Unusual Manifestation of Diarrhea-Associated Haemolytic Uraemic Syndrome in an Adult

Abstract

Hemolytic-Uremic Syndrome (HUS) is an uncommon disease characterized by microangiopathic hemolytica anaemia, thrombocytopenia, and acute renal failure. There are two forms of HUS: diarrhoea (D+)- and non-diarrhoea (D−)-associated HUS. We report the case of a 21-year-old woman presented to our department with jaundice, anaemia, thrombocytopenia, and anuria, preceded by a diarrheal prodrome, secondary to infection with Escherichia coli O157:H7. The whole clinical and laboratory investigation led to the diagnosis of HUS. Her condition was complicated with cholestasis, liver dysfunction, bleeding from the vagina, and myocardial involvement. She was treated only with fresh frozen plasma transfusions and hemodialysis, and despite the long duration of anuria (22 days), the patient showed subsequent improvement over days until full recovery one month later.

Keywords:

• Escherichia coli O157:H7
• hemolytic-uremic syndrome
• shiga toxin
• thrombotic thrombocytopenic purpura

INTRODUCTION

Hemolytic-Uremic Syndrome (HUS) is characterized by the triad of microangiopathic hemolytica anaemia (Coomb's test negative), thrombocytopenia, and acute renal failure (ARF). HUS can be further divided into two categories of diseases: the first is common in children and is associated with a prodromal period of bloody diarrhoea (D+ HUS), mainly caused by infectious agents, such as Escherichia coli O157:H7 and Shigella dysenteriae.[1],[2] The second (D-HUS) occurs especially in adolescents and adults, and its etiology includes pregnancy, oral contraceptive pills, malignancy, chemotherapy (such as cyclosporin A, tacrolimus, or mitomycin C), and autosomal dominant or autosomal recessive inheritance.[2]

CASE REPORT

A 21-year-old Caucasian female was admitted to our department due to sudden onset of anuria and jaundice (two days before admission), as well as anaemia combined with thrombocytopenia and significant increase of serum creatinine and blood urea nitrogen (BUN), on her laboratory testing. She had undergone a prodromal phase with bloody, watery and numerous (about 40–50 daily) episodes of diarrhoea, for five days, followed by several (3–4) episodes of vomiting, nausea, and diffuse abdominal pain, four days before admission to our hospital. One day before the onset of the symptoms, she had consumed beef (potentially undercooked) from a fast-food restaurant chain.

From the onset of the diarrhoeal phase, the patient had been hospitalized elsewhere, receiving intravenous fluids and antibiotics. She mentioned ampicillin and chloramphenicol as her initial administration (dosage unknown). Four days before her admission to our department, she started treatment with cotrimoxazole, 960 mg twice daily. Her medical and family history was free.

On physical examination, jaundice was noticed. No rash or lymphadenopathy was found. The lungs were normal to auscultation, and the cardiac examination revealed a systolic murmur of all the valves. No pericardial rub was detected. The abdominal examination revealed a diffuse sensitivity, especially at the epigastrium. The bowel sounds were louder and more frequent than normal. Neither the liver nor the spleen was palpable. A neurological examination was normal. Her blood pressure was 120/80 mmHg and heart rate 72 bpm. The patient was afebrile.

The electrocardiograph revealed T wave inversion, showed at V₁–V₃. The chest radiograph was normal, and the ultrasonographic (US) study showed that both kidneys were about 10 cm in length; there was no evidence of a renal mass, stone, or hydronephrosis. Nothing remarkable was noticed from the US examination of the other abdominal organs.

Laboratory examinations showed severe hemolytic anaemia (hemoglobin [Hb] 9.2 g/dL lactate dehydrogenase [LDH] 2,745 IU/L, reticulocytes 6%), leukocytosis (white blood cells: 13,800/μL), thrombocytopenia (thrombocytes 67,000/μL), schistocytes about 16% in the peripheral blood and cholestasis (total bilirubin 12 mg/dL and conjugated 7.8 mg/dL), γ-glutamyl transpeptidase (γGT) 244 IU/L, and alkaline phosphatase (ALP) 145 IU/L. There was also evidence of liver impairment (aspartate aminotransferase [AST] 144 IU/L, alanine aminotransferase [ALT] 101 IU/L, INR 1.15, albumin 3.2 g/dL), ARF (anuria, serum creatinine 8.8 mg/dL, BUN 130 mg/dL, estimated glomerular filtration rate [eGFR] 9.89 mL/min/1.73m²), and myocardial involvement (cardiac troponin I 0.54 ng/mL, normal range: 0–0.1 ng/mL); see Table 1. The levels of electrolytes were normal, while the levels of C-reactive protein (CRP) were high: 32.7 mg/dL, as well as the erythrocyte sedimentation rate (100mm/1^st h) and D-Dimers (841.7 mg/mL, normal value: <250 mg/mL). Furthermore, analysis of serum complement showed normal levels of CH50 and C₄, while the levels of C₃ were high (508 μg/mL [normal range: 26–196 μg/mL]).

Table 1 Laboratory findings

Variable	Admission	3^rd day	10^th day	15^th day	30^th day
Hemoglobin (g/dL)	9.2	9.0	10.6	10.5	10.8
Platelets (/μL)	67,000	60,000	200,000	500,000	304,000
Schistocytes (%)	16	10	6	2.5	0.5
Reticulocytes (%)	6	7	6	3	0.5
AST/ALT ( IU/L)	144/101	221/143	25/45	17/29	12/5
ALP/γGT (IU/L)	145/244	275/529	107/121	119/89	66/34
LDH (IU/L)	2,745	3,143	706	303	195
Bilirubin (total/direct) (mg/dL)	12/7.8	6.9/3.21	2/0.53	1.3/0.5	0.8/0.21
Serum creatinine (mg/dL)	8.89	7.77	4.97	5.81	1.46
Cardiac troponin I ( ng/mL )	0.54	0.419	0.05	0.067	0.04

Abbreviations: AST = aspartate aminotransferase, ALT = alanine aminotransferase, ALP = alkaline phosphatase, γGT = γ-glutamyl transpeptidase, LDH = lactate dehydrogenase.

A specimen of arterial blood, drawn while the patient was breathing room air, showed that the partial pressure of oxygen was 108 mmHg, the partial pressure of carbon dioxide was 26 mmHg, the pH was 7.38, and the concentration of bicarbonates was 15 mmol/L. PCR test and IgM antibodies for leptospira and hantaan virus were negative. Investigation for viral hepatitis B and C and human immunodeficiency virus (HIV) was negative, as it was for other viral markers (Ebstein-Barr virus, herpes simple virus and cytomegalovirus). Her autoimmune profile was normal.

The patient's investigation towards hemolysis excluded autoimmune or congenital etiology: Coomb's test was negative, there was sufficiency of glucose-6-phosphatate dehydrogenase (G6PD), and hemoglobulin electrophoresis was normal. Finally, specimens of faeces were obtained for culture, but did not reveal the presence of Escherichia coli, Shigella dysenteriae, or Salmonella, whereas the PCR test showed evidence of verotoxins (shiga toxins: stx1 and stx2) produced by Escherichia coli O157:H7.

The patient's therapeutic approach involved fresh frozen plasma, as well as red blood cell transfusions (when needed) on daily hemodialysis. From the second day of hospitalization, the jaundice started to subside, and the liver tests began to normalize. There was also a gradual decrease in the number of schistocytes and reticulocytes and the levels of cardiac troponin I (cTrnI), BUN, and serum creatinine, followed by an increase in the number of thrombocytes. Apart from a mild oligocardia (54–56 bpm) and the maintenance of anuria, the patient presented remarkable clinical improvement day-to-day. Bleeding from the vagina recessed seven days after admission. Neither significant raise of blood pressure was noticed or peripheral edemas. The patient remained afebrile.

Eventually, on the tenth day of hospitalization, the levels of transaminases, bilirubin, ALP, γGT, CRP, LDH, cTrnI, albumin, INR, D-Dimers, and blood cell count returned to normal. The estimated percentage of schistocytes and reticulocytes in the peripheral blood was 2.5% and 3%, respectively, on the 15^th day of hospitalization. Nonetheless, serum creatinine levels remained still high, 5–6 mg/dL (see Table 1).

Regarding the patient's persistent anuria, a renal biopsy was performed on the 19^th day. The histological diagnosis was indicative of HUS (see Figure 1). The patient restarted urination on the 20^th day of hospitalization, 800 ml urine per day and 1400–2200 ml the following days. Laboratory examination of 24-hour urine concentration revealed significant proteinuria (1.1 g/24h, normal range 0–150 mg/24h). Finally, the serum concentration of creatinine on the last day of hospitalization was 1.46 mg/dL and the eGFR 71 mL/min/1.73m².

Figure 1. Segmental reduplication of the glomerular capillary basement membrane. Intraluminar thrombi are absent (PAS ×  400).

DISCUSSION

Diarrhoea-associated HUS develops in about 5–10% of children with hemorrhagic colitis due to Escherichia coli O157 and is the most common cause of ARF in childhood. It is quite uncommon in adults.[1],[2] The organism apparently colonizes the intestine after being ingested in contaminated food or transmitted by direct person-to-person contact. It releases two verocytotoxins, shiga toxins (stx1 and stx2), which are responsible for the clinical manifestation of the syndrome.[3] Potential pathologic mechanisms include the direct effects of the bacterial toxins on endothelial cells and platelets, a leukocyte-mediated vasculopathy and a severe prothrombotic coagulation disturbance.[4]

Originally, a variety of serotypes were described as causing the syndrome apart from O157:H7, such as O138:H- and O26:H11/H-.[5],[6] Further infection agents involved with the pathogenesis of HUS are Shigella dysenteriae, Aeromonas, Streptococcus pneumonia, and Parvo virus.[7–10]

As far as non-diarrhoea-associated HUS is concerned, genetic studies have shown that the disease depends on the deficiency or abnormalities in complement regulatory proteins of the alternative pathway. About 30% of the patients have mutations in the gene encoding factor H, which is a protein that inhibits the activation of the alternative pathway of the complement system. More recent observations have also shown the involvement of genes that encode membrane cofactor protein and factor I.[11] It may be familiar and recurrent. Familiar HUS accounts for 5–10% of all cases of the HUS. The mortality rate (54%) is much higher than that in D+ HUS (3–5%). About half of survivors have relapses, and more than one-third require long-term dialysis.[12] The differential diagnosis in our patient, after excluding the potency of infection with Leptospira or Hantaan virus, involved thrombotic thrombocytopenic purpura (TTP). Although TTP and HUS are often difficult to distinguish, TTP is usually preferred for cases in adults in which neurologic dysfunction predominates, whereas cases involving predominantly glomerular damage, which occur mainly in children, are diagnosed as HUS.[13] Our patient did not manifestate any sign of neurologic abnormality.

The plasma of patients with TTP demonstrates unusually large forms of von Willebrand Factor (vWF). These multimers are not present in normal plasma, due to a metalloproteinase, which is called ADAMTS13 and cleaves ultra large forms of vWF.[14] Non-familiar TTP is due to an inhibitor of ADAMS13, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with HUS do not have a deficiency of ADAMS13 or a defect in vWF that leads to its resistance to protease.[13]

The manifestation of HUS in our patient was extraordinary, first, because of her age. D+ HUS, as mentioned above, is uncommon in adults. Second, the duration of anuria was significantly long (22 days). Third, it involved not only the kidneys, but also the liver, the heart, and the genital system. The patient's cholestasis may be attributed to the administration of cotrimoxazole before admission,[15] indicating strongly that antibiotics may worsen the outcome of HUS.[16] This can also justify the negative stool cultures.

Patients with D+ HUS have a much better outcome than those with D- HUS. Except for D-, other factors suggesting poor prognosis include older age at onset, a family history of HUS, recurrence, anuria for more than 14 days, intestinal gangrene, severe neurological involvement, and pneumococcal infection. In a five-year follow-up study following an episode of D+ HUS, renal function did not recover in 2.9% of patients, while 39% of patients had some abnormality of renal function at the time of follow-up.[17]

In conclusion, HUS is a rare disease in adults, accounting for less than 5% of the causes of ARF. The symptomatic therapy, especially the vigorous control of renal failure, hypertension, and electrolyte imbalance in early dialysis, combined with plasma infusion, is the mainstay of treatment. Due to the significant rate of renal impairment after recovery, it is important for such patients to be kept under periodical medical evaluation.

Notes

This study was conducted independently. The authors did not receive financial or professional assistance with the preparation of the manuscript. Some of the authors have given talks, attended conferences, and participated in advisory boards and trials sponsored by various pharmaceutical companies.