Lipoprotein-X hyperlipidaemia in Chinese paediatric patients with liver graft-versushost disease post-haematopoietic stem cell transplantation: two case reports

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Lipoprotein-X hyperlipidaemia in Chinese paediatric patients with liver graft-versus-host disease post-haematopoietic stem cell transplantation: two case reports
Wilson YK Chan, MB, BS, MPH1; Eric CY Law, MB, ChB2; TK Ling, MB, BS2; Felix CK Wong, MB, BS, MResMed2; Daniel KL Cheuk, MB, BS, MPH1; Joanna YL Tung, MB, BS, MPH1
1 Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong
2 Department of Pathology, Queen Mary Hospital, Hong Kong
 
Corresponding author: Dr Wilson YK Chan (wykchan@hku.hk)
 
 Full paper in PDF
 
Case report
Case 1
An 8-year-old girl with severe aplastic anaemia and failed immunosuppressive therapy underwent a matched-sibling bone marrow transplantation. Neutrophils and platelets were engrafted 23 and 27 days after transplantation, respectively. Regeneration of marrow and full donor chimerism were demonstrated 30 days after transplantation. Progressive liver dysfunction and cholestasis were noted 5 weeks post-transplantation with peak alanine aminotransferase level of 878 IU/L (reference value, <35), aspartate aminotransferase level 966 IU/L (reference range, 10-40), gamma-glutamyltransferase level 2065 IU/L (reference range, 13-28), total bilirubin level 445 μmol/L (reference range, 10-24), and direct bilirubin level 430 μmol/L (reference range, 5-10). Cholesterol levels were also elevated with total cholesterol level of 23.1 mmol/L (reference value, <5.2), high-density lipoprotein-cholesterol (HDL-C) level 0.5 mmol/L (reference value, >1.6), and high triglycerides (TG) level 11.8 mmol/L (reference value, <1.7). Low-density lipoprotein cholesterol (LDL-C) level could not be calculated based on indirect quantitation with the Friedewald equation as per usual practice since TG level was >4.5 mmol/L; hence, it was measured directly and was normal at 0.2 mmol/L (reference value, <4.1).
 
Apolipoprotein (Apo) A1 level was low at 0.38 g/L (reference range, 1.2-2.0) and Apo B level was elevated to 1.88 g/L (reference range, 0.41-1.07). Lipoprotein electrophoresis showed chylomicron and very low–density lipoprotein bands, and an additional beta-lipoprotein band that had migrated to cathode was detected, compatible with lipoprotein-X (Lp-X) [Fig a]. There was no family history of hypercholesterolaemia and clinical examination did not reveal any xanthoma. With improvement of cholestasis, dyslipidaemia gradually resolved by 2 years post-transplant with expectant management (Fig b and Table).
 

Figure. (a) Lipoprotein electrophoresis patterns of Cases 1 and 2. Lipoprotein species were separated by electrophoresis on agarose gel and subsequently stained with Sudan black. Lanes 1A and 1B belong to Case 1, with 1B sampled 7 days after 1A. Lanes 2A and 2B belong to Case 2, with 2B sampled 14 days after 2A. Other lanes belong to control samples and indicate the position of other lipoprotein species. Arrow indicates position of lipoprotein-X. (b) Trend of liver enzyme and bilirubin levels for Case 1. (c) Trend of liver enzyme and bilirubin levels for Case 2. (d) Lipemic and icteric peripheral blood sample from Case 2
 

Table. Lipid profile for Cases 1 and 2
 
Case 2
A 13-year-old boy with stage 4 right adrenal neuroblastoma and multiple nodal, bone and bone marrow metastases underwent chemotherapy (HKPHOSG-NB-07 N7 protocol), gross total tumour resection, and autologous cord blood transplantation followed by immunotherapy. Complete remission was achieved but he had spinal relapse 4.5 years later presenting with cord compression at the level of T5-T9 vertebrae warranting emergency laminectomy and spinal tumour excision. He then received one cycle of temozolomide and irinotecan followed by adjuvant radiotherapy 30 Gy/10 Fr to T5-T9 vertebrae and a haploidentical transplant with maternal TCRαβ-depleted and CD45RA-depleted grafts. Total lymphoid irradiation at 8 Gy, fludarabine 150 mg/m2, thiotepa 10 mg/kg and melphalan 140 mg/m2 were prescribed as conditioning. Neutrophils and platelets were engrafted 10 and 11 days after transplantation, respectively, with 99% donor chimerism evident in marrow 30 days after transplantation. His post-transplant course was complicated by severe acute graft-versus-host disease (GVHD) involving skin (grades 2-3), liver (grade 2, biopsy-proven) and gut (grade 4) requiring prolonged and heavy immunosuppression including prednisolone, cyclosporine, and mycophenolate mofetil. He also had disseminated nocardiosis complicated by left lower lobe necrotising pneumonia, parapneumonic effusion, hydropneumothorax and bronchopleural fistula. Prolonged courses of antimicrobials were required and included meropenem, levofloxacin, ceftriaxone, cotrimoxazole, linezolid and amikacin. Due to liver GVHD, the patient had grossly deranged liver function 8 months post-transplantation with peak alanine aminotransferase level of 720 IU/L, aspartate aminotransferase level 506 IU/L, and gamma-glutamyltransferase level 1916 IU/L. His worst cholestasis occurred 2 years post-transplantation with total bilirubin level of 312 μmol/L and direct bilirubin level 270 μmol/L (Fig c and Table). He was noted to have a lipemic blood sample (Fig d) at this time and lipid profile revealed total cholesterol level of 13.6 mmol/L, LDL-C (calculated) level 11.4 mmol/L, HDL-C level 0.2 mmol/L and TG level 4.2 mmol/L (Table). Physical examination did not show any xanthoma. With the clinical context of severe cholestasis, LDL-C was measured directly and revealed discordance between the measured and the calculated value (1.7 mmol/L vs 11.4 mmol/L). Low Apo A1 (0.52 g/L) and elevated Apo B (1.7 g/L) levels were revealed. Trace chylomicron band, Lp-X band and faint lipoprotein Y bands were detected on lipoprotein electrophoresis (Fig d).
 
Discussion
Liver GVHD is a known complication of allogeneic haematopoietic stem cell transplantation. It is characterised by elevation of hepatic enzymes, cholestasis, severe hypercholesterolaemia and hypertriglyceridaemia (in excess of 1000 mg/dL). In contrast to drug-mediated hypercholesterolaemia (cyclosporine, sirolimus, mycophenolate and glucocorticoids) when cholesterol level is usually <7.8 mmol/L (300 mg/dL) and mediated by LDL-C, hypercholesterolaemia caused by liver GVHD is mediated by cholestasis. In general, there are two main sources that contribute to the liver cholesterol pool, namely de novo (endogenous) cholesterol that is mainly synthesised in the liver, and dietary cholesterol (exogenous). Liver is the primary site of cholesterol biosynthesis and storage. It is also the principal site of sterol elimination by converting cholesterol to bile acids and removing free cholesterol as neutral sterols via biliary excretion.1 2 In liver GVHD-related cholestasis, impaired bile flow results in accumulation of cholesterol and bile salts, and hence elevated LDL-C level. Lipoprotein-X is another major cause of hyperlipidaemia in cholestasis when bile constituents reflux from the bile ducts or hepatocytes to the blood stream. Lipoprotein-X particles are formed when bile lipoprotein enters the blood stream and incorporates TG, Apo C and esterified cholesterol. Unlike LDL-C, Lp-X does not contain Apo B, the most important ligand to the hepatic LDL-C receptor. Therefore, Lp-X cannot be internalised into hepatocytes. Since Lp-X hypercholesterolaemia is not due to overproduction by hepatocytes, use of medications such as statins to downregulate cholesterol synthesis is ineffective.3 In addition, since Lp-X does not contain Apo B, which is the major component of LDL and one of the most important factors in the pathogenesis of atherosclerotic plaques, it is not atherogenic.4 Neither of our cases reported here had any complications of hypercholesterolaemia including exanthemata, retinal thromboembolism and pulmonary cholesteroloma. Nonetheless Lp-X may be associated with hyperviscosity syndrome and plasma exchange or apheresis may be indicated.5
 
As reported in the literature, hypercholesterolaemia secondary to intrahepatic cholestasis caused by liver GVHD can appear at any time between 2 months and 2 years after haematopoietic stem cell transplantation. The condition can be easily diagnosed by demonstrating discordance between calculated and directly measured LDL-C level, as well as lipoprotein electrophoresis. With the resolution of cholestasis, Lp-X will resolve with no specific treatment.
 
To conclude, severe hypercholesterolaemia mediated by Lp-X in post-haematopoietic stem cell transplantation patients with liver GVHD is a recognised yet overlooked phenomenon. Reports in the literature are limited for both adult and paediatric populations. To the best of our knowledge, this is the first report in Chinese children. Transplant physicians and endocrinologists should have an increased awareness of this association and avoid unnecessary and ineffective use of statins.
 
Author contributions
Concept or design: WYK Chan, JYL Tung.
Acquisition of data: WYK Chan, ECY Law, TK Ling, FCK Wong, JYL Tung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: WYK Chan.
Critical revision of the manuscript for important intellectual content: All authors.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
Patients were treated in accordance with the Declaration of Helsinki. Consents for treatment, procedures and publication were obtained.
 
References
1. Fellin R, Manzato E. Lipoprotein-X fifty years after its original discovery. Nutr Metab Cardiovasc Dis 2019;29:4-8. Crossref
2. Nemes K, Åberg F, Gylling H, Isoniemi H. Cholesterol metabolism in cholestatic liver disease and liver transplantation: from molecular mechanisms to clinical implications. World J Hepatol 2016;8:924-32. Crossref
3. Zidan H, Lo S, Wiebe D, Talano J, Alemzadeh R. Severe hypercholesterolemia mediated by lipoprotein X in a pediatric patient with chronic graft-versus-host disease of the liver. Pediatr Blood Cancer 2008;50:1280-1. Crossref
4. Miida T, Hirayama S. Controversy over the atherogenicity of lipoprotein-X. Curr Opin Endocrinol Diabetes Obes 2019;26:117-23. Crossref
5. Heinl RE, Tennant HM, Ricketts JC, et al. Lipoprotein-X disease in the setting of severe cholestatic hepatobiliary autoimmune disease. J Clin Lipidol 2017;11:282-6. Crossref

Delayed interval delivery in twin pregnancy in Hong Kong: two case reports

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Delayed interval delivery in twin pregnancy in Hong Kong: two case reports
Annie SY Hui, MRCOG1; Winnie WY Chan, MRCOG1; YM Wah, MRCOG1; L Wong, MRCOG1; Hugh Simon HS Lam, MD, FRCPCH2; TY Leung, MD, FRCOG1
1 Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
2 Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
 
Corresponding author: Dr Annie SY Hui (anniehui@cuhk.edu.hk)
 
 Full paper in PDF
 
Case report
Case 1
A 40-year-old nulliparous woman carried the index dichorionic diamniotic (DCDA) twin pregnancy, conceived in 2014 by in vitro fertilisation due to unexplained infertility. Antenatal investigations were all unremarkable.
 
At 26 weeks and 1 day of gestation she presented to our local delivery suite with signs of preterm labour. Examination revealed the cervix to be fully dilated. Maternal corticosteroids for foetal lung maturation, prophylactic antibiotics and magnesium sulphate infusion for neuroprotection were administered. Twin 1 (T1) was delivered vaginally 4 hours after admission. The baby weighed 800 g, with Apgar scores (AS) of 6 at 1 minute and 8 at 5 minutes. The first blood gas showed a pH of 7.37.
 
Soon after, uterine contractions subsided spontaneously and the cervix quickly closed. Twin 2 (T2) membranes remained intact. After counselling, the couple opted for delayed interval delivery (DID), aiming to enhance the lung maturity of T2. The cord of T1 was ligated and placed in the vagina. Oral nifedipine was added to maintain uterine quiescence. Twelve hours later, the patient developed regular uterine contractions with fever of 37.8°C. Vaginal examination revealed a fully dilated cervix with bulging membranes and shoulder presentation of T2, converted manually to cephalic presentation following uterine relaxation with the tocolytic atosiban. Twin 2 was born vaginally with a twin-to-twin delivery interval of 14 hours and weighing 780 g with AS of 4 at 1 minute, 5 at 5 minutes and 7 at 10 minutes and arterial cord gas of pH 6.94. A placental swab grew Escherichia coli and a high vaginal swab grew Pseudomonas aeruginosa. The placenta showed acute chorioamnionitis.
 
Twin 1 had acute respiratory distress syndrome and was intubated up to day 27 of life. The baby was discharged at 4 months of age with severe bronchopulmonary dysplasia. Mild speech delay at 3 years of age required additional therapy. Twin 2 benefited from antenatal corticosteroid and was weaned off mechanical ventilation on day 17 of life and discharged home at 3 months of age. Both twins have normal growth and development at the age of 6 years.
 
Case 2
A 39-year-old woman carried the index monochorionic diamniotic twin pregnancy, conceived naturally in late 2019. Antenatal investigations and ultrasound scans every 2 weeks were unremarkable until 24 weeks and 5 days of gestation when she was admitted with preterm prelabour rupture of membranes. Maternal corticosteroids for foetal lung maturation and prophylactic antibiotics were administered. Maternal leukocytosis of 15.5 × 109/L and raised C-reactive protein of 16.3 g/L were noted, but high vaginal swab and mid-stream urine cultures were negative. Three days later, she went into spontaneous labour. Magnesium sulphate infusion was commenced for neuroprotection. Twin 1 was delivered vaginally and weighed 670 g. Apgar scores were 6 at 1 minute and 8 at 5 minutes, and arterial cord gas pH was 7.349.
 
Uterine contractions subsided afterwards and the cervix closed. In view of extreme prematurity, the couple opted for DID. High ligation of the cord was performed (Fig). The patient continued to receive intravenous ampicillin, metronidazole and oral erythromycin with monitoring of vital signs. There were no signs of sepsis, and serial blood tests revealed that white cell count and C-reactive protein had normalised after delivery of T1. Serial cardiotocography of T2 showed normal foetal heart rate pattern and ultrasound confirmed normal middle cerebral artery peak systolic velocity. Nine days later, at 26 weeks and 4 days gestation, preterm prelabour rupture of membranes of T2 occurred. Labour was induced by syntocinon infusion but fresh per vaginal bleeding was noted 5 hours later. Cardiotocography showed a non-reassuring pattern but the cervix was only 3 cm dilated. Emergency lower segment caesarean section was performed for suspected foetal distress. Twin 2 was delivered weighing 860 g with AS of 6 at both 1 and 5 minutes, and arterial cord gas pH of 7.4.
 

Figure. Ultrasound depicting the position of the ligated cord of Twin 1 (0.84 cm in diameter) inside the cervical canal (4.46 cm long) of Case 2
 
Apart from severe respiratory distress syndrome, T1 had E coli septicaemia, a large left subdural haematoma and right intraventricular haemorrhage, disseminated intravascular coagulopathy, and seizures. Despite intensive treatment, T1 deteriorated and died on day 17 of life. Twin 2 remained stable and was extubated to non-invasive ventilation on day 9. Cranial ultrasounds were normal. Twin 2 was discharged home at 3 months of age and remains well at 1 year of age at the time of writing.
 
Discussion
To the best of our knowledge these two cases are the first reported DID in Hong Kong. Twin pregnancies are at higher risk of preterm delivery and DID has been proposed to improve survival of the second twin. In a recent systematic review of 492 multifetal pregnancies managed with DID, the reported twin-to-twin delivery interval ranged from 1 to 153 days with a median of 29 days. Delayed interval delivery was associated with significantly improved perinatal survival of the remaining foetus compared with the co-twin (odds ratio=5.22, 95% confidence interval=2.95-9.25).1 A delay as short as one day may be sufficient for steroid treatment to enhance foetal lung maturation, as illustrated by Case 1: T1 had respiratory distress syndrome and required a longer duration of intubation and hospitalisation than T2. Although T2 had acute foetal distress secondary to in-utero infection and shoulder presentation, T2 recovered rapidly from the acute event with no long-term sequelae.
 
The beneficial effect of DID is more often described in DCDA twins (odds ratio=14.89, 95% confidence interval=6.19-35.84).1 Data on monochorionic diamniotic twins are sparse since monochorionicity is often regarded as a contra-indication for DID due to the potential risk associated with vascular anastomoses between the twins.2 Nonetheless with complete occlusion of the first twin’s umbilical vessels on delivery, the risk of vascular instability for T2 should be minimised, as illustrated in our Case 2.3 4 Interestingly in Case 2, only T1 had in-utero infection with consequent E coli septicaemia. It is possible that the inter-twin membrane acted as a barrier and prevented or delayed spread of infection to the second twin.
 
There are several elements to consider when deciding to opt for DID. First, the underlying cause of preterm labour is often unknown at the time of presentation. If there is subclinical infection or placental abruption, leaving the second twin in utero may be detrimental. Second, a secondary ascending infection may occur following delivery of the first twin. Obstetricians should carefully consider the risks and benefits of DID versus those of delivery at periviable or extreme preterm gestation. Extra precautions should be taken before and after opting for DID, including a high ligature of the first twin’s cord, antibiotic cover, and close surveillance of maternal and foetal well-being.5
 
Author contributions
Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: ASY Hui, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: 2021.159). Both patients provided informed consent for the publication of non-identifiable information.
 
References
1. Cheung KW, Seto MT, Wang W, Lai CW, Kilby MD, Ng EH. Effect of delayed interval delivery of remaining fetus(es) in multiple pregnancies on survival: a systematic review and meta-analysis. Am J Obstet Gynecol 2020;222:306-19.e18. Crossref
2. Minakami H, Honma Y, Izumi A, Sayama M, Sato I. Emergency cervical cerclage after the first delivery in a twin pregnancy with dichorionic placenta. Am J Obstet Gynecol 1995;173:345-6. Crossref
3. Ting YH, Poon LC, Tse WT, et al. Outcome of radiofrequency ablation for selective fetal reduction before vs at or after 16 gestational weeks in complicated monochorionic pregnancy. Ultrasound Obstet Gynecol 2021;58:214-20. Crossref
4. Lu J, Ting YH, Law KM, Lau TK, Leung TY. Radiofrequency ablation for selective reduction in complicated monochorionic multiple pregnancies. Fetal Diagn Ther 2013;34:211-6. Crossref
5. Porreco RP, Farkouh LJ. Multifetal gestation: role of delayed-interval delivery. Available from: https://www.uptodate.com/contents/multifetal-gestation-role-of-delayed-interval-delivery. Accessed 4 Oct 2021.

Grave impact of undetected rpoB I572F mutation on clinical course of multidrug-resistant tuberculosis: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Grave impact of undetected rpoB I572F mutation on clinical course of multidrug-resistant tuberculosis: a case report
Alan CK Chan, MRCP (UK), FHKAM (Medicine)1; Martin CH Chan, MB, BS2; Peter CW Yip, PhD2; WC Yam, PhD, FRCPath3; CH Chau, MRCP, FHKAM (Medicine)4; Raymond FM Lam, MB, ChB, FHKCP4; LB Tai, MRCP, FHKAM (Medicine)1; CC Leung, FFPH, FHKAM (Medicine)5
1 Tuberculosis and Chest Service, Department of Health, Hong Kong SAR Government, Hong Kong
2 Public Health Laboratory Service Branch, Department of Health, Hong Kong SAR Government, Hong Kong
3 Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong
4 Tuberculosis and Chest Unit, Grantham Hospital, Hong Kong
5 Hong Kong Tuberculosis, Chest and Heart Diseases Association, Hong Kong
 
Corresponding author: Dr Alan CK Chan (chikuen_chan@dh.gov.hk)
 
 Full paper in PDF
 
Case report
Accelerating diagnosis and treatment of rifampicin-resistant/multidrug-resistant tuberculosis (MDR-TB) are key components of the World Health Organization’s End TB Strategy.1 Rifampicin resistance that arises from mutations outside the 81-base pair (bp) rifampicin-resistance determining region (RRDR) of the rpoB gene such as the I572F mutation nonetheless cannot be detected by existing World Health Organization–endorsed Xpert MTB/RIF assay or line probe assays (LPAs).2 Mutations located outside the rpoB hotspot may also be missed by the liquid medium–based BACTEC Mycobacteria Growth Indicator Tube (MGIT) culture system. We report a rare case of MDR-TB with rpoB I572F mutation (Escherichia coli numbering system) that was missed by LPA and liquid culture but confirmed by full rpoB gene sequencing to illustrate the negative impact of the mutation being undetected.
 
A 54-year-old Chinese man presented with symptoms of TB in July 2019. He had no history of anti-TB treatment. Chest radiograph on presentation showed bilateral cavitary lesions (Fig a). Sputum acid-fast bacilli smear examination was positive. Xpert MTB/RIF assay confirmed Mycobacterium tuberculosis (MTB)–positive/rifampicin-negative pulmonary TB. He was prescribed standard anti-TB treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide. Initial sputum culture (performed with an MGIT culture system) later confirmed MTB organisms susceptible to all first-line drugs. Nonetheless lung shadows did not improve on serial chest radiographs (Fig b and c) despite good compliance with directly observed therapy. Sputum culture was transiently negative between November 2019 and January 2020. Culture result of a sputum specimen saved in October 2019 became available in January 2020 and showed MTB organisms resistant to isoniazid. The LPA (GenoType MTBDRplus Version 2.0; Hain Lifescience GmbH, Nehren, Germany) performed at that juncture showed an inhA C-15T mutation but no mutation in the rpoB gene. The regimen was switched to rifampicin, levofloxacin, ethambutol and pyrazinamide. Sputum culture reverted to positive in subsequent months and acid-fast bacilli smear also reverted to positive at 12 months. The LPA repeated at 12 months showed inhA C-15T and gyrA D94A mutations. Mutation of rpoB, rrs and enhanced intracellular survival genes was not detected although whole genome sequencing (WGS) performed on isolates obtained at 12 months revealed mutations of rpoB I572F, inhA C-15T, embB D354A, pncA D63G, and gyrA D94A. Whole genome sequencing performed retrospectively on isolates obtained earlier confirmed that rpoB I572F and inhA C-15T mutations had been present since the beginning of treatment. Culture result (using liquid culture system) of a sputum specimen saved at 12 months later became available and showed bacillary resistance to streptomycin, isoniazid, ethambutol and levofloxacin, but rifampicin resistance was again missed. In view of the gene sequencing result, the regimen was switched to a bedaquiline-containing regimen at 12 months. The patient responded well to treatment thereafter (Fig d).
 

Figure. (a) A 54-year-old Chinese man with pulmonary tuberculosis. Chest radiograph on presentation showed extensive bilateral shadows with cavitation, especially in both upper zones and right lower zone. Xpert MTB/RIF assay showed MTB positive/RIF negative. Initial sputum culture (liquid medium–based) showed Mycobacterium tuberculosis (MTB) organisms susceptible to all first-line drugs. (b) Chest radiograph showing persistent shadows after about 6 months of treatment with first-line drugs when culture result of sputum specimen collected at 3 months revealed isoniazid-resistant MTB organisms. Line probe assay showed inhA C-15T mutation. Mutation associated with rifampicin resistance was not detected. The regimen was switched to rifampicin, levofloxacin, ethambutol and pyrazinamide. (c) Chest radiograph at 12 months showing persistent cavitary shadows in the left upper zone. Some improvement in shadows in right lung field was seen. The rpoB I572F mutation that conferred rifampicin resistance was detected by gene sequencing but not by line probe assay. Rifampicin resistance was again missed by phenotypic drug susceptibility testing repeated at this juncture. The regimen was changed to a bedaquiline-containing regimen. (d) Chest radiograph taken at 24 months showing improvement in bilateral lung shadows after being put on treatment with bedaquiline-containing regimen
 
Discussion
Although most cases of rifampicin resistance are linked to mutations in the 81-bp hotspot region of the rpoB gene, notably mutations at codons 526 to 531, our case illustrates the occurrence of rare mutations outside the RRDR, namely I572F, and its negative impact on treatment outcome due to amplification of further drug resistance if left undetected. In our case, initial rifampicin resistance conferred by rpoB I572F mutation was missed by Xpert MTB/RIF assay, LPA and liquid medium–based culture system. Due to the exceptionally slow growth of this strain, prolonged incubation using MGIT was required and there was also difficulty in selecting log phase growth for subsequent drug susceptibility testing (DST). Not only was turnaround time increased, but initial isoniazid resistance was also missed although it was detected in the subsequent strains phenotypically. The patient therefore received an inadequate number of drugs during the early course of anti-TB treatment resulting in further acquired drug resistance to ethambutol, pyrazinamide, and levofloxacin. Amplification of drug resistance in our case likely emerged from the segregation of a single strain into two lineages of drug-susceptible and drug-resistant organisms under the selective pressure of insufficient TB therapy. This was suggested by the presence of both wild type and resistant subpopulations during the transition from susceptibility to resistance with regard to levofloxacin from the WGS data on D94A mutation.
 
Review of the database at the TB Supranational Reference Laboratory, Centre for Health Protection, Department of Health of Hong Kong revealed a total of five cases of MDR-TB with rpoB I572F mutation (including the present case) out of 340 rifampicin-resistant isolates between 2011 and 2020, corresponding to a prevalence of 1.5%. The prevalence of rpoB I572F in Hong Kong in this study is similar to that (2%) reported from a previous local study.3 On the contrary, a much higher prevalence of rpoB I572F mutation (corresponding to Ile491Phe mutation in MTB numbering system) has been reported recently in some countries with high TB prevalence such as Eswatini (formerly Swaziland) and South Africa (30% and 15%, respectively).4 The highly variable prevalence of rpoB I572F mutation in different geographical regions highlights the importance of expanding the geographical database of this mutation to better understand its global prevalence.
 
To improve the accuracy of phenotypic DST, the World Health Organization has recently lowered the critical concentration for rifampicin susceptibility testing in MGIT from 1 mg/L to 0.5 mg/L.5 The revised recommendation helps reduce but does not eliminate the discordance observed between phenotypic and molecular methods to detect rifampicin resistance and the potential false-susceptible results from phenotypic tests due to the presence of mutations outside the RRDR. Given the potential impact of rifampicin resistance conferred by an rpoB I572F mutation on treatment outcomes, and that an increasingly higher prevalence of such mutations has been reported recently in some countries, new molecular tests that expand the drug target coverage to help guide the formulation of treatment regimens are warranted. Expanding the target 81-bp hotspot RRDR of the rpoB gene to include codon 572 has been suggested.3 More recently, a multiplex allele-specific polymerase chain reaction (PCR) assay to detect I572F mutation in rpoB has been designed using a one-step real-time PCR.6 Although novel PCR assays may enable efficient and rapid detection of rpoB I572F mutation and are simpler than sequencing methods, their implementation requires further validation and strengthening of laboratory capacities.
 
Until novel PCR assays and WGS gain widespread use, clinicians should remain alert for the more rare rpoB mutations such as the I572F mutation, and communicate promptly with laboratories for further tests if a patient does not respond well to standard first-line treatment. This is vital even if Xpert MTB/RIF assay, LPAs or phenotypic DST do not suggest the presence of rifampicin resistance to ensure the patient receives an adequate number of effective drugs for treatment success. Our case also calls for continued surveillance of the prevalence of rpoB I572F mutation and other rifampicin-resistance conferring mutations outside the RRDR to inform region-specific TB diagnostic and treatment strategies.
 
Author contributions
All authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
The authors have disclosed no conflicts of interest.
 
Declaration
Part of the findings of this study has been presented at the Hong Kong Thoracic Society clinical meeting on 26 May 2022, which was an internal meeting attended by members of the Society held in virtual format.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and provided written informed consent for publication.
 
References
1. World Health Organization. The end TB strategy. 2015. Available from: https://www.who.int/publications/i/item/WHO-HTM-TB-2015.19. Accessed 31 Jan 2023.
2. Nguyen TN, Anton-Le Berre V, Bañuls AL, Nguyen TV. Molecular diagnosis of drug-resistant tuberculosis; a literature review. Front Microbiol 2019;10:794. Crossref
3. Siu GK, Zhang Y, Lau TC, et al. Mutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2011;66:730-3. Crossref
4. Variava E, Martinson N. Occult rifampicin-resistant tuberculosis: better assays are needed. Lancet Infect Dis 2018;18:1293-5. Crossref
5. World Health Organization. Technical report on critical concentrations for drug susceptibility testing of isoniazid and the rifamycins (rifampicin, rifabutin and rifapentine). Geneva: World Health Organization; 2021.
6. André E, Goeminne L, Colmant A, Beckert P, Niemann S, Delmee M. Novel rapid PCR for the detection of Ile491Phe rpoB mutation of Mycobacterium tuberculosis, a rifampicin-resistance-conferring mutation undetected by commercial assays. Clin Microbiol Infect 2017;23:267.e5-7. Crossref

Extraosseous myeloma of liver mimicking multifocal hepatocellular carcinoma where a distinction has to be made: two case reports

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Extraosseous myeloma of liver mimicking multifocal hepatocellular carcinoma where a distinction has to be made: two case reports
HM Kwok, MB, BS, FRCR#; Eugene Sean Lo, MB, BS#; T Wong, FRCR, FHKAM (Radiology); Heather HC Lee, MB, BS/BSC, FRCR; HT Chau, MB, BS; FH Ng, FRCR, FHKAM (Radiology); WH Luk, FRCR, FHKAM (Radiology); Johnny KF Ma, FRCR, FHKAM (Radiology)
Department of Radiology, Princess Margaret Hospital, Hong Kong
# Equal contribution
 
Corresponding author: Dr HM Kwok (khm778@ha.org.hk)
 
 Full paper in PDF
 
Case report
Case 1
A 67-year-old man with kappa light chain multiple myeloma (MM) had a baseline negative skeletal survey and had undergone dual-tracer positron emission tomography–computed tomography (CT) with fluorine-18 fluorodeoxyglucose and carbon-11 acetate. An initial biochemical response to combined chemotherapy with bortezomib, thalidomide and dexamethasone later plateaued; therefore, he was switched to second-line chemotherapy with ixazomib, lenalidomide and dexamethasone. He then developed progressively deranged liver function and new-onset pancytopenia with fever during the first cycle. Ultrasound revealed multiple bi-lobar hepatic hypoechoic lesions, some with a central echogenic focus surrounded by hypoechoic rim (target appearance), suggesting possible hepatic candidiasis. Nonetheless there was progressive worsening of liver function and recurrent fever despite intravenous antifungal therapy. Urgent multiphasic CT revealed a small arterial enhancing nodule in hepatic segment V with washout. A newly developed lytic sacral lesion was suspected to be myeloma involvement. The liver CT 3 weeks later showed an interval increase in size and number of these liver lesions with similar enhancement pattern. Multifocal hepatocellular carcinoma (HCC) was one of the prime differential diagnoses (Fig 1). Hepatitis B and C tests were negative. Tumour markers including alpha-fetoprotein were normal. Due to the rapid interval lesion enlargement, absence of risk factor for HCC, and the need to exclude possible opportunistic fungal infection, ultrasound-guided liver biopsy was performed and confirmed myeloma involvement.
 

Figure 1. Case 1. Initial ultrasound scan revealed multiple well-circumscribed round hypoechoic hepatic lesions with central echogenic focus measuring up to 1.2 cm (white arrows and arrowhead in [a] & [b], respectively). Morphology resembles a ‘bullseye’ appearance and was thought to represent possible hepatic candidiasis. Subsequent multiphasic computed tomography (CT) [white arrows] revealed (c) a single hypoattenuating lesion at segment V (about 1.4 cm in diameter) demonstrating (d) arterial hyperenhancement, (e) portal venous washout and (f) delayed washout. Hepatocellular carcinoma is a possible differential for this radiological pattern. A developing left sacral lytic lesion with soft tissue component was noted on the same CT (not shown). Follow-up triphasic CT scan of the liver within 3 weeks showed multiple bi-lobar new arterial enhancing lesions (white arrows and arrowheads in [g]), (h) some with portal venous washout and delayed washout. The smaller ones (white arrowheads in [g]) were isoattenuating in portal venous and delayed phases and cannot be discretely identified. There was also rapid interval enlargement of segment V hepatic lesion, measuring up to 2.5 cm in diameter with (i) arterial enhancement, (j) portal venous washout and delayed washout (white arrowheads). Biopsy of this segment V lesion confirmed clonal plasma cells, consistent with the diagnosis of hepatic extraosseous myeloma
 
Case 2
A 51-year-old woman with lambda light chain MM diagnosed in 2011 was in remission following treatment with bortezomib, thalidomide and dexamethasone. Autologous peripheral blood stem cell transplantation was performed but she developed disease relapse 18 months later, salvaged by combined bortezomib-melphalan-prednisone. She presented within a year with a second relapse and a 1-week history of fever, increasing diffuse bone pain and abdominal distention. Mild hepatosplenomegaly was noted on physical examination. Pancytopenia was evident (haemoglobin 7.6 g/dL, platelet count 17×109/L, white blood cell count 1.7×109/L). Blood culture and hepatitis markers were negative. Ultrasound revealed a hypoechoic lesion at the right hepatic lobe, bi-lobar hepatic hyperechoic lesions with hypoechoic rim and mild ascites. In the presence of her high swinging fever, liver abscesses were suspected. Hepatosplenomegaly was confirmed on CT performed 1 day later. In addition, multiple hypodense liver lesions, most of which were subcapsular, were observed. They showed arterial contrast enhancement and became hypo-enhancing in the portovenous phase. No rim-enhancing lesions were present to suggest abscess formation. There were innumerable lytic lesions in bone, including partial collapse of T11 and L1 and a lytic lesion at the right transverse process of T10 with enhancing soft tissue mass (Fig 2). Overall features suggested progressive disease with presumably myelomatous involvement of liver and bone. She was prescribed two cycles of lenalidomide, bortezomib, and dexamethasone followed by four more cycles of lenalidomide and dexamethasone. Follow-up CT showed interval resolution of the previous noted bi-lobar liver lesions and sub-centimetre hypo-enhancing focus representing post-treatment change or residual disease, supporting the presumption of liver extraosseous myeloma (EM). Repeat bone marrow examination revealed hypercellular marrow with residual plasma cell myeloma. She then underwent hematopoietic stem cell transplantation.
 

Figure 2. Case 2. (a) & (b) Ultrasound of upper abdomen revealed a hypoechoic lesion at the right hepatic lobe [white arrows], (c) multiple hyperechoic lesions with hypoechoic rim in both hepatic lobes (one in white arrow). These were non-specific. Multiphasic computed tomography performed a day later confirmed hepatomegaly. (d) Multiple hypodense liver lesions (white arrows), most being subcapsular, were also seen. They showed (e) arterial contrast enhancement (white arrows) and (f) became hypo-enhancing on portovenous phase (white arrows). There were no rim-enhancing lesions to suggest abscess formation. Mild ascites was noted. There were innumerable lytic lesions in bone, including partial collapse of T11 and L1 and a lytic lesion at the right transverse process of T10 with enhancing soft tissue mass (not shown). Overall features suggested progressive disease with myelomatous involvement of liver and bone
 
Discussion
Extraosseous myeloma is an uncommon form of MM associated with poorer prognosis and survival.1 2 It is caused by migration of malignant plasma cells from the bone marrow microenvironment. The presence of extraosseous involvement of MM is not uncommon; it has been previously reported in more than 63% of patients in an autopsy series, with 28 to 30% having liver involvement.1 The reticuloendothelial system (liver, spleen and lymph nodes) is the most commonly affected extraosseous site.2 Although well documented in the pathology literature, this clinical entity remains under-recognised and underreported in radiology.
 
We report two cases of multifocal EM of the liver in two Chinese patients from a tertiary hospital in Hong Kong, mimicking multifocal HCC on multiphasic CT. To the best of our knowledge, this pattern has not been reported previously. First, we aim to increase radiologist awareness of the hypervascular multinodular pattern of liver EM. Second, HCC is common in Southeast Asia including Hong Kong and remains an imaging diagnosis with no histological confirmation required prior to treatment. There are overlapping imaging features of both extraosseous MM in liver and HCC. Hence, biopsy is needed for differentiation.
 
Imaging findings of EM are highly variable and non-specific. The two most common presentations are the more common diffuse form with hepatomegaly in the absence of a focal lesion due to diffuse liver parenchymal infiltration and the focal nodular form with hypodense non-calcified nodule and minimal enhancement. On ultrasound, focal patterns of involvement can be hypoechoic, hyperechoic, mixed or target (isoechoic nodule with hypoechoic rim). On CT, focal lesions are generally described as hypoattenuating with minimal enhancement and no calcification. On magnetic resonance imaging, focal lesions may be hyper- or hypo-intense on T1-weighted images and hyperintense on T2-weighted images with minimal gadolinium enhancement.2 3 Scarce literature has documented hypervascular enhancement patterns with washout on multiphasic CT or magnetic resonance imaging, and only few case reports have reported only a solitary focal mass.4 5 6 The multinodular form with hypervascular enhancement pattern has not been reported before. Currently there remains a lack of knowledge about distinction of EM of liver from other hypervascular liver tumours due to its rarity. Arterial phase imaging is vital for lesion detection since some of the lesions may be too small and too vaguely hypo-enhancing to be detected during portovenous or delayed phases. The differential diagnoses with multiple hypervascular liver masses commonly include multifocal HCC and hypervascular metastases. Its significance is underestimated, especially in areas where HCC is endemic, such as Southeast Asia. Clinicians and even radiologists may misdiagnose these lesions as HCC, which is an imaging diagnosis, and specific oncological treatment will be given without histological confirmation of the lesion leading to mismanagement. It is important to bear in mind the possibility of myeloma of liver in patients with known myeloma who present with hypervascular mass on CT. We advocate a diagnostic approach with emphasis on the use of multiphasic cross-sectional studies including CT for detection, and risk stratification (by alpha-foetal protein, and hepatitis status). If these appear atypical of HCC or EM involvement of liver, a timely biopsy to confirm the diagnosis is recommended to avoid misdiagnosis and subsequent mismanagement.
 
There are other points in the diagnostic challenge posed by EM of the liver that influence clinical management.
 
First, the variable sonographic appearance of multinodular hepatic lesions, including target appearance mimicking hepatic candidiasis, and hypoechoic lesions raising a suspicion of pyogenic abscesses, may lead to unnecessary antifungal or antibacterial treatment.
 
Second, only one single large lesion was initially seen in our first case on multiphasic CT. This was in concordance with multiple previous studies that reported cases of EM of liver where lesions are more conspicuous on ultrasound than on CT.3 Regarding the hepatic lesions on CT from our cases, they were most conspicuous on the arterial phase, while the smaller ones may be isoattenuating or minimally hypo-enhancing on portovenous or delayed phases. In addition, most lesions had a subcapsular location in the liver, an important area to review. Knowing that this entity may be underdiagnosed, further studies are needed to determine the most sensitive initial staging modality to look for liver involvement. Based on our cases, both ultrasound and multiphasic CT (including arterial, portovenous, and 5-minute delayed) phases play an important role in initial screening, subsequent characterisation, and in guiding biopsy.
 
Conclusion
Extraosseous myeloma of the liver is a rare and under-recognised entity associated with poorer prognosis and survival. Imaging features are non-specific but can mimic multifocal HCC on multiphase CT. We advocate the use of multiphasic CT (including arterial phase) for detection. The presence of hypervascular liver masses in patients with known MM should alert radiologists to this diagnosis. Definitive diagnosis should be by tissue biopsy if there is a mismatch between clinical risk factors and imaging, especially in areas endemic for HCC.
 
Author contributions
Concept or design: HM Kwok, ES Lo.
Acquisition of data: HM Kwok, ES Lo.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: HM Kwok, ES Lo.
Critical revision of the manuscript for important intellectual content: HM Kwok, ES Lo.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Acknowledgement
We would like to express our gratitude to the haematology and oncology physicians of Princess Margaret Hospital, Hong Kong, for their professional patient care and invaluable contribution to the understanding of a novel disease.
 
Declaration
Case 1 of the study was accepted as oral presentation in the 19th Asian Oceanian Congress of Radiology 2021, Malaysia.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This study was approved by the Kowloon West Cluster Research Ethics Committee [Ref No.: KW/EX-21-054 (157-19)]. Patients were treated in accordance with the Declaration of Helsinki, with informed consent provided for treatment, procedures, and publication.
 
References
1. Oshima K, Kanda Y, Nannya Y, et al. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma. Am J Hematol 2001;67:1-5. Crossref
2. Moulopoulos LA, Granfield CA, Dimopoulos MA, Kim EE, Alexanian R, Libshitz HI. Extraosseous multiple myeloma: imaging features. AJR Am J Roentgenol 1993;161:1083-7. Crossref
3. Philips S, Menias C, Vikram R, Sunnapwar A, Prasad SR. Abdominal manifestations of extraosseous myeloma: cross-sectional imaging spectrum. J Comput Assist Tomogr 2012;36:207-12. Crossref
4. Cho R, Myers DT, Onwubiko IN, Williams TR. Extraosseous multiple myeloma: imaging spectrum in the abdomen and pelvis. Abdom Radiol (NY) 2021;46:1194-209. Crossref
5. Marcon M, Cereser L, Girometti R, Cataldi P, Volpetti S, Bazzocchi M. Liver involvement by multiple myeloma presenting as hypervascular focal lesions in a patient with chronic hepatitis B infection. BJR Case Rep 2016;2:20150013. Crossref
6. Tan CH, Wang M, Fu WJ, Vikram R. Nodular extramedullary multiple myeloma: hepatic involvement presenting as hypervascular lesions on CT. Ann Acad Med Singap 2011;40:329-31. Crossref

Neutropenia and anaemia secondary to copper deficiency in a child receiving long-term jejunal feeding: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Neutropenia and anaemia secondary to copper deficiency in a child receiving long-term jejunal feeding: a case report
WY Leung, MRCPCH1; CC So, FRCPath2,3,4; Godfrey CF Chan, FRCPCH1,5; SY Ha, FRCPCH1,5; Alan KS Chiang, FRCP1,5; Daniel KL Cheuk, FHKAM (Paediatrics)1,5
1 Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong
2 Department of Pathology, Hong Kong Children’s Hospital, Hong Kong
3 Department of Pathology, Queen Elizabeth Hospital, Hong Kong
4 Department of Pathology, The University of Hong Kong, Hong Kong
5 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong
 
Corresponding author: Dr WY Leung (lwy729@ha.org.hk)
 
 Full paper in PDF
 
Case report
In January 2017, a girl was born full term to non-consanguineous Chinese parents. Oesophageal atresia with a distal tracheo-oesophageal fistula was diagnosed soon after birth. Emergency surgical repair was attempted on day 1 of life but was complicated by complete transection of the left main bronchus that was subsequently repaired. The tracheo-oesophageal fistula was divided and a gastrostomy created. End-to-end anastomosis of the proximal and distal oesophagus was performed at age 6 months. Gastrostomy feeding was switched to jejunal feeding at 7 months because of gastroesophageal reflux and recurrent aspiration pneumonia. Attempted fundoplication at 17 months failed due to a small tubular stomach. She was prescribed oral ranitidine 30 mg three times daily.
 
At birth, the child’s haematology results were normal but by age 2 years she had developed persistent severe neutropenia (lowest neutrophil count 0.13 × 109/L) and microcytic anaemia, with a lowest haemoglobin of 6.6 g/dL and lowest mean corpuscular volume of 65.5 fL. Platelet count was normal and she had no major infection or signs of anaemia. She was on continuous jejunal feeding with high-energy infant formula (Infatrini; Nutricia, Zoetermeer, The Netherlands) 640 mL daily as well as iron(III)-hydroxide polymaltose complex (IPC) 25 mg daily and multivitamin drops (Poly-Vi-Sol; Mead-Johnson Nutrition, Chicago [IL], United States) 1 mL daily. The high-energy infant formula provided 416 μg of copper daily, equivalent to 1.2 times the recommended dietary allowance.
 
Growth was satisfactory with her body weight at the 25th centile and height at the 10th centile. No new physical sign was detected. Peripheral blood smear showed occasional macro-ovalocytes. A dimorphic red cell picture was not seen and there were no hypersegmented neutrophils. Serum iron of 4.6 μmol/L (normal, 4-25 μmol/L), total iron-binding capacity of 103 μmol/L (normal, 41-77 μmol/L), and transferrin saturation of 4% (normal, 7%-44%) were suggestive of iron deficiency. Haemoglobin pattern analysis was negative for thalassaemia. Serum active vitamin B12 level was low at 23.6 pmol/L (normal, >46.2 pmol/L) and serum and red blood cell folate, serum bilirubin and lactate dehydrogenase levels were normal. Direct antiglobulin test, antinuclear antibody, C3, C4, anti-intrinsic factor antibody, antiparietal cell antibody and antineutrophil antibody were all negative.
 
Intramuscular vitamin B12 was given and ranitidine was stopped. The dose of IPC was increased to 15 mg twice daily and administered via the gastric tube.
 
Despite normalisation of serum iron and vitamin B12 level, anaemia and neutropenia persisted. Haemoglobin further dropped to 6.6 g/dL and red blood cell transfusion was required. She responded to a dose of granulocyte colony-stimulating factor with the neutrophil count rising from 0.25 × 109/L to 1.74 × 109/L. Nonetheless, her neutrophil count dropped to 0.33 × 109/L 5 days later. Bone marrow aspiration and trephine biopsy was performed to evaluate the cause of refractory cytopenias and revealed reduced granulopoiesis, reactive histiocytosis and iron block. Vacuolated myeloid and erythroid precursors were observed (Fig 1). Megakaryopoiesis was adequate and no sideroblasts were evident on iron staining. These findings suggested copper deficiency or zinc toxicity. Serum copper was subsequently found to be <2.0 μmol/L (normal, 13-24 μmol/L), consistent with severe copper deficiency, whilst serum zinc level was normal.
 

Figure 1. A 28-month-old girl with neutropenia and anaemia. Bone marrow aspirate showing vacuolated myeloid precursors (red arrows) and vacuolated erythroid precursors (yellow arrows)
 
Copper deficiency was treated with mineral mixture powder (Seravit; Nutricia) via the gastric tube from age 28 months as direct copper supplement was not available. The mineral mixture powder was administered at a dose of 2.5 g daily, providing 115 μg copper each day. On day 9 after commencement of copper supplementation, the absolute neutrophil count increased from the lowest level of 0.29 × 109/L to 1.09 × 109/L and haemoglobin level increased from the lowest level of 9.6 g/dL to 10.6 g/dL. The mineral mixture powder was further increased to 2.5 g twice daily. A small amount of milk was introduced to the stomach to allow absorption of the micronutrients. On day 16, the haemoglobin and neutrophil count normalised (haemoglobin, 12.2 g/dL; absolute neutrophil count, 2.03 × 109/L) and by 7 weeks, serum copper had normalised. The mineral mixture powder was stopped after 8 weeks, at age 30 months. At age 35 months, haemoglobin, neutrophil count, copper, and iron levels remained normal (Fig 2).
 

Figure 2. Haemoglobin, neutrophil, iron, and copper levels in a girl with neutropenia and anaemia. At age 26 months, iron(III)-hydroxide polymaltose complex (IPC) was increased from 10 mg daily to 10 mg twice daily via a jejunostomy tube. At age 27 months, IPC was increased to 15 mg twice daily via a gastrostomy tube. Blood transfusion (blue arrowhead) and granulocyte colony-stimulating factor (orange arrow) were given at age 28 months. Mineral mixture powder was given from age 28 months to 30 months (yellow arrow)
 
Discussion
The index patient presented with haematological abnormalities due to acquired copper deficiency following long-term jejunal feeding, which is not well reported in the literature.1 Jacobson et al2 reported three paediatric patients with exclusive jejunal feeding who developed cytopenias, one of whom had concurrent combined iron and vitamin B12 deficiency similar to our patient. Premature infants and children with intestinal failure on parenteral nutrition with inadequate copper supplementation are also at increased risk of acquired copper deficiency.3
 
Although the amount of iron, copper and vitamin B12 provided was above the recommended dietary requirement, deficiencies occurred because of problems in absorption. Most copper absorption occurs in the stomach and proximal duodenum. The acidic environment in the stomach facilitates solubilisation by dissociating it from copper-containing dietary macromolecules. Jejunal administration of IPC, multivitamin drops and infant formula bypassed the stomach and ranitidine reduced the acidity of the jejunal environment.
 
Copper-dependent enzymes are essential for normal function of the haematopoietic, skeletal, and central nervous systems. Although absent in the index patient, clinical signs of copper deficiency such as fragile, abnormally formed hair, depigmentation of the skin, oedema, myeloneuropathy, ataxia and cognitive deficits should be actively sought. Anaemia and neutropenia are the predominant haematological manifestations. Thrombocytopenia rarely occurs. Serum ferritin and erythropoietin are usually elevated. Serum ceruloplasmin is low. Anaemia is caused by the reduced activity of ceruloplasmin ferroxidase, copper/zinc superoxidase and cytochrome-c oxidase.4 Upon copper supplementation, neutropenia typically improves within a few weeks and anaemia improves within a few months. Cytoplasmic vacuolation in erythroid and myeloid precursors is the prominent feature in the bone marrow. Dysplastic features, such as megaloblastic changes and ring sideroblasts, may be observed.4 Vacuolated erythroblasts and myeloid precursors are classically observed in Pearson syndrome,5 acute alcoholism, chloramphenicol and linezolid toxicity, acute erythroid leukaemia and acute metabolic disturbance. These causes were unlikely in the index patient in the absence of an associated history or pathological features. Primary myelodysplasia is an important differential diagnosis but blood count recovery on copper replacement would not be expected.
 
This case highlights the importance of nutritional monitoring in patients receiving exclusive jejunal feeding. We recommend checking full blood count, liver and renal function tests, electrolytes, iron profile, vitamin B12, copper and zinc level every 3 months. Unexplained anaemia or neutropenia should prompt investigations for possible micronutrient deficiency to avoid unnecessary invasive investigations.
 
Author contributions
Concept or design: All authors.
Acquisition of data: WY Leung, CC So.
Analysis or interpretation of data: WY Leung.
Drafting of the manuscript: WY Leung, CC So.
Critical revision of the manuscript for important intellectual content: All authors.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The parent of the patient provided written consent for publication.
 
References
1. Barraclough H, Cooke K. Are patients fed directly into the jejunum at risk of copper deficiency? Arch Dis Child 2019;104:817-9. Crossref
2. Jacobson AE, Kahwash SB, Chawla A. Refractory cytopenias secondary to copper deficiency in children receiving exclusive jejunal nutrition. Pediatr Blood Cancer 2017;64:e26617. Crossref
3. Leite HP, Koch Nogueira PC, Uchoa KM, Carvalho de Camargo MF. Copper deficiency in children with intestinal failure: risk factors and influence on hematological cytopenias. JPEN J Parenter Enteral Nutr 2021;45:57-64. Crossref
4. Chen CC, Takeshima F, Miyazaki T, et al. Clinicopathological analysis of hematological disorders in tube-fed patients with copper deficiency. Intern Med 2007;46:839-44. Crossref
5. Knerr I, Metzler M, Niemeyer CM, et al. Hematologic features and clinical course of an infant with Pearson syndrome caused by a novel deletion of mitochondrial DNA. J Pediatr Hematol Oncol 2003;25:948-51. Crossref

Bilateral breast multiple myeloma: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Bilateral breast multiple myeloma: a case report
Cyrus KM Mo, MB, ChB, FRCR1; Alta YT Lai, FRCR, FHKAM (Radiology)1; Sherwin SW Lo, FRCR, FHKAM (Radiology)2; TS Wong, MB, BS3; Wendy WC Wong1, FRCR, FHKAM (Radiology)1
1 Department of Radiology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
2 Department of Radiology, Gleneagles Hospital, Hong Kong
3 Department of Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
 
Corresponding author: Dr Cyrus KM Mo (mkm463@ha.org.hk)
 
 Full paper in PDF
 
Introduction
Multiple myeloma (MM) is a malignant disorder characterised by excessive proliferation of single clonal plasma cells derived from B cells in the bone marrow with increased formation of monoclonal immunoglobulins.1 Multiple myeloma may involve extramedullary organs or soft tissues (extramedullary plasmacytoma), commonly in the upper aerodigestive tract with a predilection for the head and neck.1 Breast plasmacytoma is very rare. We present a case of MM with extensive extramedullary involvement including bilateral breasts, and mainly focus on the imaging features of breast plasmacytoma across multi-modalities.
 
Case report
A 59-year-old female presented for scheduled ultrasound scan of abdomen for follow-up of a complicated renal cyst in December 2019. She had a previous history of diabetes mellitus, hypertension, hyperlipidaemia and hepatitis B infection. She was diagnosed with MM 10 years previously and had previously failed hematopoietic stem cell transplantation. Ultrasound scan revealed an enlarged hypoechoic nodule in the liver that corresponded to the liver lesion detected on earlier computed tomography (CT) urogram. She also complained of a palpable nodule in the right lower quadrant of the abdomen, present for a few months. Magnetic resonance imaging (MRI) with contrast of liver was arranged to assess the liver lesion and abdominal wall nodule.
 
The MRI 1 month later showed significant enlargement of the liver lesion with heterogeneous contrast enhancement and restricted diffusion. No definite contrast washout was demonstrated in the portovenous phase. The nodule in the right lower quadrant of the abdominal wall demonstrated contrast enhancement and restricted diffusion as well. Features of both lesions were suggestive of malignancy. The MRI also revealed a 1.3 cm T1 isointense T2 hyperintense contrast enhancing nodule with restricted diffusion in the outer lower quadrant of the left breast (Fig 1).
 

Figure 1. Selected magnetic resonance imaging images: (a) pre-contrast T1-weighted axial image, (b) post-contrast T1-weighted axial image, (c) T2-weighted fat-saturated axial image, (d) diffusion weighted image, and (e) apparent diffusion coefficient. The lesion (arrowheads) in the lower outer quadrant of the left breast demonstrated homogeneous contrast enhancement and restricted diffusion
 
Ultrasound-guided fine needle aspiration of the right lower quadrant abdominal wall nodule was performed in February 2020. The pathological diagnosis was plasmacytoma.
 
Dual-tracer positron emission tomography (PET)/CT was performed in early March 2020 at a private institution to assess disease involvement. There were multiple acetate (Ac) and fludeoxyglucose (FDG)-avid soft tissue nodules in bilateral breasts, measuring up to 1.5 × 1.4 cm with FDG maximum standard unit value (SUVmax) 8.4 and Ac SUVmax 5.0 in left breast (Fig 2a) and 1.4 × 1.0 cm with FDG SUVmax 7.0 and Ac SUVmax 6.6 in right breast. There were a few left axillary level I lymph nodes measuring up to 0.9 × 0.8 cm with FDG SUVmax 3.3 and Ac SUVmax 3.9.
 

Figure 2. Selected mammography, ultrasound image, fludeoxyglucose (FDG) positron emission tomography/computed tomography fusion image and histopathological slides of left breast lesion. (a) A focal FDG-avid lesion in the left breast at the 3:00 position. (b) Craniocaudal view of left mammography. Several oval ill-defined equal-to-high density lesions were detected in the left breast. No associated microcalcification was identified. (c) The largest mass in the left breast located at the 3:00 position 3 cm from the nipple was evident as an ill-defined heterogeneous mass with hypoechoic and echogenic areas. (d) Light photomicrograph of haematoxylin and eosin stain on 400 x magnification. Tumour cells possess eosinophilic cytoplasm with perinuclear hof and hyperchromatic nuclei with occasional nucleoli. (e & f) Light photomicrograph of immunohistochemistry staining on 400 x magnification. Tumour cells are negative for AE1/AE3 (pancytokeratin) and positive for CD138 (Syndecan-1)
 
Bilateral mammography and breast ultrasound were arranged in early April 2020 to assess bilateral breast lesions. There were multiple oval and ill-defined equal-to-high density lesions in both breasts. The largest lesion located at the upper outer quadrant of the right breast measured 3.6 × 2.8 cm and was palpable. No associated suspicious microcalcifications were detected. There was no architectural distortion, skin thickening or enlarged lymph nodes on mammography (Fig 2b).
 
Subsequent breast ultrasound on the same section revealed scattered oedematous areas in both breasts. A heterogeneous mass with hypoechoic and echogenic areas was detected in the left breast at a 3:00 position, 3 cm from the nipple (Fig 2c). Posterior enhancement was evident. This mass corresponded to the lesion detected on previous MRI. The size was 2.7 × 2.5 × 2.5 cm. There was interval enlargement compared with previous MRI (which was 1.3 cm). Multiple hypoechoic, echogenic, and heterogeneous masses and nodules were identified in other areas of both breasts. The largest one in the right breast located at a 9:00 position 5 cm from the nipple measured 4.5 × 2.6 × 4.1 cm. There was an irregular hypoechoic enlarged left axillary lymph node with loss of fatty hilum. Ultrasound-guided fine needle aspiration of this node and core biopsies of the dominant masses in each breast were performed in the same section. The pathological diagnoses of the breast masses and left axillary lymph node were consistent with plasmacytoma (Fig 2d-f). Two weeks later (mid-April 2020), the patient was admitted with multilobar pneumonia and severe metabolic acidosis and disseminated intravascular coagulation. Unfortunately, she passed away 4 days later.
 
Discussion
Breast plasmacytoma is extremely rare. Approximately 50 cases have been reported in the literature since 1925.2 3 4 5 The prevalence is unknown. Surov et al6 reported a prevalence of 1.5% for breast plasmacytoma among patients with plasmacytoma in their institution. Involvement of the breast was a secondary event of MM in 85% and more than half of the lesions were unilateral.6
 
There are some differences in the ultrasonographic features of breast MM between this case and those reported in the literature. For the cases described by Ali et al2 and Park5, breast MM was revealed as a well-defined oval hypoechoic mass on ultrasound. In our patient, it was an indistinct oval heterogeneous mass with hypoechoic and echogenic areas.
 
Compared with typical primary breast cancer (invasive ductal carcinoma) that is usually revealed as an irregular spiculated high-density mass on mammogram and an anti-parallel hypoechoic irregular spiculated mass on ultrasound, there are no characteristic imaging features of breast MM. On mammography, it can present as a single or multiple high-density round or oval lesion(s) that is/are circumscribed or ill-defined.2 It can show as diffuse infiltration. Association with microcalcifications is rarely reported. On ultrasound, the features are well-defined echo-poor, hypoechoic, or hyperechoic solid masses with hypervascularity.2 Mixed hypo- to hyper-echoic masses with indistinct margins are also possible. Posterior acoustic features are variable. Posterior acoustic enhancement can be evident but absence of acoustic transmission or even posterior acoustic shadowing has been reported in some cases.
 
There are limited case reports of MRI and PET/ CT features of breast MM. On MRI, it shows as a T1-weighted intermediate to hypointense T2-weighted hyperintense lesion with homogeneous or rim enhancement. Restricted diffusion and early rapid contrast enhancement with washout kinetics are the reported features.5 It appears as a homogeneous soft tissue lesion with high FDG uptake on PET/CT.
 
No case report has discussed the features of breast MM on dual-tracer PET/CT. It was revealed as an Ac-avid lesion in our patient, indicative of high metabolism of malignant plasma cells. There are provisos in this case report. The MRI protocols did not relate specifically to breast imaging and contrast kinetics was not performed.
 
Conclusion
There are no specific radiological features of breast MM. In bilateral multiple breast masses, the differential diagnoses are lymphoma, metastasis, synchronous primary breast cancer, secondary involvement of haematological disorder or benign conditions such as fibroadenoma. Biopsy for histopathological diagnosis is advised.
 
Author contributions
Concept or design: CKM Mo, AYT Lai.
Acquisition of data: SSW Lo, TS Wong.
Analysis or interpretation of data: SSW Lo, TS Wong.
Drafting of the manuscript: CKM Mo, AYT Lai, WWC Wong.
Critical revision of the manuscript for important intellectual content: CKM Mo, AYT Lai, WWC Wong.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
The authors have no conflicts of interest to disclose.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. Informed consent for publication was unobtainable from the deceased patient's next-of-kin despite all reasonable efforts.
 
References
1. Angtuaco EJ, Fassas AB, Walker R, Sethi R, Barlogie B. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004;231:11-23. Crossref
2. Ali HO, Nasir Z, Marzouk AM. Multiple myeloma breast involvement: a case report. Case Rep Radiol 2019;2019:2079439. Crossref
3. Kaviani A, Djamali-Zavareie M, Noparast M, Keyhani-Rofagha S. Recurrence of primary extramedullary plasmacytoma in breast both simulating primary breast carcinoma. World J Surg Oncol 2004;2:29. Crossref
4. Lee HS, Kim JY, Kang CS, Kim SH, Kang JH. Imaging features of bilateral breast plasmacytoma as unusual initial presentation of multiple myeloma: case report and literature review. Acta Radiol Short Rep 2014;3:2047981614557666. Crossref
5. Park YM. Imaging findings of plasmacytoma of both breasts as a preceding manifestation of multiple myeloma. Case Rep Med 2016;2016:6595610. Crossref
6. Surov A, Holzhausen HJ, Ruschke K, Arnold D, Spielmann RP. Breast plasmacytoma. Acta Radiol 2010;51:498-504. Crossref

Abscess formation following accidental ingestion of fish bone with migration to the submandibular gland: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Abscess formation following accidental ingestion of fish bone with migration to the submandibular gland: a case report
Alan TL Lau, MB, ChB1; Raymond KY Tsang, MS, FHKAM (Otorhinolaryngology)2; Nikie HY Sun, MB, ChB3
1 Department of Otorhinolaryngology, Queen Mary Hospital, Hong Kong
2 Department of Surgery, The University of Hong Kong, Hong Kong
3 Department of Otorhinolaryngology, Queen Mary Hospital, Hong Kong
 
Corresponding author: Dr Alan TL Lau (ltl194@ha.org.hk)
 
 Full paper in PDF
 
Introduction
Deep neck space infection is associated with significant morbidity and mortality, with the submandibular space being a common site of infection. Causes include odontogenic infections, submandibular sialadenitis, lymphadenitis, trauma, or surgery. This case report describes an uncommon cause of fish bone migration to the submandibular gland with consequent abscess formation. Apart from fish bones, a variety of foreign bodies in salivary glands has been described in previous case reports, including toothbrush bristles, slivers of fingernails, wood splinters, hairs or blades of grass.1
 
Case report
A 38-year-old woman with good past health accidentally ingested a fish bone in September 2020. She subsequently developed a sore throat, right neck pain and swelling. She attended the emergency department at Queen Mary Hospital 2 days later due to progressive symptoms. On admission, she had a fever of 38.1°C with blood pressure 161/80 mm Hg and pulse 113 beats per minute. Physical examination revealed a palpable tender right upper neck swelling. The right floor of mouth was oedematous and tender on palpation. At the opening of the Wharton’s duct, no foreign body was palpable, and no pus was evident. Flexible laryngoscopy of the pharynx and larynx was normal. An urgent computer tomography with contrast revealed a 14-mm linear foreign body at the right submandibular gland with surrounding right submandibular abscess (Fig 1).
 

Figure 1. (a) Axial contrast computer tomography of the neck. The white arrow indicates the 14 mm linear opacity at the right submandibular gland with surrounding submandibular abscess. (b) Coronal contrast computer tomography of the neck showing right submandibular abscess (white arrow)
 
Emergency exploration under general anaesthesia was performed. First, transoral exploration was performed through an incision at the right posterolateral floor of mouth to retrieve the foreign body and drain the pus. In view of negative transoral exploration, transcervical exploration was performed. An abscess cavity was revealed at the medial surface of the right submandibular gland and pus was drained. Right submandibular sialoadenectomy was performed and subsequently a 14-mm fish bone was found impacted at the medial surface of the right submandibular gland (Fig 2). A 15Fr silicon drain was inserted to the wound bed. The patient was monitored in the intensive care unit postoperatively and was extubated the day following surgery. Intravenous amoxicillin-clavulanate (1.2 grams every 8 hours) was prescribed. Culture of pus was negative. Fever and neck swelling subsided and the drain was removed on postoperative day 3. The patient was discharged on postoperative day 5 with diet well tolerated. At 2-week follow-up, the neck and oral wound were well healed. The hypoglossal nerve, lingual nerve and facial nerve function was intact.
 

Figure 2. Specimen of right submandibular gland and fish bone. The length of the fish bone was 14 mm
 
Discussion
A fish bone can usually be retrieved easily via endoscopy when lodged in the oral cavity, pharynx, or oesophagus. Nonetheless, some patients with a negative endoscopic finding may present later with neck swelling and fever that may indicate a deep neck space infection or migration of the foreign body to the neck. Extraluminal migration of foreign vein, subcutaneous neck, the thyroid gland, and the cervical spine has been reported in previous case reports.2
 
Migration of fish bone to the submandibular gland is uncommon. There have been two hypotheses for such an event: direct trauma and retrograde migration. Some theories suggest that continuous flow of saliva from ducts into the oral cavity, the duct orifice being mobile and able to twist in all directions, and small diameter of duct at the orifice render retrograde migration rare.1 In a previous study of sialoendoscopic assessment of patients with suspected obstruction in the ductal system of salivary glands, 3.9% had sialoliths related to fish bone, with the left submandibular gland being the dominant site (92.3%). Compared with the submandibular gland, foreign body at the parotid glands is much less common.3
 
Foreign body at the submandibular gland can have a variety of consequences. A patient with acute right submandibular sialadenitis due to an impacted fish bone has been reported who presented with tender submandibular swelling.4 The patient had no recall of foreign body ingestion. Plain radiograph of the neck revealed a radiopaque foreign body. The infection eventually required antibiotic treatment and submandibular gland excision, with identification of a fish bone at the excised gland. Another patient presented with chronic sialadenitis. A fish bone–induced sialolith was successfully removed with sialoendoscopy.5 A third patient presented with deep neck space infection with abscess formation, as in our patient.
 
Different techniques have been applied to remove foreign body from the submandibular gland.6 For sialoendoscopy, a higher success rate has been observed with foreign bodies in the distal duct while those located in the more proximal part and secondary branches of the Wharton’s duct have been difficult to remove. Surgery may be required if endoscopic treatment is not suitable, either using a transoral approach or transcervical approach with submandibular gland sialadenectomy. In this case report, a transcervical approach was eventually adopted.
 
Conclusion
The mainstay of treatment for submandibular abscess is airway protection, antibiotic treatment, and surgical drainage. Timely diagnosis and treatment are key to success. Despite being a rare cause, submandibular gland foreign body complicated by abscess formation should be considered as a differential diagnosis in patients with submandibular swelling who report swallowing of a fish bone.
 
Author contributions
Concept or design: RKY Tsang.
Acquisition of data: NHY Sun.
Analysis or interpretation of data: ATL Lau.
Drafting of the manuscript: ATL Lau.
Critical revision of the manuscript for important intellectual content: RKY Tsang.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Acknowledgement
Dr Joseph CK Chung and Dr Sylvia SY Yu have made a substantial contribution in terms of academic advice to the publication of this case report.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The study was conducted in accordance with guidelines of the Hong Kong West Cluster Research Ethics Committee (IRB Ref No.: UW21-094). Informed consent was obtained from the patient.
 
References
1. Su YX, Lao XM, Zheng GS, Liang, LZ, Huang XH, Liao GQ. Sialoendoscopic management of submandibular gland obstruction caused by intraglandular foreign body. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e17-21. Crossref
2. Hsu CL, Chen CW. A prolonged buried fish bone mimicking Ludwig angina. Am J Otolaryngol 2011;32:75-6. Crossref
3. Xie L, Zheng L, Yu C, et al. Foreign body induced sialolithiasis treated by sialoendoscopic intervention. J Craniofac Surg 2014;25:1372-5. Crossref
4. Riccio FJ, Scavo VJ. Unusual foreign body etiology of sialadenitis. Arch Otolaryngol 1967;86:210-2. Crossref
5. Iwai T, Sugiyama S, Hayashi Y, et al. Sialendoscopic removal of fish bone-induced sialoliths in the duct of the submandibular gland. Auris Nasus Larynx 2018;45:343-5. Crossref
6. Li P, Zhu H, Huang D. Detection of a metallic foreign body in the Wharton duct: a case report. Medicine (Baltimore) 2018;97:e12939. Crossref
 

A rather difficult case of acute generalised exanthematous pustulosis: would colchicine be a treatment option?

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
A rather difficult case of acute generalised exanthematous pustulosis: would colchicine be a treatment option?
Rabia Oztas Kara, MD; Bahar Sevimli Dikicier, MD; Mahizer Yaldiz, MD; Hande Tekmenler, MD
Department of Dermatology, Sakarya University Faculty of Medicine, Sakarya, Turkey
 
Corresponding author: Dr Rabia Oztas Kara (r.oztas.kara@gmail.com)
 
 Full paper in PDF
 
Case report
A 24-year-old lactating female patient presented with redness, burning, and rash on the face and body on the fifth day of hydroxychloroquine (HCQ) treatment, prescribed after diagnosis of coronavirus disease 2019 infection. Physical examination revealed numerous non-follicular pustular lesions on an erythematous background that started on the face and neck and extended to the whole body, especially in the folds and extremities, and in the palmoplantar regions (Fig 1a). Conjunctival involvement was also evident. Examination was otherwise unremarkable and the patient was afebrile.
 

Figure 1. (a) Numerous non-follicular pustules on an erythematous base on the leg. (b) Non-follicular pustules recurring in areas of desquamation. (c) Complete recovery after desquamation
 
Laboratory examinations were likewise unremarkable (Table). Histopathological examination of punch biopsy of the leg lesions, subcorneal pustule formation in the epidermis, oedema in the papillary dermis, and lymphocytic infiltration in the upper dermis was performed (Fig 2). There was no individual or family history of psoriasis, and the patient denied taking any medication except HCQ in the last 3 months. Based on these findings, the patient was diagnosed with HCQ-induced (acute generalised exanthematous pustulosis [AGEP]). Intravenous methylprednisolone 60 mg/day, etodolac, topical methylprednisolone, and moisturiser were prescribed. An initial partial response was achieved but on the 15th day of treatment, pustular lesions, itching, and complaints of burning recurred and the patient developed a fever of 38°C (Fig 1b). Blood cultures grew Staphylococcus aureus, sensitive to ciprofloxacin. Systemic ciprofloxacin 750 mg twice a day (1500 mg daily) was started with the addition of 0.5 mg colchicine thrice a day (1.5 mg daily). Her general condition improved and the skin lesions completely regressed with desquamation (Fig 1c). Systemic methylprednisolone treatment was tapered and stopped. Colchicine treatment was continued for 1 month and the dose then decreased to 0.5 mg twice a day for a further month before being stopped. The patient continues to attend for follow-up and remains well. A patch test for HCQ is planned when lactation stops.
 

Table. Laboratory blood test results
 

Figure 2. Subcorneal pustule formation in the epidermis, oedema in the papillary dermis, and perivascular inflammation accompanied by eosinophils and neutrophils in the upper dermis (a: ×10, b: ×40)
 
Discussion
Drugs constitute 90% of the aetiology of AGEP. The remaining 10% are due to infection. Although the pathogenesis of AGEP is not fully understood, the accumulation of cytokines released by helper T cells and drug-induced antigen-antibody complexes in the skin is blamed.1
 
The cutaneous side-effects of hydroxychloroquine include AGEP, urticaria, pruritus, xerosis, maculopapular rash, psoriasis, erythroderma, Stevens–Johnson syndrome, hair loss, and hair whitening.2 Since hydroxychloroquine is a weak base with a long half-life, it passes into breast milk in minimal amounts.
 
In previously reported cases of HCQ-induced AGEP, the duration of exposure to HCQ was reported to be 2 to 30 days prior to symptom onset3 and time to recovery after stopping HCQ has been reported to be 7 to 81 days.4 The long persistence of symptoms can be explained by the long half-life of HCQ, approximately 40 to 50 days.5
 
Acute generalised exanthematous pustulosis cases due to HCQ have been reported during the pandemic. The typical features of these cases are a more prolonged course and a need for systemic steroid treatment. In this patient, colchicine was started because a complete response was not obtained with systemic corticosteroid treatment.
 
Colchicine suppresses inflammation at many stages. It has an antimitotic impact by binding to tubulin, preventing its polymerisation into new microtubules, inhibits neutrophil chemotaxis, and reduces free oxygen radical production by neutrophils. It is more useful in the treatment of neutrophilic dermatoses such as pustular conditions with predominant neutrophilic infiltrates, eg, pustular psoriasis. For this reason and the lack of response to systemic corticosteroid treatment, colchicine was added to our patient’s treatment regimen.
 
We conclude that colchicine may be a treatment option for AGEP, a rare side-effect of HCQ, especially when it is resistant to systemic corticosteroid. It can also be used as an effective treatment during lactation due to its better safety profile.
 
Author contributions
Concept or design: All authors.
Acquisition of data: R Oztas Kara, H Tekmenler.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: R Oztas Kara, H Tekmenler.
Critical revision of the manuscript for important intellectual content: All authors.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
The authors have no conflicts of interest to disclosure.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for the treatment/procedures and consent for publication.
 
References
1. Halevy S, Kardaun SH, Davidovici B, Wechsler J, EuroSCAR and RegiSCAR Study Group. The spectrum of histopathological features in acute generalized exanthematous pustulosis: a study of 102 cases. Br J Dermatol 2010;163:1245-52. Crossref
2. Salido M, Joven B, D’cruz, DP, Khamashta MA, Hughes GR. Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly associated with formulation change: comment on the letter by Alarcón. Arthritis Rheum 2002;46:3392-6. Crossref
3. Liccioli G, Marrani E, Giani T, Simonini G, Barni S, Mori F. The first pediatric case of acute generalized exanthematous pustulosis caused by hydroxychloroquine. Pharmacology 2019;104:57-9. Crossref
4. Pearson KC, Morrell DS, Runge SR, Jolly P. Prolonged pustular eruption from hydroxychloroquine: an unusual case of acute generalized exanthematous pustulosis. Cutis 2016;97:212-6.
5. İslamoğlu ZG, Karabağli P. A case of recalcitrant acute generalized exanthematous pustulosis with Sjogren’s syndrome: successfully treated with low-dose cyclosporine. Clin Case Rep 2019;7:1721-4. Crossref
 

Importance of cascade family screening and precision medicine for patients with familial hyperkalaemia: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Importance of cascade family screening and precision medicine for patients with familial hyperkalaemia: a case report
HY Lam, MB, BS1; Eugene YH Chan, MRCPCH (UK), FHKAM (Paediatrics)2; Joanna YL Tung, MB, BS, MRCPCH (UK)2; Samantha LK Lee, MB, BS, MPH (HKU)2 Jasmine LF Fung, BBiomedSc3; Mianne Lee, MSc3; Brian HY Chung, MD2,3; Alison LT Ma, MRCPCH (UK), FRCPCH (UK)2
1 Department of Paediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong
3 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong
 
Corresponding author: Ms HY Lam (charlottelamhy@gmail.com)
 
 Full paper in PDF
 
Case report
The patient was the only child of a non-consanguineous Chinese couple and was born at full term by normal vaginal delivery with a birth weight of 2.85 kg. She had good past health except for admission for a reflex-anoxic attack at age 7 months. Physical examination at that time was unremarkable with normal growth parameters and normal blood pressure for her age. Investigations showed normal anion gap metabolic acidosis and hyperkalaemia with a potassium of 7.1 mmol/L but normal serum sodium and renal function. In view of the biochemical findings, the provisional diagnosis was type IV renal tubular acidosis. Fludrocortisone was started with sodium bicarbonate and furosemide and a low potassium diet commenced. However, recurrent episodes of hyperkalaemia continued despite good compliance, requiring potassium binder and medication adjustment.
 
In December 2019, because of the suboptimal control of hyperkalaemia, with a fluctuating potassium level of 4.5 to 6.4 mmol/L, the patient was referred to our unit at age 10 years. Her blood pressure remained normal throughout. Blood test results revealed hyperreninaemic hyperaldosteronism with elevated supine renin at 5.59 ng/mL/hr (reference: 0.15-2.33 ng/mL/hr) and elevated aldosterone at 785 pmol/L (reference: 28-444 pmol/L). Pseudohypoaldosteronism type I was suspected initially.
 
Trio whole exome sequencing revealed a paternally inherited novel missense change in WNK4:NM_032387.5:c.1685A>G:p.(Glu562Gly), confirming a diagnosis of pseudohypoaldosteronism type IIB. This patient was coincidentally part of a larger whole exome sequencing cohort where the study was focused on cost-effectiveness of rapid whole exome sequencing.1 The patient was treated with oral 25 mg hydrochlorothiazide once daily and remained stable with normal growth and development. The serum potassium and blood pressure were well controlled and there were no dental or renal complications on follow-up examination.
 
Family cascade screening revealed that her father, paternal grandmother, and paternal aunt had hyperkalaemia. All were subsequently confirmed to have the same mutation (Fig 1). Retrospectively, the father had provided a history of kidney stone, hyperkalaemia, hypercalciuria and hypertension since age 35 years. He was found to have a serum potassium level of 7 mmol/L during the cascade screening. Although asymptomatic, his electrocardiogram already showed hyperkalaemic changes with tented T waves and high blood pressure at 176/116 mmHg. He was started on hydrochlorothiazide with normalisation of both serum potassium and blood pressure a few days later. The paternal grandmother also had a history of hyperkalaemia and partially controlled hypertension. The paternal aunt was asymptomatic with good past health but was found to be hypertensive and hyperkalaemic on screening. They were also started on hydrochlorothiazide with good response.
 

Figure 1. Pedigree of the family affected with Gordon’s syndrome
 
Discussion
We report a Chinese family with the rare cause of hyperkalaemia and type IV renal tubular acidosis due to an autosomal dominant condition called Pseudohypoaldosteronism type II (PHAII). Whole exome sequencing established the diagnosis in our index patient, and subsequently, other affected family members were identified through cascade family screening.
 
Pseudohypoaldosteronism type II, also referred to as familial hyperkalaemic hypertension, or Gordon’s syndrome, was first described in 1964.2 By 2013, around 100 to 200 individuals and families with PHAII had been reported.3 Hyperkalaemia with normal renal function is the main characteristic. Other common features include metabolic acidosis, diminished renal potassium excretion, hypercalciuria, low plasma renin/aldosterone levels and hypertension. Short stature and dental abnormalities have also been reported.4
 
Mutation in the gene encoding with-no-lysine kinase 4 (WNK4), one of the novel proteins involved in the pathogenesis of PHAII, was identified in our patient. Other identified genes include WNK1, kelch-like 3 and cullin 3.3 The WNK4 is one of the WNK isoforms that regulates sodium-chloride co-transporter (NCC) in the distal convoluted tubule. Without the inhibitory effect of normal WNK4, sodium and chloride reabsorption are increased via the NCC, leading to volume expansion and consequent hypertension. The NCC is more proximal to the epithelial sodium channel at the distal convoluted tubule. Excessive sodium reabsorption at NCC results in reduced sodium delivery to epithelial sodium channels for potassium secretion at Na+/K+ exchange.3 This theory explains why thiazide is effective in PHAII as it inhibits NCC. Increased intracellular sodium due to increased NCC activity will cause decreased basolateral Na+/Ca2+ exchange that may result in hypercalciuria as in the father of our index patient. It has been suggested that mutant WNK4 decreases the activity of renal outer medullary potassium channels more than wild-type WNK4. Another proposed mechanism of this Chloride Shunt Syndrome is increased chloride reabsorption through paracellular pathways due to the mutant WNK4, resulting in reduced negativity at the distal epithelial sodium channel.3 These can all lead to reduced urinary potassium excretion (Fig 2) with consequent increase in serum potassium. With increased potassium retention, the excretion of hydrogen is impaired leading to metabolic acidosis. Hypertension tends to appear later in life, in men aged 30-40 years and in women aged 40-50 years,5 but can also be absent in 20% of cases.3
 

Figure 2. Proposed mechanisms of hyperkalaemia in pseudohypoaldosteronism type II
 
In this patient, pseudohypoaldosteronism type I was initially suspected in view of the grossly elevated renin and aldosterone levels. However, the age of disease onset and normal sodium level were atypical. The elevated renin and aldosterone levels in our patient could be explained by the use of furosemide that could have resulted in hypovolaemia and thus activation of the renin-angiotensin-aldosterone-system. This made the interpretation of the biochemical picture challenging. In this regard, the use of genetic testing demonstrated superiority in guiding the diagnosis of these chronic conditions in which a classic clinical phenotype had already been modified by existing treatments.
 
Our case also highlights the importance of cascade family screening. The three family members were identified to have potentially life-threatening hyperkalaemia and were treated promptly based on their genetic mutation. Affected patients will continue regular follow-up with serum electrolyte and blood pressure monitoring. With specific treatment, the disease can be well-controlled. This case illustrates the importance of precision medicine, as well as its benefits of personalised and targeted interventions.
 
Author contributions
Concept or design: HY Lam, ALT Ma.
Acquisition of data: YH Chan, ALT Ma.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: HY Lam, EYH Chan.
Critical revision of the manuscript for important intellectual content: All authors.
 
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
The genetic investigation was supported by the Health and Medical Research Fund (HMRF) by the Hong Kong Food and Health Bureau (Project Ref No: 06172806) and The Society for the Relief of Disabled Children.
 
Ethics approval
The patient was treated in accordance with the tenets of the Declaration of Helsinki. The father of the patient consented verbally to publication of this case report.
 
References
1. Chung CC, Leung GK, Mak CC, et al. Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. Lancet Reg Health West Pac 2020;1:100001. Crossref
2. Paver WK, Pauline GJ. Hypertension and hyperpotassaemia without renal disease in a young male. Med J Aust 1964;2:305-6. Crossref
3. Healy JK. Pseudohypoaldosteronism type II: history, arguments, answers, and still some questions. Hypertension 2014;63:648-54. Crossref
4. Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986;8:93-102. Crossref
5. Farfel A, Mayan H, Melnikov S, Holtzman EJ, Pinhas-Hamiel O, Farfel Z. Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension. Nephrol Dial Transplant 2011;26:1547-53. Crossref

Acquired C1-inhibitor deficiency in chronic lymphocytic leukaemia: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Acquired C1-inhibitor deficiency in chronic lymphocytic leukaemia: a case report
Andy SO Tang, MD, MRCP (UK)1; QY Wong, MB, BS2; ST Yeo, BPharm (Hon)2; Jenny TH Lee, MB, BS3; TS Leong, MB, BS, MRCP (UK)4; LP Chew, MD, FRCP (UK)4
1 Haematology Unit, Department of Internal Medicine, Miri Hospital, Ministry of Health, Sarawak, Malaysia
2 Department of Internal Medicine, Miri Hospital, Ministry of Health, Sarawak, Malaysia
3 Department of Pathology, Sarawak General Hospital, Ministry of Health, Sarawak, Malaysia
4 Haematology Unit, Department of Internal Medicine, Sarawak General Hospital, Ministry of Health, Sarawak, Malaysia
 
Corresponding author: Dr Andy SO Tang (andytangsingong@gmail.com)
 
 Full paper in PDF
 
Case report
Acquired C1-inhibitor deficiency is a rare disorder with varying manifestations and an estimated prevalence of 1 per 100 000 to 500 000 population.1 We present a case of acquired angio-oedema that manifested after a diagnosis of chronic lymphocytic leukaemia (CLL).
 
In June 2017, a 60-year-old man who was previously healthy was found to have lymphocytosis on routine health screening. Physical examination showed multiple lymph nodes with no hepatosplenomegaly. A lymph node biopsy was consistent with small lymphocytic lymphoma. Bone marrow examination revealed small mature-looking lymphocytes with a background of smudge cells. The leukaemia cells co-expressed the CD5 antigen and B-cell surface antigens, with restricted kappa immunoglobulin light chain expression. Fluorescence in situ hybridisation analysis demonstrated a homozygous 13q14.2 gene deletion. Serum kappa and lambda free light chain (FLC) results were 99.50 mg/L (reference 6.70-22.40 mg/L) and 12.50 mg/L (reference 8.30-27.00 mg/L), respectively, with a kappa to lambda ratio of 7.96. Beta-2 microglobulin level was 4.64 mg/L (reference 1.09-2.53 mg/L). The patient screened seronegative for human immunodeficiency virus, syphilis, and hepatitis B and C. Overall findings were consistent with a diagnosis of CLL Rai stage II (Binet stage B), with Eastern Cooperative Oncology Group performance status zero. A ‘wait and watch’ approach was adopted initially until mid-2018 when the patient started to report fatigue and absolute lymphocyte count doubled in less than 6 months. Owing to limited resources, the patient was given weekly intravenous rituximab (500 mg) but developed herpes zoster infection after two cycles. Treatment was changed to chlorambucil (8 mg once daily) and prednisolone (20 mg once daily) for 10 days per cycle, repeating every 28 days, with acyclovir prophylaxis.
 
At 1 year after this treatment started, the patient presented with an acute event of angio-oedema that began as a tingling around his face and mouth similar to a bee sting and swelling of his lips and tongue (Fig 1), sparing the larynx, abdomen, extremities, and genital involvement. There were no identifiable inciting episodes. He denied intake of angiotensin-converting enzyme inhibitors, traditional medications, or over-the-counter drugs. He had no history of atopy or angio-oedema.
 

Figure 1. (a, b) Photographs showing 60-year-old man with angio-oedema of the lips and tongue
 
The patient remained well until early 2020 when he presented with similar episodes of angio-oedema that recurred on three occasions. A complete workup revealed a C1 esterase inhibitor antigen level of 4 mg/dL (reference 19-37 mg/dL) with function being 9% (reference <66%). Complement C1q level measured using radial immunodiffusion assay was undetectable with low complement 3 and 4 [0.29 g/L (reference value 0.9-1.8 g/L), <0.02 g/L (reference value 0.15-0.45 g/L), respectively]. Owing to restricted resources, anti-C1 inhibitor antibodies and monoclonal component isotypes were unavailable. Autoimmune screening (antinuclear antibody and rheumatoid factor) and serum cryoglobulin were negative. Skin biopsy showed features of angio-oedema without atypical lymphocytes (Fig 2). During the fourth acute attack of angio-oedema, the patient was given tranexamic acid and danazol and symptoms completely resolved within 24 hours.
 

Figure 2. Skin punch biopsy showed solar elastosis in background of prominent oedema (H&E stain, ×200)
 
The overall clinical manifestations and laboratory findings were consistent with the diagnosis of acquired angio-oedema due to C1 deficiency in association with CLL. We decided to initiate chemotherapy—rituximab, cyclophosphamide, vincristine, and prednisolone. After two cycles, the patient developed urticaria vasculitis over his limbs that responded to cetirizine and resolved completely after completing six cycles of chemotherapy. C1 esterase inhibitor functional assay normalised. He remained free of any recurrent angio-oedema and urticaria during the 1-year follow-up period. He was able to resume work and could live independently.
 
Discussion
Angio-oedema can be hereditary or acquired. The latter often presents after the fifth decade of life with no family history.1 Symptom onset and absence of family history led to a diagnosis of acquired angio-oedema in our patient due to C1 esterase inhibitor deficiency. The median time to diagnosis is reported to vary between 10 months and 10 years.2 Our patient was diagnosed 9 months after symptom onset and during the third episode of angio-oedema. To the best of our knowledge, only about 20 cases of CLL have been reported to be associated with angio-oedema.2 Many diseases are reported to be associated with acquired angio-oedema, with lymphoproliferative disorders and B-cell malignancies the most common.3
 
In acquired angio-oedema, C1 esterase inhibitor protein level is decreased due to excessive consumption, or may be dysfunctional due to the presence of antibodies against C1 inhibitor, leading to defective inhibition of the complements and kinin system. This results in exaggerated response in the classic complement pathway and production of bradykinin leading to angio-oedema, in which C1q and C4 level is low, as in our case.2 Our patient also developed urticaria vasculitis. This was likely due to C1q depletion and low complement, as previously reported.2 Urticaria vasculitis, which likely involves tumour-associated immune complexes, has been described as a rare association with haematological malignancy.4 The achievement of disease remission led to resolution of both angio-oedema and urticarial vasculitis in our case.
 
Our patient demonstrated a kappa-restricted serum FLC with the summated FLC being 112 mg/L, confirming the monoclonal nature of serum FLC. Studies have shown that serum FLC may be elevated in almost 50% of patients with CLL. This finding is an adverse prognostic factor for time to treatment and overall survival.5
 
The mainstay of treatment for acute acquired angio-oedema includes C1 esterase inhibitor concentrate from human plasma or recombinant C1 inhibitor concentrate.3 Nonetheless these products are not widely available in most healthcare facilities, including our centre where fresh frozen plasma is a reasonable alternative, although not without potential risks. Long-term prophylactic treatment with antifibrinolytic agents and danazol has been shown to be equally efficacious,2 with a recommendation to avoid the former in the presence of thromboembolic risk factors.2 It is vital to treat the underlying disease to prevent acute attacks, regardless of the treatment options.2 Our patient has had no further attacks of angio-oedema after receiving rituximab, cyclophosphamide, vincristine, and prednisolone chemotherapy. This is in concordance with the literature that reports resolution of angio-oedema after treatment of the underlying malignancy.4
 
Our case highlights the challenge posed in managing a patient with CLL and atypical features. Clinical suspicion should be heightened in patients who present with recurrent episodes of angio-oedema. Treating the underlying malignancy often leads to complete resolution of symptoms.
 
Author contributions
Concept or design: ASO Tang, TS Leong, LP Chew.
Acquisition of data: ASO Tang, JTH Lee, QY Wong, ST Yeo.
Analysis or interpretation of data: JTH Lee, QY Wong, ST Yeo.
Drafting of the manuscript: ASO Tang, TS Leong, LP Chew.
Critical revision of the manuscript for important intellectual content: All authors.
 
Conflicts of interest
The authors declare that they have no conflict of interest or financial disclosure.
 
Acknowledgement
The authors would like to thank the Director General of Health Malaysia and Clinical Research Centre (CRC) Miri Hospital for permission to publish this paper.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This article does contain studies with human participants and was registered via National Medical Research Register Malaysia with a Research ID of NMRR-20-1666-56020. The patient(s) provided written informed consent for all treatments and procedures and consent for publication.
 
References
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