A 34-year-old man with tea-coloured urine

Key points

• Dark or tea-coloured urine has many different causes, including dehydration, medications, urinary tract infections, and hemolytic disorders.

• Levels of haptoglobin — a glycoprotein, synthesized in the liver, that binds and clears free hemoglobin from the circulation — are reduced in hemolysis, liver disease, malnutrition, and congenital deficiency.

• Congenital haptoglobin deficiency, although rare, should be considered in patients with unexplained, persistently low haptoglobin — especially those of East Asian (e.g., Chinese, Korean, Japanese) and Southeast Asian (e.g., Thai, Vietnamese) ancestry — and can be confirmed with genetic testing.

• Patients with complete congenital haptoglobin deficiency are typically asymptomatic but may be at risk of anaphylactic transfusion reactions caused by anti-haptoglobin antibodies; those who require multiple transfusions should receive washed or haptoglobin-deficient blood products.

A healthy 34-year-old man presented to his local walk-in clinic with dysuria and dark (tea-coloured) urine. He did not have any previous episodes of dark urine and denied any other infectious symptoms, fevers, night sweats, or weight loss. He had no notable medical history and was not taking any medications. He was a nonsmoker and reported drinking 10 to 20 alcoholic drinks per week. He had no other identified risk factors for viral hepatitis, HIV, or liver disease, with no family history of similar symptoms or known liver disease. He was of Chinese descent and had immigrated to Canada as a teenager.

On physical examination, the patient was noted to have jaundice and scleral icterus without hepatosplenomegaly, peripheral edema, petechial rash, or purpura. In the initial investigations, his primary care physician considered hemolysis as a cause of the dark urine and jaundice. His complete blood count revealed a normal hemoglobin and platelet count, with mild leukocytosis, with a leukocyte count of 13 (reference interval [RI] 4 to 10) × 10⁹/L (Table 1). He was, however, found to have elevated total bilirubin (59 [RI ≤ 22] μmol/L) and low serum haptoglobin (0.25 [RI 0.30 to 2.0] g/L). Liver enzymes, international normalized ratio, and lactate dehydrogenase (LDH) levels were within normal limits. The primary care physician diagnosed a urinary tract infection (UTI) based on the patient’s symptoms and urine culture, which grew Proteus mirabilis. His UTI was successfully treated with antibiotics and the dysuria and dark urine resolved over the following few days.

Table 1:

Patient laboratory values

Test	Reference interval	Initial visit	5 days	4 months	9 months
Hemoglobin, g/L	135–170	160	158	159	158
MCV, fL	80–100	93	92	89	90.4
Reticulocyte, × 109/L	10–100	–	–	83	83
Blood film	–	–	–	–	No RBC abnormalities
Serum creatinine, μmol/L	62–120	95	–	78	108
ALT, U/L	≤ 41	16	–	29	40
ALP, U/L	40–129	69	–	68	71
Toal bilirubin, μmol/L	≤ 21	59	16	23	27
Direct bilirubin, μmol/L	≤ 3	–	5	7	6
Albumin, g/L	35–52	52	–	50	49
Haptoglobin, g/L	0.30–2.00	0.25	–	< 0.03	< 0.10
LDH, U/L	≤ 225	–	214	190	171
Urine colour	–	Tea-coloured	Clear	Clear	Clear

Note: ALP = alkaline phosphatase, ALT = alanine aminotransferase, LDH = lactate dehydrogenase, MCV = mean corpuscular volume, RBC = red blood cell.

Given the patient’s elevated bilirubin and low haptoglobin levels, which were out of keeping with a UTI, he was referred to a gastroenterologist to assess for underlying liver disease. At his gastroenterology appointment, 2 months after the initial presentation, his haptoglobin was undetectably low (< 0.03 g/L) but his bilirubin had normalized. Abdominal ultrasonography showed a normal liver and spleen. Given the absence of liver synthetic dysfunction and the lack of risk factors for liver disease outside of alcohol use, his low haptoglobin was not considered to be secondary to decreased hepatic production.

The patient was subsequently referred to our internal medicine clinic, where he was assessed 2 months after his gastroenterology appointment. On physical examination, he had no evidence of jaundice, scleral icterus, hepatosplenomegaly, ascites, peripheral edema, petechiae, or purpura. We completed further investigations for potential sources of hemolysis to explain the patient’s persistently low haptoglobin. He had a normal complete blood count, normal peripheral blood smear, and negative direct antiglobulin test. Flow cytometry using fluorescein-labelled proaerolysin (FLAER) did not identify any paroxysmal nocturnal hemoglobinuria (PNH) clone. A glucose-6-phosphate dehydrogenase (G6PD) assay was not performed. The patient’s haptoglobin level remained undetectably low on repeat testing despite normalization of his bilirubin and absence of other laboratory evidence of hemolysis, including normal reticulocyte count and LDH.

We referred the patient to a hematologist for further investigation of persistently low haptoglobin. Given his East Asian ancestry and persistently undetectable haptoglobin in the absence of hemolysis or hepatic dysfunction, congenital haptoglobin deficiency was suspected. Haptoglobin genotyping was performed using polymerase chain reaction (PCR) and showed a heterozygous genotype of the HP gene (HP²/HP^del), indicating 1 allele with a haptoglobin gene deletion. He was also found to carry the rs2000999 A allele, a single nucleotide polymorphism associated with reduced serum haptoglobin levels. Together, these genetic findings were consistent with a low haptoglobin phenotype, confirming congenital haptoglobin deficiency.

The hematologist counselled the patient regarding the diagnosis and management of congenital haptoglobin deficiency. Given that the haptoglobin deficiency was identified incidentally in the setting of his UTI, the patient was informed that his tea-coloured urine and elevated bilirubin could have been related to the infection itself or to transient hemolysis. As he did not have complete deficiency, based on an initially low but detectable haptoglobin level and a genotype associated with partial expression, he was advised that there was no clinical concern for increased risk of transfusion-related reactions, and that no special precautions were required. At 6-month follow up, he remained well, with no recurrent episodes of dark, tea-coloured urine.

Discussion

The differential diagnosis for dark, tea-coloured urine is broad (Box 1).¹ Evaluation should include a thorough history and physical examination, along with targeted investigations for underlying causes, including hemolysis. Laboratory investigations for hemolysis include reticulocyte count, indirect bilirubin, LDH, and haptoglobin levels.^2,3

Box 1: Causes of dark or tea-coloured urine^* .

Increased solute concentration

• Dehydration

Pigment or metabolites from medications or food

• Medications: metronidazole, nitrofurantoin, rifampin, doxorubicin, levodopa (including carbidopa–levodopa combinations), senna-containing laxatives

• Foods: beetroot, rhubarb, fava beans, aloe, or food dyes or colourings

Hematuria from renal or urinary tract pathology

• Urinary tract infections

• Kidney stones

• Glomerulonephritis

• Urologic malignancies (bladder, kidney, ureter)

Hemoglobinuria from hemolysis, especially intravascular hemolysis, when free hemoglobin is released into the circulation and filtered by the kidneys ^†

• Hereditary causes: membranopathies (e.g., hereditary spherocytosis), enzymopathies (e.g., glucose-6-phosphate dehydrogenase deficiency), or hemoglobinopathies (e.g., thalassemia, sickle cell disease)

• Acquired causes: autoimmune hemolytic anemia, microangiopathic hemolytic anemias (e.g., thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hemolytic uremic syndrome), infections (e.g., malaria), mechanical destruction (e.g., prosthetic heart valves), or paroxysmal nocturnal hemoglobinuria

Myoglobinuria from muscle injury or necrosis

• Rhabdomyolysis (trauma, exertion, or medication-induced)

Bilirubinuria from excess conjugated bilirubin entering the circulation and being filtered by the kidneys

• Hepatocellular disease (e.g., viral hepatitis, cirrhosis)

• Cholestasis or obstruction (e.g., gallstones, cholangiocarcinoma, pancreatic cancer)

Other systemic or metabolic causes

• Porphyria

• Heavy metal poisoning

• Alkaptonuria

Haptoglobin is a glycoprotein synthesized in the liver.⁴ Its primary function is to irreversibly bind toxic free hemoglobin released during erythrocyte lysis. This binding forms a stable haptoglobin–hemoglobin complex, which is protective against oxidative damage and is rapidly removed from systemic circulation. Serum haptoglobin concentration is determined by the balance between production and consumption, which can be influenced by a range of clinical states. Low haptoglobin occurs in the setting of hemolysis as haptoglobin–hemoglobin complexes are cleared. Haptoglobin may also be reduced because of impaired synthesis (e.g., from liver disease, malnutrition), increased consumption (e.g., from sepsis), or, rarely, congenital absence from genetic alterations in the haptoglobin gene (Figure 1). Causes of low haptoglobin are outlined in Table 2. As a positive acute-phase reactant, haptoglobin levels may also rise in response to systemic inflammation, infection, trauma, or malignancy. It is important to note that haptoglobin levels are often low in young children and not necessarily indicative of increased erythrocyte turnover.

Figure 1:

Causes of low haptoglobin. Created in BioRender. Hsia, C. (2025). https://BioRender.com/uzzr8py.

Table 2:

Causes of low haptoglobin and targeted investigations

Cause	Targeted investigations*
Liver disease leading to reduced hepatic synthesis of haptoglobin: Metabolic dysfunction–associated steatotic liver disease Alcohol-associated liver disease Chronic viral hepatitis Cirrhosis	Liver enzymes and function tests (i.e., alanine aminotransferase, alkaline phosphatase, albumin, total and direct bilirubin, international normalized ratio, and partial thromboplastin time) Viral hepatitis serologies Abdominal ultrasonography
Hemolysis from binding and clearance of free hemoglobin: Hereditary causes: membranopathies (e.g., hereditary spherocytosis), enzymopathies (e.g., G6PD deficiency), or hemoglobinopathies (e.g., thalassemia, sickle cell disease) Acquired causes: autoimmune hemolytic anemia, microangiopathic hemolytic anemias (e.g., thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hemolytic uremic syndrome), infections (e.g., malaria), mechanical destruction (e.g., prosthetic heart valves), or paroxysmal nocturnal hemoglobinuria	Reticulocyte count, total and direct bilirubin, lactate dehydrogenase Peripheral blood smear Direct antiglobulin test Hemoglobin electrophoresis G6PD assay Flow cytometry for paroxysmal nocturnal hemoglobinuria
Severe malnutrition, given that impaired hepatic protein synthesis reduces haptoglobin levels	Albumin, prealbumin Liver enzymes and function tests (i.e., alanine aminotransferase, alkaline phosphatase, albumin, total and direct bilirubin, international normalized ratio, and partial thromboplastin time) Ferritin, transferrin saturation Vitamin B12
Sepsis or infection leading to increased consumption of haptoglobin	Microbiologic testing, including (as relevant) blood cultures, site-specific cultures (e.g., urine, sputum, line), respiratory viral PCR Focused imaging to localize source (e.g., chest radiography, ultrasonography)
Congenital haptoglobin deficiency (autosomal recessive) caused by mutations or deletions in haptoglobin genes	Haptoglobin genotyping by PCR

Note: G6PD = glucose-6-phosphate dehydrogenase, PCR = polymerase chain reaction.

^*This table highlights selected investigations and is not exhaustive; investigations should be guided by clinical context.

When evaluating a patient with low haptoglobin, clinicians should ask about signs and symptoms of hemolysis such as jaundice, scleral icterus, and dark (tea-coloured) urine. They should also screen for symptoms and risk factors for liver disease, including alcohol use, medications, and recent travel. Ethnicity and family history are relevant when considering hereditary causes of hemolysis and low haptoglobin levels. Physical examination should focus on signs of hemolysis and liver disease. Initial laboratory investigations for low haptoglobin should include complete blood count, reticulocyte count, peripheral blood smear, and testing levels of total and direct bilirubin, liver enzymes, and LDH. Historical haptoglobin levels should be reviewed. If the patient has signs of hemolysis (e.g., anemia with associated elevated reticulocyte count, LDH, or indirect hyperbilirubinemia), further work-up may include a direct antiglobulin test for autoimmune hemolytic anemia, hemoglobin electrophoresis for an underlying hemoglobinopathy, testing for G6PD deficiency, and flow cytometry using FLAER for PNH.

Our patient presented with dark, tea-coloured urine and was found to have persistently low haptoglobin levels of unclear cause, raising the suspicion of an underlying congenital haptoglobin deficiency. Congenital haptoglobin deficiency is a rare but documented cause of chronically low (hypohaptoglobinemia) or absent (anhaptoglobinemia) serum haptoglobin levels. The reported prevalence of absent haptoglobin is 1 in 640 and 1 in 3500 in Chinese and Japanese populations, respectively, while 0.9% to 4% of East and Southeast Asian populations have heterozygous genotypes.⁴ The haptoglobin gene exhibits polymorphism, with 2 codominant alleles, HP¹ and HP². This leads to 3 potential phenotypes (HP^1-1, HP^2-1, and HP²-²). Deletion of both alleles (HP^del/HP^del) results in undetectable serum haptoglobin levels, whereas single deletion can lead to decreased, although not absent, levels. In addition, 2 single nucleotide polymorphisms, rs5471 C and rs2000999 A, are associated with low serum haptoglobin levels.⁴

People with congenital haptoglobin deficiency are generally asymptomatic. However, in cases of complete deficiency, exposure to haptoglobin from transfused blood products can lead to development of anti-haptoglobin antibodies.⁵ Once sensitization has occurred, subsequent transfusions can trigger severe allergic reactions, including anaphylaxis. Thus, a single transfusion does not typically necessitate the use of washed or haptoglobin-deficient products, but the risk increases with repeated transfusions. In such cases, patients should receive washed components or blood products obtained from haptoglobin-deficient donors. Sensitization can be confirmed by measuring anti-haptoglobin antibodies in the patient’s serum.⁵

Congenital haptoglobin deficiency should be suspected when haptoglobin remains persistently low in the absence of hemolysis or liver disease. For our patient, the diagnosis was initially obscured by the presentation of dark urine and elevated bilirubin in the setting of a UTI. These findings could have been related to the infection itself or to possible transient hemolysis. The finding of a low but detectable haptoglobin at presentation, followed by undetectable levels, suggests that the initial value may have been transiently elevated as an acute-phase reactant in the context of infection. The diagnosis of congenital haptoglobin deficiency was ultimately confirmed through haptoglobin genotyping using PCR-based methods.⁶

Congenital haptoglobin deficiency is most commonly reported in people of East Asian (e.g., Chinese, Korean, Japanese) and Southeast Asian (e.g., Thai, Vietnamese) ancestry, and limited to case reports and case series in other populations. This case underscores the importance of maintaining a broad differential for dark, tea-coloured urine and of recognizing persistently low haptoglobin levels, in the absence of hemolysis or liver disease, as a potential indicator of congenital deficiency.

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