Acute liver failure due to hepatitis A virus presented with Guillain-Barré syndrome and ocular myasthenia gravis

Abstract

Hepatitis A is one of the most common causes of acute viral hepatitis in children. Immunological manifestations involving the nervous system are rare with hepatitis A infection. We report a case of a toddler who presented with acute liver failure secondary to hepatitis A infection. The child showed clinical and laboratory improvement initially with conservative management. However, after the initial improvement, she developed acute-onset ptosis along with areflexia. Serological and neurophysiological tests revealed the occurrence of ocular variant Guillain-Barré syndrome and ocular myasthenia gravis, which was only partially responsive to treatment (intravenous immunoglobulin and pyridostigmine). A sudden clinical deterioration was noted after the onset of ptosis. She succumbed on day 40 of hospitalisation due to hospital-acquired infection along with the primary hepatic pathology. This is a rare coincidental presentation of acute viral hepatitis A infection with autoimmune manifestations.

Backgroud

Hepatitis A is a hepatotropic virus belonging to the picornaviridae family of RNA virus.¹ It is one of the most common causes of acute viral hepatitis (AVH) in children.² It is more common in low/middle-income countries associated with poor sanitation and high rates of faecal-oral transmission.³

Although it is a self-limiting disease with a short course of illness, sometimes it can lead to acute liver failure (ALF) (4%).⁴ Immunological manifestations involving the nervous system are rare in infections caused by hepatitis A compared with other hepatotropic viruses. Guillain-Barré syndrome (GBS) has been reported in a few cases of acute hepatitis A infection.⁵ However, there has been no report on the association of myasthenia gravis (MG) with hepatitis A as per literature reviews. There are a few cases of coincidence of GBS and MG in adults.⁶

We report a case of hepatitis A infection complicated with ocular variant GBS and ocular MG.

Case presentation

A previously well toddler girl presented with fever, loss of appetite, vomiting and abdominal pain for 10 days. She developed yellowish discolouration of her eyes and urine from day five of the illness. The child had a history of one episode of blood in the vomitus. She was in an altered sensorium for 12 hours prior to admission. At the time of presentation, the child was encephalopathic with a Glasgow Coma Scale of 10. On primary assessment, she was haemodynamically stable with normal vitals. The general physical examination showed deep icterus and pallor. Abdominal examination revealed hepatomegaly (liver span of 10 cm) and splenomegaly (spleen of 5 cm below left costal margin along the splenic axis). On percussion, there was shifting dullness. The rest of the systemic examination was normal. A provisional diagnosis of hepatic encephalopathy (HE) likely due to infective aetiology was kept and relevant investigations were sent. Aetiological workup revealed positive hepatitis A IgM.

On conservative management, the child showed clinical and laboratory improvement over the course of the stay. ALF was resolved and sepsis parameters were almost normalised by the day of hospitalisation (DOH) 10.

From DOH 12, she started having new-onset fever spikes with elevation in inflammatory markers (table 1).

Table 1.

Trend of blood investigations during the hospital course

Date	DOH-1	DOH-6	DOH-10	DOH-12	DOH-18	DOH-25	DOH-30	DOH-40
Hb (g/L)	105	97	95	70	68	94	67	6
Total leucocyte count (x 10ˆ9/L)	20.61	7.23	9.85	16.85	4.07	4.06	5.09	4.32
Platelet count (x 10ˆ9/L)	53	58	75	55	52	49	47.59	35
TB/DB (mg/dL)	7.9/3.8	8.7/4.8	3.8/2.2	4.8/2.8	5.6/3.2	4.3/2.9	5.6/3.9	8.8/6.4
SGOT/SGPT (U/L)	920/788	1063/345	275/153	87/175	85/44	42/77	40/58	32/14
PT/INR	22/2.01	14.4/1.31	12.1/1.03	14.7/1.37	18.4/1.85	19.3/2.1	25.4/2.5	28.4/3.1
Albumin (mg/dL)	2	1.8	2.6	2.7	2.5	3.4	1.9	1.5
C reactive protein (mg/L)	74	33	9	78	86	55	78	258
Procalcitonin (ng/mL)	5	1.01	0.21	3.4	3.5	3.7	6.9	24

DB, direct bilirubin; DOH, Day of Hospitalisation; Hb, haemoglobin; INR, international standardised ratio; PT, prothrombin time; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamic pyruvate transaminase; TB, total bilirubin.

New-onset ptosis was noted on DOH 16 which progressively increased over the course. It was associated with the absence of deep tendon reflexes. The rest of the neurological examination was normal. Evaluation of ptosis was done with consultation from the paediatric neurology team. Possibilities of GBS and ocular MG were kept which were confirmed by nerve conduction study (NCS) and repetitive nerve stimulation test (RNST). Following the onset of ptosis, the child went on a stormy downhill course clinically with gradually progressive encephalopathy along with worsening coagulopathy and pancytopenia. The child was started on prednisolone at 2 mg/kg for autoimmune complications. As there was only partial response and due to strong suspicion of sepsis, the steroid was stopped and intravenous Ig was given at 2 g/kg over 5 days. As the sepsis parameters worsened (table 1), antibiotics were upgraded to meropenem and vancomycin after drawing samples for blood culture. Persistent thrombocytopaenia evoked a suspicion of fungal sepsis, and hence, antifungal (fluconazole) was also added. Blood, urine, endotracheal and fungal cultures were sterile giving no clue of the organism infecting the body. Two cycles of plasmapheresis were done subsequently as there was no improvement in GBS and MG with intravenous Ig. However, the child did not show any clinical or laboratory improvement and developed grade 3 HE. She was intubated and kept on mechanical ventilation. The third cycle of plasmapheresis was planned, however, could not be done due to the refractory seizure. As there was no improvement in the sepsis, antibiotics were further upgraded to colistin after 5 days. However, the child continued to deteriorate.

Figure 1.

Clinical course of the patient. CRP, C reactive protein; DOH, day of hospitalisation; INR, international standardised ratio.

Investigations

At the time of presentation, the haemogram showed mild anaemia (haemoglobin—105 g/L) with thrombocytopaenia (platelet count—53 x 10ˆ9/L) and elevated total leucocyte count (20.61 x 10ˆ9/L). The liver function test was as follows—total bilirubin of 7.95 mg/dL, direct bilirubin- 3.79 mg/dL, serum glutamic oxaloacetate transaminase—920 U/L, serum glutamic pyruvate transaminase—788 U/L, serum albumin—2 mg/dL. The child had coagulopathy with prothrombin time and international standardised ratio (INR) being 22 and 2.01, respectively, which was not corrected with injectable vitamin K. This supported the diagnosis of ALF.

Aetiological workup for ALF showed positive hepatitis A IgM serology. The rest of the hepatotropic viral serologies (hepatitis B, C and E) were negative. Tropical infections (enteric, malaria, dengue, leptospirosis, rickettsia) were ruled out. Blood and urine cultures were sterile. The final diagnosis of AVH A induced ALF was made.

NCS showed a conduction block in the left median motor and left tibial motor nerves with preserved distal latencies, compound motor action potential and conduction velocity in all nerves with normal F wave latencies. This was supportive of a diagnosis of GBS. RNST was done which showed a 21.6% decrement in the response compared with the first response in the left orbicularis oculi muscle with no electrodecremental response in the right orbicularis oculi, bilateral median nerves. This helped in the diagnosis of MG. Serum antiacetylcholinesterase (AChE) antibodies and antiganglioside (GM)-2 antibodies were markedly elevated suggestive of ocular MG and GBS, respectively.

As she had an atypical course considered for hepatitis A infection, other aetiologies were also considered. Wilson’s disease was ruled out (absent Kayser Fleischer ring, normal serum ceruloplasmin level and urine copper level). Workup for autoimmune liver disease was also negative (showed normal IgG level with negative autoimmune antibody panel). MRI was done, which showed T2/Fluid attenuated Inversion Recovery (FLAIR) hyperintensity in the bilateral caudate nucleus, lentiform nucleus, thalami, midbrain, pons and medulla.

Differential diagnosis

Autoimmune hepatitis and Wilson disease were two close differentials of our case.

Treatment

Conservative management for ALF with HE (vitamin K, antiemetic, antipyretic, intravenous fluid, empirical intravenous antibiotic piperacillin-tazobactam, lactulose and rifaximin) was given on which the child showed clinical and laboratory improvement over the course of her stay. ALF was resolved by DOH 10. She started having new-onset fever spikes from DOH 12. As there was worsening of thrombocytopenia with an elevation of sepsis parameters, antibiotics were upgraded to meropenem and vancomycin with the addition of antifungal (fluconazole).

Steroid (prednisolone) was started for autoimmune complications at 2 mg/kg. Pyridostigmine was given for ocular MG, for which she had a partial response. In view of sepsis, the steroid was stopped, and was given intravenous Ig at 2 g/kg. As there was only partial improvement with intravenous Ig, plasmapheresis was done twice.

Outcome and follow-up

Later, over the course, she succumbed to her illness after 1.5 months of hospital stay (partly to primary hepatic pathology and partly due to hospital-acquired sepsis). The role of autoimmune complications in mortality is considered less.

Discussion

Hepatitis A is a self-remitting infection that usually presents with gastrointestinal symptoms. Extraintestinal manifestations are not uncommon.⁴ Neurological complications of hepatitis A like optic neuritis, transverse myelitis and GBS are rarely reported.^{5 7}

GBS is an autoimmune polyneuropathy.⁸ Different variants of GBS are acute demyelinating polyneuropathy, acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy and Miller-Fisher (MF) variant.⁹ The clinical triad of the MF variant includes areflexia, ataxia and ophthalmoplegia. In our case, areflexia, with external ophthalmoplegia in the form of ptosis was present. Ataxia could not be checked as the child was sick and bedridden. GBS is a clinical diagnosis. NCS and autoimmune panels are crucial for diagnosing atypical variants of GBS. Autoantibodies associated with GBS include antibodies against GM1, GM2, GD1a, GD1b, GQ1b and GT1a. Treatment options for GBS are intravenous Ig and plasmapheresis. In our case, NCS showed an AMAN pattern of GBS, and anti-GM2 antibody was positive. We gave our child intravenous Ig at 2 g/kg. GBS usually responds well to intravenous Ig. However, our case had only partial symptomatic improvement.

Most studies showed an antecedent history of infection in patients with GBS. More than 15 case reports of GBS with hepatitis A virus have been documented of which less than 5 are documented in children. Almost all cases showed an early development of immunological phenomenon along with the onset of jaundice.¹⁰ The case we reported is unique in that the manifestation of GBS was predominantly ocular in the form of ptosis. However, all the previous studies showed the classical GBS findings of areflexia and paraparesis. Also, in our case, the manifestation of GBS was late in the course of the illness. Unlike previous cases, the response to intravenous Ig was not satisfactory in our patient.

Juvenile MG is an autoimmune disorder that causes the destruction of the acetylcholine receptor (AchR).¹¹ Autoantibodies in MG have targeted AchR and muscle-specific kinase (MuSK). These autoantibodies lead to reduced activity of AchR by complement-mediated lysis of postsynaptic membrane, increased rate of receptor degradation, and direct activity inhibition. In patients with whom autoantibodies against AchR or MuSK are not detected, lipoprotein receptor-related membrane protein-4 (LRP-4) is another target of autoantibody. LRP-4 is a protein needed for the activation of MuSK. Skeletal muscle fatigability that fluctuates is the hallmark feature of MG. The extraocular muscle is the most common muscle involved in MG. Cases in which only ocular muscles are involved are called ocular MG. If other skeletal muscles are affected, then it is termed generalised MG. Around 10%–35% of juvenile MG is ocular MG.¹² Our case also had ocular MG in the form of ptosis. Edrophonium challenge test, and autoantibody assay are the common diagnostic tests in the case of MG. In our child, anti-AchR antibody was strongly positive. Electrophysiological modalities include RNST and single-fibre electromyography which are the most commonly applied and the most sensitive test, respectively. Cholinesterase inhibitors are the initial line of treatment for MG. For our case, we gave pyridostigmine and there was a partial response. Other treatment modalities include intravenous high-dose methylprednisolone and thymectomy with immunosuppressant before and after the procedure. To conclude, this is a rare coincidental presentation of AVH A infection with autoimmune manifestations.

Patient’s perspective.

• It was really disheartening for us to see our cheerful little daughter in hospital bed. Doctors and we tried our best to save her, but failed. We were informed by our doctors that there were many features that is usually not present with this infection. Even though our doctors could identify the issues she had, the exact reason of which could not be found out. We take this opportunity to inform the medical community about the situation my daughter had gone through with the hope that this would help some children in some part of the world.

Learning points.

• Rare neurological complications should be closely monitored in all cases of acute liver failure (ALF).

• Autoimmune activation can be the reason for the late worsening in any case of ALF.

• Myasthenia and Guillain-Barré syndrome should be considered in the differentials of any child presenting with ptosis, in a case of acute viral hepatitis.

• Sepsis could be a confounding factor which could have been a deciding factor in the clinical recovery of the patient.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).