Incidental pancytopenia in the setting of urolithiasis: severe copper deficiency without classic risk factors

Summary

Pancytopenia is a significant haematological finding with a broad differential, ranging from benign conditions to life-threatening malignancies. Copper deficiency is a recognised but uncommon cause of non-clonal cytopenias. We report a case of copper deficiency in a woman in her 80s who presented with urolithiasis and was found to have acute pancytopenia. A thorough evaluation identified undetectable copper levels despite the absence of classic risk factors such as gastrointestinal surgery, malabsorptive disorders or zinc supplementation. Our patient’s copper deficiency was most likely multifactorial arising from insufficient dietary intake and chronic mild gastrointestinal dysfunction. Emerging evidence suggests that hypocupremia may be more common than previously appreciated, and clinicians should consider copper deficiency in the differential diagnosis of pancytopenia.

Background

Pancytopenia represents a significant haematological finding with diverse aetiologies, ranging from benign and reversible conditions to life-threatening malignancies. Acute leukaemias and myelodysplastic syndromes (MDS) are among the most common causes.¹

In a study of adults with new-onset pancytopenia with no history of haematolymphoid neoplasia or prior bone marrow studies, 64% were due to clonal haematopoietic disorders, most commonly acute myeloid leukaemia (AML) or MDS.² Copper deficiency is uncommon even among the non-clonal causes of cytopenias.^{3 4}

Nutritional deficiencies typically present as chronic illnesses. Traditional risk factors include a history of bariatric surgery or malabsorptive states induced by diseases like coeliac or inflammatory bowel disease.⁵ For copper deficiency, the most common cause is excessive exposure to zinc from supplements or denture creams. Zinc and copper compete for absorption within the gastrointestinal tract; hence an excess of one will lead to a deficiency in the other.⁶ However, copper deficiency appears to be increasingly recognised, in part because Western diets often provide intake at the lower end of the recommended range.⁷

In this case, we highlight copper deficiency as an acute and reversible cause of pancytopenia. Despite a thorough diagnostic workup, no clear underlying aetiology was identified, underscoring the importance of including copper screening in the diagnostic evaluation of pancytopenia.

Case presentation

A woman in her 80s with a medical history of type 2 diabetes, hypertension, chronic kidney disease, osteoarthritis, anxiety/depression, obesity, osteoporosis and a splenic artery aneurysm presented to the emergency department with severe, persistent sharp left lower quadrant abdominal pain and constipation for 3 days. She also reported 3 weeks of progressive fatigue. On review of systems, she has had a longstanding history of periods of alternating diarrhoea and constipation. Social history was notable for the fact that the patient was a Catholic nun, and denied intake of alcohol, tobacco and illicit drugs. Family history was notable for a brother with chronic myelomonocytic leukaemia and non-Hodgkin’s lymphoma in her mother.

Examination revealed a woman in mild distress. Vitals were significant for tachycardia (109 bpm). The abdominal exam was notable for normoactive bowel sounds without distension, pain in the left lower quadrant on palpation, without rebound tenderness. There was no cervical, supraclavicular, axillary or inguinal lymphadenopathy.

Investigations

ECG and chest radiography were unremarkable. Laboratory studies demonstrated acute kidney injury (AKI) (Cr 2.47, baseline 0.8–0.9; ref 0.52–1.04) with elevated liver associated enzymes (aspartate aminotransferase (AST) 100 U/L, alanine aminotransferase (ALT) 166 U/L, alkaline phosphatase (ALP) 154 U/L; ref AST 3–24 U/L, ALT 15–41 U/L, ALP 45–117 U/L) and a high-sensitivity troponin was within normal limits. Initial complete blood count (CBC) showed leucopenia (white blood cells (WBC) 3.26×10⁹/L, absolute neutrophil count (ANC) 800/µL; ref WBC 4–10.8×10⁹/L, ANC 1700–8100/µL) with otherwise preserved cell lines. Subsequent CBC demonstrated pancytopenia (WBC 2.56×10⁹/L, ANC 0.4×10³/µL, haemoglobin 93 g/L, haematocrit 28.6%, platelets 137×10⁹/L). Urinalysis revealed haematuria, proteinuria and pyuria, with lactic acid elevated at 3.4 mmol/L; urine and blood cultures showed no growth. CT of the abdomen without contrast was performed, due to the patient’s AKI, which revealed 4 mm urolith in the left ureterovesical junction and mild left-sided hydroureteronephrosis. The liver was normal in size and contour, without any suspicious lesions.

Peripheral smear showed anisopoikilocytosis, microcytes, macrocytes, ovalocytes, teardrop cells, burr cells and polychromasia, consistent with dysplastic erythropoiesis. WBCs demonstrated abnormal granulation without blasts, and platelets were enlarged and reduced in number. Serum free light chains had a Kappa/Lambda ratio of 1.36 (ref 0.26–1.65), serum/urine protein electrophoresis were without monoclonal spikes. Peripheral flow cytometry revealed reduced granulocytes with no increase in blasts or abnormal B or T cells. Antinuclear antibody (ANA) was positive (1:320 speckled) with an elevated erythrocyte sedimentation rate (ESR), elevated haptoglobin but normal lactate dehydrogenase (LDH) levels. Anti-dsDNA and anti-Smith antibodies were negative, and C3 (146 mg/dL; ref 90–180 mg/dL) and C4 (23 mg/dL; ref 10–40 mg/dL) complement levels were within normal limits.

Metabolic studies revealed normal vitamin B12 (695 pg/mL; ref 180–900 pg/mL) and folate (9.4 ng/mL; ref 2.7–17.0 ng/mL), with elevated methylmalonic acid (MMA) (0.45 µmol/L; ref 0.0–0.4 µmol/L) and normal ferritin (178.5 ng/mL; ref 7.3–270 ng/mL). Most notably, serum copper was severely decreased (<10 µg/dL; ref 80–155 µg/dL) with low ceruloplasmin (3 mg/dL; ref 20–35 mg/dL). Zinc levels were normal (103.4 mcg/dL; ref 60–120 mcg/dL).

Differential diagnosis

Pancytopenia alone is most commonly associated with hematopoietic neoplasm; however, the concurrent stone raised initial concern for tumour lysis syndrome (TLS). However, TLS was considered unlikely, as uric acid, phosphate, potassium and calcium levels were all normal.

Among blood neoplasms, AML/MDS were considered most likely based on the patient’s demographics;² however, these were unlikely based on the peripheral smear without blasts and normal flow cytometry.⁸

Aplastic anaemia was considered but deemed less likely given the patient’s elevated reticulocyte counts and polychromasia. Autoimmune aetiologies were considered due to ANA positivity and elevated ESR; however, the absence of clinical features, negative antibodies and normal complement levels and LDH strongly argue against this.

Infectious aetiologies were evaluated: HIV, hepatitis A/B/C and interferon gamma release assay for tuberculosis were negative.

Her social history made drug-related or alcohol-related pancytopenia unlikely. Splenic sequestration was unlikely given absent splenomegaly on CT.

Nutritional evaluation revealed undetectable copper (<10 µg/dL), low ceruloplasmin, normal zinc and elevated MMA. The patient’s elevated liver enzymes, reduced ceruloplasmin and copper levels raised consideration for Wilson’s disease; however, a new diagnosis at over 80 years old would be atypical, and abdominal imaging was unremarkable with no neurological or haemolytic features.

Overall evaluation supported concurrent copper and vitamin B12 deficiency as contributors to the patient’s pancytopenia.

Treatment

The patient was started on continuous intravenous normal saline and tamsulosin to facilitate stone passage, a urine hat for stone collection, and empirically treated with ceftriaxone for presumed urinary tract infection. Within 24 hours, her symptoms resolved before the urine hat was obtained. Repeat CT scan confirmed the passage of the stone, and serum chemistry showed improved renal and liver function. She was started on copper supplementation (2 mg daily) along with sublingual vitamin B12 (5000 mcg daily).

Outcome and follow-up

Prior to the initiation of copper supplementation, repeat complete CBC indicated that the patient remained mildly anaemic with haemoglobin 10.5 g/dL and haematocrit 33.9%, but WBC count had normalised to 4.55×10³/µL (ANC of 1.4×10³/µL), and platelet count was within normal range (274×10³/µL).

One month after beginning oral copper supplements, CBC showed improvement in haemoglobin (11.4 g/dL) and haematocrit (34.2%), with normal WBC/platelet counts.

The underlying cause of this patient’s copper deficiency remains unclear. The patient had no history of intra-abdominal surgery, zinc supplementation or denture use. She did, however, report a long history of constipation and diarrhoea, previously attributed to irritable bowel syndrome. An oesophagogastroduodenoscopy (EGD) performed 5 years earlier had revealed only mild chronic inactive gastritis, no dysplasia, intestinal metaplasia or Helicobacter pylori infection. Colonoscopy at the same time revealed mild diverticulosis and a sessile polyp, which was removed.

Given her elevated ESR and positive ANA, additional evaluation was pursued for autoimmune/malabsorptive disorders. Testing for pernicious anaemia showed negative gastric parietal cell immunoglobulin (Ig)G and intrinsic factor antibodies. Although she had previously been told she might have coeliac disease, repeat screening performed while she was consuming a gluten-containing diet was negative for deamidated gliadin IgA and tissue transglutaminase IgA antibodies, with normal total IgA levels.

Following initiation of 2 mg daily copper supplementation, her serum copper level improved but remained low at 31.9 µg/dL, likely indicating reduced intestinal absorptive capacity. Her supplementation increased to 4 mg daily, which resolved her copper deficiency (repeat level 96 µg/dL).

Discussion

Pancytopenia is a common clinical finding with a broad differential, requiring a systematic approach since it represents a manifestation of an underlying process. Among the range of potential etiologies, copper deficiency is one of the least common and often overlooked.

In this case, the diagnostic challenge was heightened by the concerning family history of haematopoietic neoplasms and concurrent urolithiasis, suspected to be a uric acid stone. Since we were unable to collect the urolith for direct chemical analysis, we relied on surrogate radiographic densitometry findings. The urolith was found to have 302 Hounsfield Units (HU) on CT scan, a density consistent with a uric acid composition (<572.3 HU).⁹

Given the curious confluence of copper deficiency, urolithiasis and pancytopenia, a medical librarian performed a comprehensive literature search (online supplemental A), which revealed mixed evidence regarding copper’s relationship with nephrolithiasis. One study found a negative association,⁹ while two reported a positive association^{10 11} between higher copper intake and nephrolithiasis. Zhu et al hypothesised this discrepancy may reflect copper’s dual pro- and antioxidant properties, suggesting a potential bidirectional relationship; however, more research is needed to understand this relationship.⁹

We hypothesise that functional vitamin B12 deficiency, transient bone marrow suppression from acute illness (obstructive urolithiasis) and haemodilution from crystalloid infusion contributed to the patient’s cytopenias in the setting of an underlying copper deficiency. The patient had an elevated MMA despite a normal serum vitamin B12 level, which may reflect a functional vitamin B12 deficiency or reduced renal clearance in the setting of her AKI. Typically, nutritional deficiencies like copper deficiency manifest over weeks to months; however, this patient’s pancytopenia emerged acutely, worsening over her 3-day hospitalisation. Partial improvement in CBC values occurred prior to initiation of copper supplementation, suggesting that transient factors, such as resolving acute illness-related marrow suppression, may have contributed to the pancytopenia. However, the presence of severe hypocupremia, along with normalisation of serum copper levels and further improvement in haematological parameters following supplementation, suggests that copper deficiency was a contributing factor rather than the sole aetiology.

Copper is an essential trace element involved in numerous physiological pathways, including energy production, iron metabolism, connective tissue maturation, neurotransmission and immune regulation.¹² Common causes of copper deficiency include inadequate dietary intake, parenteral nutrition without supplementation, malabsorptive states, increased metabolic needs associated with conditions such as major burns, renal replacement therapy, chronic zinc use from dentures or denture paste and rare genetic disorders like Menkes disease.¹³

Our patient had no classic features of severe nutritional deficiency, such as weight loss and muscle wasting, no history of parenteral nutrition, zinc supplementation or severe malabsorptive disorder. Instead, her copper deficiency was most likely multifactorial, primarily arising from an unrecognised malabsorptive state with insufficient dietary intake in Western diets^{7 14} as a contributing factor.

In reviewing the literature, we identified multiple case reports and retrospective analyses describing copper deficiency of unclear aetiology. In a retrospective review of the haematological manifestations of copper deficiency conducted at a single US academic institution, 12 of the 40 cases of copper deficiency had no identifiable cause.¹⁵ In another study, patients referred for evaluation of unexplained anaemia or myelodysplasia were screened for copper deficiency. Among the 126 serum copper levels obtained, eight patients had copper deficiency, three of which had no clear cause.¹⁶ Both studies were retrospective reviews, leaving uncertainty about how comprehensively the aetiology of copper deficiency was evaluated. We identified several case reports describing copper deficiency of unclear aetiology. One report mentioned an unspecified gastrointestinal evaluation,¹⁷ while others provided little to no workup details.^{18 19} Two reports considered autoimmune causes; the evaluations were limited—one testing anti-tissue transglutaminase (TTG) IgG alone,¹⁷ and the other including ANA, rheumatic factor, anti-SSA/SSB Abs, without anti-TTG IgG.¹⁹ Taken together, hypocupremia may be more common than previously appreciated. Notably, our case includes a more comprehensive diagnostic evaluation including a comprehensive autoimmune panel and prior EGD and colonoscopies compared with the previously published reports.

This case has several limitations. A bone marrow biopsy was deferred given the patient’s improving haematological lab values, reassuring peripheral smear and flow cytometry findings, and the risk associated with an invasive procedure. Therefore, primary marrow disorders, including MDS and aplastic anaemia, cannot be definitively excluded. Additionally, although testing for HIV, viral hepatitis and tuberculosis were negative, other infectious aetiologies associated with pancytopenia, such as parvovirus B19, Epstein-Barr virus and cytomegalovirus, were not evaluated due to low clinical suspicion.

Treatment of copper deficiency consists of copper repletion, typically 2–4 mg daily administered orally when gastrointestinal absorption is intact, or 0.3–0.4 mg daily intravenously in adults when parenteral replacement is required.^{12 20} Haematological abnormalities generally resolve within weeks of supplementation, as observed in our case presentation. Ongoing monitoring of copper and ceruloplasmin levels is recommended to ensure sustained repletion.²¹

Patient’s perspective.

I had had multiple episodes of fatigue and weakness for a week or a bit longer, so much so that I could not comb my hair and could not move my legs. I was hospitalised three times for these symptoms, and my primary care provider and I both thought that I was dying. On my third hospitalisation, we found the abnormal bloodwork and eventual copper deficiency. I did not know anything about copper deficiency at the time and did not even know we had it in our bodies. Since starting copper supplements, these symptoms have miraculously gone away, and I have been feeling better. After the hospitalisation, I met with a haematologist, and she had no idea why my copper levels were so low. However, since starting copper supplementation, my levels have improved, and I was able to stop taking them.

Getting my prescribed copper supplements from the pharmacy was difficult. After the hospitalisation where I found this diagnosis, there was a delay while my outpatient pharmacy located and dispensed the copper supplements. When I was rehospitalised shortly after, having only recently started supplementation and before my copper levels were fully repleted, the inpatient pharmacy did not have copper supplements available, and I was told to have my friend bring in my supplements from home.

I am thankful that I got tested and that I received treatment and that I have been able to feel better since.

Learning points.

• Copper deficiency is an uncommon cause of pancytopenia that may present acutely even in the absence of classic risk factors such as gastrointestinal surgery, malabsorptive disorders or zinc supplementation.

• Hypocupremia may be more common than previously recognised and the absence of traditional risk factors should not preclude clinicians from considering copper deficiency in the differential diagnosis.

• Copper deficiency is an uncommon cause of pancytopenia that may present acutely even in the absence of classic risk factors such as gastrointestinal surgery, malabsorptive disorders or zinc supplementation.