No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Development of hyperammonemic encephalopathy in patients with multiple myeloma may be associated with the appearance of peripheral blood myeloma cells
Leukemia & Lymphoma
... This unusual case provides an opportunity to review hypotheses for the mechanisms of MM-related hyperammonemia. To our knowledge, the occurrence of hyperammonemia in NSMM has been reported only once before [9]. Upon closer scrutiny of that case, oligosecretory disease could not be ruled out, given the absence of comprehensive testing for trace levels of M-proteins undetectable by conventional methods. ...
... Upon closer scrutiny of that case, oligosecretory disease could not be ruled out, given the absence of comprehensive testing for trace levels of M-proteins undetectable by conventional methods. In our case, rare One proposed mechanism for hyperammonemia in MM is hepatic infiltration by malignant plasma cells, leading to liver failure or porto-systemic shunting [5,9,10]. Ammonia is largely produced within the gastrointestinal tract through the catabolism of nitrogencontaining compounds by bacteria, and subsequently processed by the liver [11,12]. ...
... Our case had several high-risk features, including gain of chromosome 1q by FISH cytogenetic analysis and pleomorphic morphology. While HE can be a late manifestation of MM, in some cases like ours it is the initial presenting symptom, requiring early recognition and timely management [5,9]. ...
Background
Hyperammonemic encephalopathy (HE) is a rare and life-threatening complication of multiple myeloma, with underlying mechanisms that are not fully understood. In contrast to previously reported cases, most of which have been associated with IgG or IgA isotypes, we describe a patient with HE as the presenting symptom of non-producer multiple myeloma (NPMM).
Case presentation
A 60-year-old man developed lethargy that progressed into coma. He was found to have an elevated ammonia level, despite normal hepatic function. He was diagnosed with HE secondary to NPMM, demonstrating 80% plasma cells without light chain expression in the bone marrow and absence of a monoclonal protein in the serum or urine, including by matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX). Myeloma-directed therapy with daratumumab, bortezomib, cyclophosphamide and dexamethasone successfully reversed his HE. At clinical relapse, he received salvage chemotherapy followed by venetoclax therapy, leading to a short period of neurological recovery.
Conclusions
This case demonstrates that HE can occur in a patient with NPMM and challenges the mechanism suggested by limited prior studies; i.e., that excess ammonia in multiple myeloma arises from degradation of M-proteins. We postulate that the neoplastic plasma cells in NPMM have amplified amino acid metabolism, despite lacking detectable intracellular or secreted immunoglobulins.
... Hyperammonemic encephalopathy in the absence of liver disease is a rare complication of advanced multiple myeloma (MM) that is fatal without immediate intervention. Doxorubicin, cyclophosphamide, and melphalan have been used for treatment in the cases reported to date [1,2]. Bortezomib is the first proteasome inhibitor used in the treatment of MM. ...
... Hyperammonemic encephalopathy (HE) is a rare cause of an altered conscious state in multiple myeloma (MM) [1,2]. It is usually associated with chronic liver disease, porto-systemic shunts, and fulminant hepatic failure. ...
... As well as HE being a rare cause of altered conscious state in MM [7], it is associated with a high tumor burden and plasma cell leukemia [1]. The pathogenesis of HE in MM is unclear, although it is certainly related to malignant plasma cells, given the prompt neurological improvement associated with effective therapy. ...
... The characteristics of hyperammonemic encephalopathy secondary to MM have also not been well studied. One review reports three cases that show an association of the appearance of peripheral blood myeloma cells to the development of hyperammonemic encephalopathy [12]. Our case supports this rare association, with our patient's altered mental status developing shortly following his progression to plasma cell leukemia (plasma cells comprising 35% of the white blood count). ...
... Simultaneous continuous venovenous hemodialysis and extended daily hemodialysis Vincristine + high dose dexamethasone [12] Patient with medically refractory hyperammonemia survived and was discharged home. ...
Multiple myeloma (MM) typically presents with hypercalcemia, renal insufficiency, anemia, and bone lesions. Elevated ammonia level manifesting as altered mental status is a rare complication in MM. We report an interesting case of hyperammonemic encephalopathy in a 73-year-old male with advanced relapsing kappa-light chain MM.
... Hyperammonemia, a well-known complication of hepatic dysfunction often resulting in encephalopathy, has rarely been reported as a complication of multiple myeloma, with approximately 45 reported cases (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). This condition has been most reported with the IgA lambda subtype where it has been categorized as a marker of a more aggressive and often resistant variant leading to rapid clinical decline (1,5). ...
... In multiple myeloma, hyperammonemia is a rare complication with an undefined etiology. Inclusive of our four cases, there have been approximately 45 reported cases, but likely many others have gone unrecognized (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Hyperammonemic encephalopathy has most often been reported in the IgG and IgA subtype of myeloma, less commonly in light chain myeloma, and rarely with the IgD subtype (5). ...
Hyperammonemia, a well-known complication of liver failure causing encephalopathy, has rarely been reported as a complication of multiple myeloma. We report four additional cases of hyperammonemia in patients with treatment refractory multiple myeloma. In these cases, we found that hyperammonemia remains a morbid complication of resistant disease without directed myeloma therapy. Our brief review has reaffirmed that hyperammonemia is a poor prognostic marker in myeloma with an undetermined mechanism. This complication’s poor response to traditional therapies, including rifaximin and lactulose, prompts our discussion urging early recognition and myeloma directed therapy. Clinical observations may support that proteasome inhibitors may be most effective in the treatment of these patients.
... Исследование с включением 27 пациентов с множественной миеломой и гипераммониемической энцефалопатией показало, что у большинства из них наблюдалось агрессивное или резистентное к химиотерапии течение заболевания с уровнем смертности 44% [22]. Предполагается, что развитие печеночной энцефалопатии может быть ассоциировано с появлением клеток миеломы периферической крови [23]. ...
Гипераммониемия у взрослых в 90% случаев связана с тяжелым заболеванием печени. В остальных случаях необходимо учитывать другие (не связанные с циррозом) причины. Измерение уровня аммиака в крови должно проводиться всем пациентам с энцефалопатией неясного генеза, даже если функция печени у них не нарушена. Осведомленность практикующих врачей о нецирротической гипераммониемической энцефалопатии может способствовать ранней ее диагностике, началу лечения, улучшить выживаемость пациентов. В этом обзоре основное внимание уделяется этиологии, патофизиологии и основным механизмам развития нецирротической гипераммониемической энцефалопатии, а также обсуждаются возможные методы лечения.
Hyperammonemia in adults is 90% associated with severe liver disease. In other cases, it is necessary to consider other (not related to cirrhosis) causes. Blood ammonia levels should be measured in all patients with unexplained encephalopathy, even when liver function is normal. Awareness of сlinician about non-cirrhotic hyperammonemic encephalopathy can contribute to its early diagnosis, initiation of treatment, and improve patient survival. This review focuses on the etiology, physiology, and underlying mechanisms of noncirrhotic hyperammonemic encephalopathy and discusses possible treatment options.
... This hypothesis is in line with the evidence from the case series of increased HE risk in patients with MM and the presence of plasma cells in peripheral blood. 2 In addition, a review of 27 HE cases showed a higher frequency of IgA MM. 3 Secondary plasma cell leukemia (PCL), nearly 40% of all cases of PCL, is associated with end-stage disease and a worse patient outcome, 4 as in our patient. In the absence of liver failure, recent studies suggest that either aggressive plasma cell clone can produce ammonia or myeloma-related humoral factors can influence amino acid metabolism leading to an increase in blood ammonium. ...
... 5,6 Ikewaki found the presence of myeloma cells in the peripheral blood and suggested that the in ltration of myeloma cells into the liver was the cause of hyperammonaemia. 7 Howman further elaborated on this, theorizing that the hypercoagulable state in myeloma combined with liver in ltration by plasma cells can result in portal hypertension and a portosystemic shunt leading to hyperammonemia. However, this has yet to be identi ed in studies so far and there are some reported cases of hyperammonemic encephalopathy without peripheral presence of myeloma cells. ...
Background: Hyperammonemic encephalopathy is a rare cause of altered level of consciousness in patients. When investigating encephalopathy, common causes are ischaemic, metabolic, toxic, inflammation, demyelinating, degenerative, hereditary and infection. In this case reports, we present a rare case of encephalopathy in a patient with hyperammonaemia on a background of multiple myeloma.
Case presentation: A 67-year old caucasian male with a background history of monoclonal gammopathy of undetermined significance, presented with confusion, asterixis and recurrent falls. As part of the work up he was found to have a high ammonia level at 123umol/L (normal 0-50umol/L). The patient also had a bone biopsy as he had mild pancytopenia and hyperproteinemia and was diagnosed with multiple myeloma, likely a progression from his paraproteinemia disorder. The patient significantly improved to his baseline with normalisation of ammonia level once he was commenced with Velcade based chemotherapy as well an adjunctive treatment with lactulose.
Conclusion: Hyperammonemia in multiple myeloma is a rare but an important differential in patients with encephalopathy. The diagnosis of this is important so that an appropriate treatment can be provided.
... Glutamine, through the action of glutaminase, produces ammonia and therefore ammonaemia; this biochemical cycle tends to explain the real reason why, in recent decades, in patients with MM, but also in patients with plasma cell leukemia and in myeloma cell cultures, a condition of hyperammonemia has been described. This condition may be responsible for a persistent or transient hyperammonemic encephalopathy unresponsive to the treatment used for the encephalopathy of patients with severe hepatic insufficiency, and largely reversible with the pharmacological treatment of MM [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69]. ...
The high output heart failure is a clinical condition in which the systemic congestion is associated to a high output state, and it can be observed in a non-negligible percentage of hematological diseases, particularly in multiple myeloma, a condition in which the risk of adverse cardiovascular events may increase, with a worse prognosis for patients. For this reason, though an accurate literature search, we provided in this review a complete overview of different pathogenetic mechanisms responsible for high output heart failure in multiple myeloma. Indeed, this clinical finding is present in the 8% of multiple myeloma patients, and it may be caused by artero-venous shunts, enhanced angiogenesis, glutamminolysis, hyperammonemia and hemorheological alterations with increase in plasma viscosity. The high output heart failure in multiple myeloma is associated with significant morbidity and mortality, emphasizing the need for a multidisciplinary approach.
... The pathophysiology of hyperammonaemia in multiple myeloma is unknown. It has been hypothesised that leukaemia transformation may increase the likelihood of hyperammonaemia 12 and plasma cell infiltration of the liver leading to porto-systemic shunting 13 ; likewise, metabolising and degrading large quantities of immunoglobulins has been suggested to increase ammonia levels, in excess of the normal rate of hepatic clearance, especially in advanced stages of the disease. 14 The most frequent subtype of immunoglobulin produced by multiple myeloma seems to be IgG, followed by IgA. 4 Our patient had a subtype of IgG and was in an advanced stage of the disease, with very high levels of ammonia (151 mol/L); these findings agree with those reported in the literature. ...
... Hyperammonemia related to chemotherapy and hematopoietic stem cell transplantation (HSCT) is a known but rare and not well-understood condition and has so far been mainly described in hematological malignancies [1][2][3][4][5] (reviewed in [6]). In addition and not related to therapy but to the disease itself, multiple myeloma has been associated with an increased risk of hyperammonemia [7][8][9]. Besides the aforementioned conditions with an underlying malignant disease, hyperammonemia after unrelated cord blood transplantation was described in a 14-month-old boy with mucopolysaccharidosis type I [10]. ...
... One potential mechanism is the possibility of plasma cell infiltration of hepatic tissues causing porto-systemic shunting of blood [1,19,20]. There have also been suggestions that some subtypes of MM might undergo a leukemic change which would predispose these patients to hyperammonemia [9]. A third mechanism that has been proposed, and the most likely, is the production of ammonia by the plasma cells themselves. ...
Hyperammonemia attributed to multiple myeloma (MM) has been rarely reported. We present 6 patients from our institution and 34 from the literature with MM-induced hyperammonemic encephalopathy. The median age was 67 years with male:female ratio of 1.8:1. The median ammonia level was 114umol/L. IgG and IgA MM was seen in 40% and 35% of cases, respectively. The in-patient mortality was 48%. The in-patient mortality was 31% in patients who received MM-directed therapy and 100% in those who did not received MM-directed therapy. Hyperammonemic encephalopathy is a rare complication in MM and is associated with high in-patient mortality.
... GS plays a key role in ammonia detoxification in the brain, but a high activity of this enzyme can be harmful, since it depletes ATP and glutamate pools [231]. Hyperammonemia and hyperammonemic encephalopathy can be induced as a result of chemotherapy, and they have also been reported to be associated to multiple myeloma, plasma cell leukemia, leiomyosarcoma or neuroendocrine tumors in some patients [232], [233], [234], [235]. ...
Tumor cells suffer a metabolic reprogramming which allows them to use metabolic fuels (glucose, glutamine, lipids) through anabolic fates to support their enhanced proliferation and other carcinogenesis-related features. The present review tries to address and summarize the broad and growing information available about this reprogramming, whose pieces, put together, make up a complex scheme that encompass different complexity scales, from cells to systemic networks.
... A recent study of 27 patients with multiple myeloma and NCHE showed that most had immunoglobin-A type, aggressive or chemotherapy-resistant disease; the overall mortality rate was 44% (33). The development of hepatic encephalopathy was associated with the appearance of peripheral blood myeloma cells (34). The pathophysiology of hyperammonaemia in multiple myeloma is largely unknown. ...
Adult hyperammonaemia is associated with severe liver disease in 90% of cases. In the remainder, noncirrhotic causes should be considered. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin, even when liver function is normal. Clinician awareness of noncirrhotic hyperammonaemic encephalopathy can contribute to early diagnosis and the initiation of sometimes life-saving treatment. This review focuses on the physiology, aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy and discusses the available treatment modalities.
Les syndromes lymphoprolifératifs sont caractérisés par la prolifération, le plus souvent clonale de cellules lymphoïdes B, T, ou NK. Leurs manifestations cliniques sont liées au syndrome tumoral (adénopathies, splénomégalie, insuffisance médullaire par envahissement, localisations tissulaires extra ganglionnaires), mais aussi à la production de médiateurs de type chimiokines et/ou cytokines, responsables de manifestations systémiques par action à distance, pouvant apparaître au premier plan comme complication aiguë et masquer la prolifération qui en est à l’origine. Dans le cas de certains syndromes lymphoprolifératifs B, l’immunoglobuline (Ig) monoclonale sécrétée peut être la source de complications à distance, soit du fait de propriétés physico-chimiques particulières soit par activité anticorps, soit par un mécanisme physiopathologique encore non établi. Enfin, la prolifération lymphoïde peut favoriser, par la réaction immunitaire antitumorale qu’elle suscite, l’émergence d’une auto-immunité secondaire et/ou d’un déficit immunitaire secondaire pouvant apparaître au premier plan comme complication aiguë. Dans le respect de l’esprit de ce livre, nous aborderons les complications aiguës « classiques » directement liées au syndrome tumoral comme le syndrome de lyse. Les complications aiguës liées à la production de cytokines entraînant un syndrome d’activation macrophagique, ou associées à la production d’autoanticorps comme certaines formes de microangiopathies thrombotiques, sont détaillées dans d’autres chapitres de ce livre. Nous envisagerons également, dans ce chapitre, des complications aiguës rares essentiellement liées à la production d’une immunoglobuline monoclonale par un clone lymphocytaire et/ou plasmocytaire B en illustrant, dans certaines situations, le contraste entre la gravité des symptômes avec parfois mise en jeu du pronostic vital et le caractère minoritaire du clone lymphocytaire ou plasmocytaire avec syndrome tumoral minime.
Though elevated ammonia is often associated with the presence of intrinsic liver disease, several other causes need to be considered. Elevated ammonia can either be related to increased production of ammonia due to a catabolic state (e.g., protein degradation) or due to decreased clearance. Diagnostic workup of elevated ammonia levels involves consideration of the following questions: (1) Is there evidence of underlying liver disease? (2) Is hyperammonemia due to increased production or decreased clearance of ammonia? (3) Is elevated ammonia simply a bystander to obvious clinical scenarios (e.g., septic shock), or does it imply the need for further workup of unrecognized entities (e.g., urea cycle defect) that need prompt attention?
We observed a case of hyperammonaemic encephalopathy in a patient without liver dysfunction which revealed meningeal involvement of IgD multiple myeloma. We have reviewed briefly the hyperammonaemic syndrome and we believe that this diagnosis has to be considered in differential diagnosis of encephalopathies in patients with multiple myeloma.
In this study, we show that malignant plasma cells from patients with either primary (n=12) or secondary (n=15) plasma cell leukemia (PCL) do not express CD56 at all, neither in the bone marrow nor the peripheral blood in 81% of cases. On the other hand, multiple myeloma (MM) at diagnosis overexpress it in 63 of 94 (67%) cases (P=0.0001). In three secondary PCL evaluated serially, CD56 was also lacking at diagnosis showing that CD56 is not downregulated at the end stage of the disease but rather not upregulated in this subset of patients. This last concept is strengthened by the observation that 29% of MM patients lacking CD56 or weakly expressing it at diagnosis present a detectable leukemic phase vs 11% only in CD561 MM (P=0.06). Forty percent of all the CD56(-/weak) malignant plasma cell disorders present or develop a leukemic phase vs only 15% of CD56+ cases (P < 0.008). CD56(-/weak) MM subset is also associated with a significantly less aggressive osteolytic potential (P=0.012). We conclude that the lack or weak expression of CD56 is a characteristic feature of PCL but also delineates a special subset of MM at diagnosis mainly characterized by a lower osteolytic potential and a trend for malignant plasma cells to circulate in the peripheral blood more overtly.
A 78-year-old man was admitted because of lumbago and chest pain. A diagnosis of non-secretory primary plasma cell leukemia was made based on the laboratory findings and his history. However, the plaque-forming cells assay of bone marrow cells revealed secretion of monoclonal immunoglobulin from the myeloma cells. Hyperammonemia was detected in the serum. Although the patient was treated with 4 courses of combination chemotherapy (vincristine, adriamycin, cyclophosphamide, methylprednisolone), he died of respiratory failure five months after diagnosis. Autopsy showed widespread multiple myeloma and prominent infiltration of myeloma cell in the sinusoid of the liver. Recently, there have been a few reports which increased the plasma ammonia concentration with multiple myeloma. This report strongly suggested that liver infiltration of myeloma cell caused hyperammonemia.
Two patients with multiple myeloma who appeared to be producing ammonia are reported. Both patients showed hyperammonemia and amino acid disturbances, such as a low Fischer ratio. One patient had Bence Jones protein (lambda) type myeloma and became comatose, but the hyperammonemia and disturbance of consciousness were improved by chemotherapy for the myeloma. The other patient had IgA kappa type myeloma and somnolence and died of malignant pleurisy despite intensive chemotherapy. Autopsy showed widespread multiple myeloma and an almost normal liver. Ammonia levels in the supernatant of cultured myeloma cells from the patient's pleural effusion increased almost linearly from the time of cell seeding. These observations showed that ammonia was produced at a high level by these human myeloma cells. We also found that one of the common myeloma cell lines, RPMI 8226, could produce ammonia as well.
A 63-year-old man was admitted to our hospital with tremor and somnolence, followed soon by coma. Anemia and retinal bleeding were observed. The blood smear exhibited rouleaux formation and leukoerythroblastosis. A bone marrow aspiration resulted in dry tap. The biopsy specimens revealed remarkable infiltration of myeloma cells with fibrosis. The M-component of IgG-lambda type and hyper-ammonemia were detected in the serum. Liver and renal functions, however, were within normal range. His consciousness recovered after plasmapheresis. Two courses of VMCP (vincristine, melphalan, carboquone and prednisolone) did not affect the paraproteinemia. Five courses of VAD (vincristine, adriamycin and dexamethasone) could lower the level of IgG. He died of pneumonia. The plasma of some patients with multiple myeloma may contain unidentified factors which increase the plasma ammonia.
A 69-year-old male presented with fever, ascites and leg edema in February, 1994. He had a pathological fracture of cervical supine in October. Pathological findings at operation showed plasmacytoma. Bone marrow aspiration showed 16.2% myeloma cells. So he was diagnosed as multiple myeloma presenting biclonal gammopathy of IgA-L and IgD-K. Ascites was massive and drainage of 2 to 4 liter per week was required. Ascites was supposed to be related to multiple myeloma, because the IL-6 level in the ascites was increased (2,440 pg/ml), although repeated cytologic studies were negative. After the operation, he developed hyperammonemic drowsiness. It was also suggested that hyperammonemia was associated with multiple myeloma. In addition to radiation therapy for the cervical lesion, MP therapy, Interferon-alpha, VAD therapy and intraperitoneal cyclophosphamide infusion were administered. But no improvement of ascites or hyperammonemia were noticed. Here we described a case of multiple myeloma with very notable clinical features.
Of 5 multiple myeloma patients with hyperammonemia, autopsy was performed in 4 patients, while amino acid metabolism was examined in 3 patients. As a result they were classified into the following 3 types; A, liver dysfunction and severe liver infiltration of myeloma cells. B, severe liver infiltration without liver dysfunction. C, Neither liver dysfunction nor severe liver infiltration. In one type A patient, isoleucine decreased. In two patients without liver dysfunction (one type C patient and another patient in whom autopsy was not performed) valine, leucine and isoleucine decreased, and tyrosine decreased slightly. The Fischer ratio decreased in these 2 patients, while it decreased slightly in a type A patient. Clinically, in 4 patients hyperammonemia was observed during periods of poor general condition and when refractory to chemotherapy. In an aggressive type case, consciousness disturbance was developed rapidly and multiple myeloma was diagnosed. In all patients, consciousness disturbance was noted. Hyperammonemia might have been caused by hepatic failure or systemic-portal shunt in patients with liver infiltration. In those without liver infiltration, it was suggested that hyperammonemia was caused by myeloma related humoral factors that influence amino acid metabolism.
We report two cases of hyperammonemic encephalopathy in patients with multiple myeloma. This rare complication, whose pathophysiology remains unknown, is associated with disease progression and so with a very bad prognosis. We believe that this complication should be included in the differential diagnosis of encephalopathy occurring in multiple myeloma.
The novel multiple myeloma (MM) cell line MOLP-5 and its homologous sister cell line B407, a lymphoblastoid cell line (LCL), were established from the peripheral blood of a 71-year-old Japanese patient with Bence-Jones kappa-type multiple myeloma (stage IIIB with hyperammonaemia and hypercalcaemia). The growth of MOLP-5 cells is constitutively dependent on bone marrow stroma (BST) cells; none of the cytokines tested nor the culture supernatant of the bone marrow stroma cells could support the growth of MOLP-5. Wright-Giemsa-stained MOLP-5 cells showed typical plasma cell morphology with abundant cytoplasm and one to three nuclei. The immunoprofile of MOLP-5 corresponds to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) kappa light chain, CD28, CD29, CD38, CD40, CD44, CD49d, CD54, CD56, CD58, CD71, CD138 and PCA-1; the cells were negative for surface Ig and various other B-cell, T-cell and myelomonocyte-associated immunomarkers. Interleukin 6 (IL-6) receptor mRNA was found in the reverse transcriptase polymerase chain reaction (RT-PCR) analysis. IL-6 and IL-10 could induce cellular proliferation in short-term induction experiments. IL-6 or IL-10 production was not detected by specific enzyme-linked immunoabsorbent assay (ELISA). MOLP-5 cells expressed parathyroid hormone-related protein (PTHrP) at the mRNA level. Cytogenetic analysis showed the typical t(11; 14) chromosome abnormality. The novel MOLP-5 cell line together with the B407 B-LCL sister line will be useful model systems in the investigation of the biology of MM.
Recently, there have been several reports describing patients with multiple myeloma complicated by consciousness disturbance due to hyperammonemia. Here we report a patient with multiple myeloma and hyperammonemia, who died after rapid progression of the disease. A 71-year-old man who had been diagnosed as having Bence Jones protein (kappa)-type multiple myeloma in 1996 was readmitted to our hospital in February 1997 because of worsening bone pain, renal dysfunction, and hypercalcemia. Bone marrow aspiration yielded an almost dry tap, and the bone marrow was found to be completely occupied by immature plasma cells. Although liver dysfunction was slight, the serum ammonia level was high and increased gradually. Despite treatment, the patient died due to cerebral embolism and progression of plasmacytic leukemia in October 1997. Peripheral blood sampled at the time of death showed a serum ammonia level of 204 micrograms/dl, and the myeloma calls were cultured using monolayered bone marrow stromal cells as feeder cells. This led to the successful establishment of a cell line. The level of ammonia in the supernatant was high, indicating that the cultured myeloma cells produced and released ammonia.
