Marked improvement in hyperammonaemic encephalopathy from multimodal treatment of metastatic neuroendocrine tumour

Abstract

Gastroenteropancreatic neuroendocrine tumours (GEPNETs) are a heterogenous group of tumours which are rising in incidence. Morbidity and mortality related to these tumours is dependent on the location of metastatic spread. Hyperammonaemia and subsequent encephalopathy has previously been described in GEPNET and is typically associated with a poor prognosis. We describe a case of a 55-year-old woman with hyperammonaemic encephalopathy and a new diagnosis of GEPNET. Given the poor prognosis and the outcomes in this patient group we feel this case highlights the benefit of a multimodality treatment approach including peptide receptor radionucleotide therapy and transarterial chemoembolisation.

Background

Gastroenteropancreatic neuroendocrine tumours (GEPNETs) are an uncommon group of tumours with increasing incidence.¹ GEPNETs are marked by their significant heterogeneity—not just in the anatomical site of primary, but also in biological behaviour, ranging from indolent to aggressive.² The mainstay of treatment for low-grade GEPNETs are somatostatin analogues, which improve progression-free survival (PFS) and decrease hormonal secretion with few adverse events.³ Other systemic options include everolimus⁴ and sunitinib.⁵ Peptide receptor radionuclide therapy (PRRT) has shown promise in improving PFS for this rare tumour.⁶ PRRT allows for radionuclides to be given systemically but with the advantage of binding directly to well differentiated neuroendocrine tumour (NET) cells which express high levels of somatostatin receptors.

Case presentation

A 55-year-old woman was incidentally noted to have deranged liver function tests (LFTs). These are listed in table 1. The remainder of her biochemistry was normal. She also recently experienced worsening aphasia, vomiting, dysarthria and ataxia. Her background medical history was unremarkable, and she did not take any medications.

Table 1.

Liver function tests

	−1 month prediagnosis	Diagnosis	1st TACE	2nd TACE	PRRT
Bilirubin (3–15 µmol/L)	12	10	8	9	10
ALP (30–115 U/L)	196	188	175	165	126
GGT (5–35 U/L)	309	227	129	64	29
AST (10–35 U/L)	74	75	34	22	29
ALT (5–30 U/L)	164	150	99	26	17
Albumin (36–47 g/L)	42	41	41	41	41

ALP, Alkaline Phosphatase; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; GGT, Gamma-Glutamyl Transferase; PRRT, peptide receptor radionuclide therapy; TACE, transarterial chemoembolisation.

Ultrasonography of the abdomen and CT of the chest, abdomen and pelvis showed multiple, bi-lobar, liver lesions and a lesion in the tail of the pancreas consistent with a neuroendocrine tumour (NET). The serum chromogranin A was 2154 µg/L (ref <102) and the urinary 5-HIAA was 113 μmol/day (ref 0–40). She was commenced on long acting lanreotide 90 mg 4 weekly.

Due to concern regarding a paraneoplastic vasculitis she was admitted to hospital for urgent investigation. Biopsy of the liver lesion showed a grade 2 NET with further features listed in table 2. Following this she experienced further neurological deterioration which consisted of loss of concrete thinking, occasional confusion and a fluctuating level of consciousness. Cranial nerve examination showed bilateral gaze evoked nystagmus. There were no clinical features on examination consistent with cirrhosis.

Table 2.

Results of investigations

Investigation	Result
FDG PET (at diagnosis)	Significant avidity in bilobar liver lesions; enlarged left lobe of liver. Avid nodules in peripancreatic lymph node, tail of pancreas and anterior pericardial fat.
68Gallium-DOTATATE PET	Significant avidity in liver, tail of pancreas, as well as lymph nodes (peripancreatic, internal mammary), consistent with metastatic PNET.
Pathology (core liver biopsy)	4 cores taken—3 of 4 show malignant cells consistent with neuroendocrine tumour. Immunohistochemistry: strongly positive for synaptophysin, occasional staining for chromogranin and serotonin. Negative for gastrin and glucagon. Mitotic rate: 5/10HPF. Ki67 index: 2%. WHO 2010/2017 grade: 2. The liver shows mild fibrosis along with mild atrophy and hyperplasia.
Chromogranin A	2154 µg/L (ref <102.0)
MRI brain (post gadolinium)	No evidence of focal enhancing lesions or areas of leptomeningeal enhancement to suggest metastatic disease is identified. Some small focal areas of T2/T2 FLAIR hyperintensity are identified in the subcortical white matter, presumably related to chronic ischaemic changes.
Lumbar puncture	Clear colourless fluid. Protein 0.30 g/L. Glucose 2.7 mmol/L. Nil RBCs, polymorphs or mononuclear cells. CSF IgG 0.020. CSF albumin 0.154. IgG/albumin ratio 0.13. Nil oligoclonal bands detected. Nil malignant cells on cytology.

CSF, Cerebrospinal fluid; FLAIR, Fluid-attenuated inversion recovery; HPF, High powered field; PET, positron emission tomography; PNET, pancreatic neuroendocrine tumour; RBCs, red cells.

Work up for thromboembolic stroke was unremarkable. The serum ammonia level was noted to be 170 μmol/L (15–55). The remainder of investigations are summarised in table 2.

With neurology advice, dexamethasone was commenced at 4 mg orally per day. This led to a significant improvement in symptoms and the patient was able to be discharged within 4 days. Symptoms did not recur on steroid wean.

Due to the poor prognosis associated with hyperammonaemic encephalopathy, the patient was referred for transarterial chemoembolisation (TACE). During an admission to hospital, there was a further neurological deterioration following TACE. Dexamethasone was recommenced with a rapid improvement in neurology and the patient was well. Subsequent TACE performed with steroid cover was uneventful. Serum ammonia levels over time slowly decreased (figure 1).

Figure 1.

Serum ammonia over time. PRRT, peptide receptor radionuclide therapy; TACE, transarterial chemoembolisation.

Restaging with ⁶⁸Gallium-DOTATATE PET demonstrated progressive disease in the liver. She commenced PRRT with ¹⁷⁷Lu-DOTA⁰Tyr³-octreotate.⁷ Following four cycles of treatment she had marked improvement in her LFTs and ammonia (28 μmol/L) levels. Her chromogranin A remained elevated (201 µg/L) but normalised 18 months following PRRT. Urinary 5-HIAA was not monitored serially.

Outcome and ollow-up

Subsequent restaging ⁶⁸Gallium-DOTATE PET scan showed a reduction in the volume of her liver disease (figure 2). She remains on lanreotide and her imaging has remained stable for 36 months after her last dose of PRRT. She remains well with stable disease almost 4 years postdiagnosis with no neurological symptoms.

Figure 2.

Response to TACE and PRRT: axial slices are presented of the low dose CT (left) and fused positron emission tomography (PET)/CT (right) components of the ⁶⁸Ga-DOTATATE PET and ¹⁸F-FDG PET, at baseline, post-TACE and post-PRRT. These images show partial metabolic (FDG) response. PRRT, peptide receptor radionuclide therapy; TACE, transarterial chemoembolisation.

Discussion

NETs are increasing with a reported incidence of 5.25/10 000 population per year.¹ They are often metastatic at diagnosis with hepatic involvement being common.⁸ While there has been a rapid increase in the number of systemic options for NETs, many patients still have progressive disease and liver related mortality.

Hyperammonaemic encephalopathy is rare in solid tumours outside of the setting of hepatocellular carcinoma.⁹ Hyperammonaemic encephalopathy has been noted in case series of NETs,^10–14 but is rare in the absence of synthetic liver dysfunction. While the aetiology of hyperammonaemia may be heterogenous in these cases, in this instance we describe a patient exhibiting clinical and biochemical features of excess serum ammonia.

This pathology was reversible with the administration of corticosteroids and acutely induced on occasions in which hepatic blood flow was altered (TACE procedure). While the pathophysiology of the patient’s rapid improvement on dexamethasone is not well-defined, we postulate that dexamethasone may have reduced hepatic oedema with a subsequent reduction in shunted ammonia. The administration of anticancer therapy with TACE and PRRT may have reduced the volume of malignant liver parenchyma and hence the volume of altered vasculature. This reduction in vasculature may have decreased any associated shunting and hence systemic ammonia.

Clinical syndromes of hyperammonaemia have been rarely described in NETs and are associated with a poor prognosis.¹⁰ Hyperammonaemia occurs when the urea cycle cannot manage systemic ammonia load. This can be caused by excessive ammonia intake, bypass of hepatic metabolism or poor function of the urea cycle. Bypass of the liver by portal blood can occur in instances of congenital porto-systemic shunts, iatrogenic shunts inserted for the resolution of portal hypertension and in the development of collaterals in conditions such as non-cirrhotic portal hypertension and portal vein thrombosis.¹⁵ Portosystemic shunting due to distorted vascular architecture from metastatic deposits has been postulated to occur in other cases of hyperammonaemia related to liver metastases. Typically, symptoms of ammonia toxicity present as a spectrum of neurological features ranging from vomiting, lethargy, somnolence to stroke-like symptoms.

We feel this case is significant because it demonstrates that hyperammonaemic encephalopathy is not necessarily a poor prognostic sign. Antitumour treatments such as PRRT can be effective in inducing a response, which is typically not the case in other forms of treatment for NET. However, PRRT is difficult to give acutely and temporising measures was as steroids and TACE may be required. This case shows that bridging with steroids and TACE to PRRT as part of multimodality treatment can offer hope to clinicians in a clinical scenario which is typically associated with a poor outcome.

Learning points.

• Hyperammonaemic encephalopathy should be considered in patients with mental status change, significant liver metastases and normal synthetic liver function.

• Multimodal treatment including liver directed therapy and peptide receptor radionuclide therapy can effectively treat liver dominant disease in metastatic neuroendocrine tumours.

• If treated effectively hyperammonaemic encephalopathy does not necessarily portend a poor prognosis.

Ethics statements

Patient consent for publication

Obtained.