physiotherapy.

 

He was seen 2 months later in the clinic with a one week complaint of right hand weakness.  Clinically he had a right ulnar neuropathy and new left common peroneal neuropathy. One week later he had also developed a right median neuropathy.  He had lost further weight.  His BP was 180/110 and urinalysis showed a trace of protein.  Urea and creatinine levels were within normal limits.  Repeat HBV testing showed him still to be HBeAg positive.  His HBV DNA load was 2.42*1010 copies/ml.

 

A sural nerve biopsy showed evidence of a florid vasculitis indistinguishable from polyarteritis nodosa (PAN) affecting an epineurial artery less than 1 mm in diameter.  This was associated with severe reduction in the number of myelinated fibres of all classes. A renal angiogram was normal and a coeliac angiogram demonstrated resistive flow to the liver only.

 

A diagnosis of HBV-related PAN with mononeuritis multiplex (MM) was made. He was treated with a regimen of anti-inflammatory and anti-viral treatment consisting of prednisolone (initially 60 mg/day, reduced at weekly intervals), lamivudine (100 mg/day) together with a 5-day course of intravenous immunoglobulin (400 mg/kg/day).  One week later he was also started on alpha interferon (5 mega units/day s.c.).  His blood pressure was controlled with bendroflumethazide, doxazosin and atenolol.  Two weeks later despite aggressive treatment he developed a right radial nerve palsy and so a course of five plasma exchanges was begun. After 6 weeks of treatment, there had been no new peripheral nerve signs but he appeared increasingly cachectic.  The Hepatitis B viral load dropped to 79,200 copies/ml (fall of 5.48 log units). He developed peritonism and a CT scan of the abdomen showed multiple wedge-shaped infarcts in both kidneys and intra-peritoneal free air with no cause seen.  He underwent laparotomy that showed small bowel perforation which was repaired. His steroid, lamivudine and alpha-interferon drugs were maintained throughout.  Two weeks after surgery his viral load had fallen to 8360 copies/ml but his general condition continued to deteriorate. When peritonitis recurred the patient was treated conservatively and died 4 days later. 

 

Post mortem examination revealed that the underlying cause of death was peritonitis secondary to dehiscence of a previously oversewn ileal perforation with evidence of healing arteritis in the adjacent mesentery.  There was also widespread evidence of healing arteritis elsewhere, for example affecting median and ulnar nerves bilaterally, heart, liver and kidney.

 

DISCUSSION

Clinical features of HBV-related PAN

PAN is a systemic vasculitis that affects muscular arteries but does not involve arterioles or capillaries1.  It was first associated with HBV in 19702.  Typically patients with PAN develop fever, malaise, fatigue, progressive weight loss and myalgia.  Large joint arthritis is seen in up to 50%. Cutaneous features include livedo reticularis, nodules, ulcerations and digital ischaemia.  Mononeuritis multiplex (MM) is seen in 60% of patients with PAN affecting the most distal nerves first3 and nerve conduction studies show an axonal neuropathy.  About half of patients have GI involvement (for example mesenteric infarction or aneurysmal rupture) associated with a high mortality rate4.  Renal inflammation is seen in 40% with microaneurysms and renal infarcts causing varying degrees of renal insufficiency5. Hypertension is a characteristic feature of acute PAN, seen in ~30% of patients including ours, due to renal ischaemia stimulating the renin-angiotensin system6.  There are mild elevations in liver transaminases in most cases6.  10% of patients with PAN have ischaemic strokes or cerebral haemorrhages7.  There may be subclinical cardiac involvement but PAN usually spares the lungs. 

 

PAN usually develops within the first 6 months of HBV infection and may be the first indication of an HBV infection8.  Seroconversion from HBeAg positivity to the production of anti–hepatitis Be antibodies usually signals recovery.  HBV infection is thought to now account for only 10-15% of all cases of PAN in the developed world5,9due to the advent of HBV vaccination and screening of blood donors.  Annual incidence rates for PAN range from 2 to 77 cases per million annually5,10 being highest in areas endemic for HBV.  The incidence of HBV infection in the UK is 7.4 per 100,00011, the majority being acquired through injecting drug use12 or sexual contact.  Rates of HBV infection increased in Scotland in the late 1990s12 with a rate of 18 per 100,000 in Grampian in 199913. 

 

Pathogenesis of HBV-related PAN

PAN is a systemic necrotizing vasculitis that affects medium sized arteries1.  PAN is not associated with a positive ANCA which is seen in small vessel vasculitis such as microscopic polyangitis or Wegener’s granulomatosis6.  When associated with HBV, PAN has been attributed to immune complex–mediated disease since the virus's surface antigen and antibody complexes are present in the circulation2.  HBsAg, immunoglobulin, and complement are found in the vasculitic lesions of muscular arteries and vasa nervorum6,14.  There is however debate about which HBV-related antigen forms immune complexes in PAN6.  Recent case reports of PAN associated with a HBV precore mutation were successfully treated with anti-viral treatment, steroids and plasma exchange15 suggesting that the e antigen is not essential for pathogenesis.

 

Treatment of HBV-related PAN

Idiopathic or non-viral PAN is treated with corticosteroids and cytotoxic agents.  However HBV-related PAN treated with immunosuppressive agents alone may be associated with liver damage 16, persistent infection and has a poorer outcome than non-viral PAN17. Monotherapy with steroids in HBV-infected patients without PAN delays HBeAg seroconversion18. The use of antiviral agents has improved treatment of HBV-related cases19.  There have been no randomised controlled trials in treating HBV-related PAN perhaps understandably given it is such a rare disorder.  Recent studies report use of steroids to reduce inflammation from PAN, plasma exchanges to remove immune complexes in the acute phase, and anti-viral drugs to inhibit viral replication.  One strategy involves the initial use of prednisolone (1 mg/kg per day)6,19 together with a 6-week course of plasma exchange (approximately 3 exchanges per week).  The steroids are tapered off over 2 weeks followed by the initiation of antiviral therapy (e.g., lamivudine at 100 mg/d).  This treatment regimen is associated with clearance of the HBeAg and a 5.6% relapse rate for PAN6.  In one observational study using this regimen there was clinical recovery in 9 out of 10 patients and seroconversion in 6 out of 920.  The authors report an overall 7-year survival rate of 83% using this regimen8,20.  A recent paper contrasted 2 patients with HBV-related PAN.  One patient who stopped his initial treatment, relapsed and died of cerebral infarction and there was a favourable outcome in a second on a regimen of initial corticosteroids, lamivudine and plasma exchanges21.  Steroids appear to have a priming effect in HBV treatment as studies have shown that the virologic response to lamivudine and interferon in chronic HBV infection is enhanced by a prior course of corticosteroids which is not seen if steroids and anti-viral drugs are initiated together22.  It has been proposed that traditional immunosuppression with cytotoxic drugs and prolonged steroids should no longer be used in HBV-related PAN given that plasma exchange with antiviral drugs and an initial short course of steroids appears to be a successful treatment6.  However it is recognised that in cases that do not respond to the regimen of initial steroids followed by anti-viral therapy and plasma exchange may require long-term steroids and cyclophosphamide20.

 

Antiviral agents are essential, as they reduce the production of HBV antigens and help to achieve HBeAg seroconversion.  Prospective studies show improved mortality and relapse rates with use of antiviral agents21.  Some studies report that antiviral treatment alone has been successful in treating HBV-related PAN23,24.  Anti-viral therapy tends to be continued until seroconversion occurs21.  The combination of lamivudine and interferon alpha-2b may be more beneficial in chronic HBV infection than either drug alone25 whilst HBV-related PAN can respond to a combination of lamivudine and interferon alpha-2b26.

 

Discussion of Case

This case demonstrates that HBV-related PAN can be a difficult multisystem disorder to treat.  Our patient was treated initially with steroids, anti-viral therapy (lamivudine and alpha-interferon) and immunoglobulin.  As the illness progressed we initiated plasma exchange  Possible alternative treatment options would be to reduce and stop the steroids at an early stage (e.g. 2 weeks) and initiate plasma exchange from the onset.  Further, starting steroids prior to anti-viral therapy might have had a priming effect on anti-viral treatment.  Immunoglobulin is not routinely used in treating HBV-related PAN, however one case report describes rapid improvement in HBV-related PAN using intravenous immunogloblulin27.

 

Conclusion

This fatal case of HBV-related PAN illustrates that Hepatitis B is an important cause of mononeuritis multiplex that can be difficult to treat and is associated with significant morbidity and mortality.  Current evidence for treatment of HBV-related PAN is based predominantly on case series, and although outcomes are undoubtedly improving, the quality of the evidence is poor.  Physicians need to be aware of this condition given the rise in rates of HBV infection in Scotland12.

 

Acknowledgement

Thanks to Dr James Mackenzie for help with the pathological studies and Professor Andrew Rees for advice with the manuscript.

 

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