Muhammad SN; Abdel Meguid E; Robert Novo’s

Review Article

Austin J Anat. 2017; 4(1): 1064.

Haemolytic Uraemic Syndrome (HUS): Clinical Medicine Versus Clinical Anatomy

Muhammad SN¹*, Abdel Meguid E²* and Robert Novo’s³

¹Specialist Biomedical Scientist, Co-Founder and Chief in Research, Renal Patient Support Group (RPSG), UK

²Centre for Biomedical Sciences Education, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK

³Hospital Practitioner, Paediatric Nephrologic Unit, University Hospital, Lille, France

*Corresponding author: Muhammad SN, Specialist Biomedical Scientist, Co-Founder and Chief in Research, Renal Patient Support Group (RPSG), England, UK

Received: January 16, 2017; Accepted: February 13, 2017; Published: February 16, 2017

Abstract

Haemolytic Uraemic Syndrome (HUS) is an acquired disorder affecting mainly infants and children. The triad of this clinical syndrome is defined by: 1) Thrombotic or Microangiopathic Haemolytic Anaemia with schistocytes 2) Thrombocytopenia and 3) Acute Renal Failure (ARF) which can develop into Chronic Kidney Disease (CKD). The aim of this article is to provide an editorial/ commentary on the Clinical Medicine versus Clinical Anatomy of HUS.

HUS is the most common cause of Acute Renal Failure (ARF) in children with an equal sex incidence [1]. The annual incidence of VTEC infection varies geographically; it can range from 1 to 30 cases per 100,000 in industrialized countries. It is a rare syndrome post-puberty but it is also closely related to Thrombotic Thrombocytopenia (TTP) which is common in adults. The annual incidence of the Verocytotoxin-producing Esherichia Coli (VTEC) infection varies geographically from year to year, ranging from 1-30 cases per 100,000 in industrialized countries and is associated with HUS. HUS occurs in sporadic cases epidemics; between 1st January [2] and 31st December [2] in England, a total of 3717 cases were reported with evidence of Shiga Toxin-Producing E. Coli (STEC) infection; sometimes following outbreaks. In Hamburg [3], there was an outbreak with more than 900 cases. The disease has seasonal variation, being more common in the warmer months in children.

Renal histopathology is characterized by abnormal morphology applicable to afferent arterioles and glomeruli. The glomeruli show evidence of global sclerosis and glomerular thrombotic microangiopathy endothelial cell swelling; capillary wall thickening and glomerular basement membranes also evident. Interstitial fibro edematous change and tubular atrophy are marked. Arterial, arteriolar and capillary lumina are narrow with obstruction and intimal thickening. The nature of vascular involvement in the kidneys supports the hypothesis that HUS is mediated by systemic toxemia and endothelial cells are the primary target cells owing to action of Verocytotoxin. Histopathological findings provide clues not only to the diagnosis but also in the support of prognosis. Diffuse tubular interstitial change and global sclerosis indicate the degree of blood flow obstruction and prognosis. Renal blood flow obstruction caused by diffused arterial and arteriolar luminal stenosis may lead to irreversible changes in renal pathology

Keywords: Haemolytic Uraemic Syndrome (HUS); Clinical medicine; Clinical anatomy; Chronic kidney disease; Acute renal failure; Haematology

Introduction

Haemolytic Uraemic Syndrome (HUS) occurs due to Shigalike toxin activity via aberrant complement activation. HUS is typically classified into two primary types: 1) HUS due to infections, often associated with diarrohea (D+HUS, Shiga toxin-producing Escherichia Coli-HUS), with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus; 2) HUS related to complement, such HUS is also known as “atypical HUS” and is not diarrohea associated (D-HUS, aHUS) [4]. Clinical features include proteinuria, renal impairment and history of E. coli diarrohea (hallmark of typical HUS). Encephalopathy is rare but can cause death. HUS is seen increasingly following outbreaks of infection with Verotoxin (VT)-producing organisms. It represents a growing public health problem and data suggest that more awareness of specific micro-organisms causing diarrhoea, (and those thus leading to HUS and/ or HUS related symptoms) may become more important in future health consultations [3].

E.coli 0157:H7 is the most commonly notified VT-producing organism in the UK and France. Clinical manifestations may vary from an asymptomatic infection to bloody diarrhoea, haemorrhagic colitis and HUS. Verotoxin Enterococcal (VTEC)-associated HUS was seen in up to 20% of patients in recent outbreaks, mainly affecting children [5]. Table 1 summarizes the defining classification of HUS and (Table 2) summarizes features of HUS, respectively.

Table 1: Classification of HUS.




  
    HUS - Classifications
  
  
    Typical
  
  
    Infection related
      Shiga toxin producing E. coli/ Shigella 
      Pneumococcal infection 
      HIV 
      Other viral or bacterial infections 
  
  
    Atypical
  
  
    Complement factor abnormality
      Factor H deficiency and Factor I deficiency 
  
  
    Miscellaneous
  
  
    Cumulative Trauma Disorder (CTD), drugs, malignancy



Table 1:  Classification of HUS.

Table 2: Defining features of HUS.




  
    HUS -    Defining Features
  
  
    
      Renal    involvement 
      Evidence of    coagulopathy –intravascular coagulation in the kidney 
      Antipathy -    marked fragmentation of red cells 
      The disorder    is associated with activation of neutrophils 
      Typical HUS    is secondary to GI infection with Verocytotoxin-producing E-coli 0157:H7    (VTEC), less often Shigella 
      Complement    activation used to attack foreign bodies 
      Complement system    highly regulated to prevent it from damaging healthy tissues/ organs 
      Platelet    activation, damage to endothelial cells (cells that line the blood vessels),    white blood cell activation causing haemolysis
      Thrombotic    Microangiopathy (TMA) – formation of blood clots in small vessels throughout    the body and over time, causing multiple organ damage
    
  
  
    Table    adopted from (Blaser 2004; Licht et al. 2009)



Table 2:  Defining features of HUS.

HUS epidemiology

HUS is the most common cause of Acute Renal Failure (ARF) in children with an equal sex incidence [1]. The annual incidence of VTEC infection varies geographically; it can range from 1 to 30 cases per 100,000 in industrialized countries. There is seasonal variation, thus being more common in warmer months. It is more common in those under 5-years.

Between 1^st January [6] and 31^st December [6] in England, a total of 3717 cases were reported with evidence of Shiga Toxin-producing E. Coli (STEC) infection, and the crude incidence of STEC infection was 1•80/100 000 person-years. Incidence was highest in children aged 1-4 years (7•63/100 000 person-years) [2].

HUS diarrohea association

Most common cause of HUS and intrinsic ARF in paediatrics in the UK, France and USA industrialized countries is diarrhoea. There are no specific therapies to treat the diarrohea. Mortality is as high as 8.5 % and up to 30 % of survivors may develop further Glomerular Filtration Rate (GFR) impairment or albuminuria [6].

Use of anti-motility drugs may increase the risk of developing HUS and it is a rare syndrome post-puberty [1]. Atypical HUS (aHUS) can be inherited or acquired and does not appear to vary by race, gender or geographic area. Data on the prevalence of aHUS is limited [7,8] (Table 3).

Table 3: HUS signs.




  
    HUS - Signs
  
  
    
      Patients present    with anaemia 
      Petechiae, purpura,    and fever are common 
      GI bleeding is    often found and a bloody diarrohea 
      GI disease may be    severe with haemorrhagic colitis, toxic megacolon, rectal prolapse, and bowel    necrosis 
      Neurological    symptoms 
      Cardiac involvement    may lead to Congestive Heart Failure (CHF) and arrhythmias 
      Microinfarcts in    the pancreas (pancreatitis) or, rarely, Insulin Dependent Diabetes Mellitus    (IDDM) 
    
  
  
    (Table    adopted from Licht et al., 2009)



Table 3:  HUS signs.

HUS and laboratory tests/ investigations

Haemolysis and red cell fragmentation are usually evident at presentation, although this rarely develops later in the disease even after platelet count improvement (Table 4). Coagulation studies are usually normal with mildly raised D-dimer titres in contrast to Disseminated Intravascular Coagulation (DIC) [9]. The Von- Willebrand Factor (VWF) levels are usually markedly raised during acute illness while analysis may/ may not show ultra-large multimers [10]. Poor prognostic features at presentation include a high neutrophil count [11]. Severe thrombocytopenia is uncommon but prolonged thrombocytopenia for more than 10 days is associated with long-term renal picture. Factor VIII levels do not correlate with clinical outcome [12]. Table 5 summarizes laboratory tests/ investigations according to Haematology specialty. Figure 1 depicts HUS red cell morphology under microscopy.

Figure 1: HUS red cell morphology under microscopy. RBC fragmentation with obvious schistocytes/ helmet cells. Note decrease in platelets which is a typical picture in HUS patients. Schistocytes are irregularly shaped fragments with two pointed ends without central pallor (Barcellini & Fattizzo 2015). Slide taken from (https://emedicine.medscape.com/article/779218-workup) (accessed December 2016).

    
    
    Figure 1: HUS red cell morphology under microscopy. RBC fragmentation
with obvious schistocytes/ helmet cells. Note decrease in platelets which is a
typical picture in HUS patients. Schistocytes are irregularly shaped fragments
with two pointed ends without central pallor (Barcellini & Fattizzo 2015).
Slide taken from (https://emedicine.medscape.com/article/779218-workup)
(accessed December 2016).

Table 4: HUS symptoms.




  
    HUS -    Symptoms
  
  
    
      The kidneys are    swollen and pale 
      Many flea-bite    hemorrhages are on the surface 
      GI involvement may    lead to symptoms of an acute abdomen, with occasional perforation 
      Hypertension 
      Anuria – Oliguria,    depending on overall GFR/ renal function
    
  
  
    (Table    adopted from Licht et al., 2009)



Table 4:  HUS symptoms.

Table 5: HUS – Haematology.




  
    HUS -    Haematology
  
  
    Full Blood Count (FBC) highlights an anaemic picture on presentation 
  
  
    Coagulation highlights APTT and PT are both normal - suggests sepsis    rather than HUS/TTP 
  
  
    Platelet and    fibrin micro-thrombi is evident within the renal microvasculature 
  
  
    Thrombocytopenia is universal at some point in the illness 
  
  
    Haematinics highlight there is variability in Iron titres 
  
  
    Direct Coombes Test is Negative 
  
  
    Plasma Haptoglobin levels is decreased owing to Red Blood Cell (RBC)    breakdown/ degradation 
  
  
    Raised Fraction Degradation Products (FDPs) 
  
  
    There is a    slightly elevated D-Dimer 
  
  
    There may    be  microcytosis 
  
  
    Red cell    enzymes and osmotic fragility are normal 
  
  
    Reticulocyte    count is elevated 
  
  
    (Table adapted from Taylor et al.,    1999; Taylor 2001a; Taylor 2001b; Taylor et al., 2004)



Table 5:  HUS – Haematology.

Prognosis and treatment

Treatment is by supportive measure, and the main treatments are either Haemodialysis (HD) or Peritoneal Dialysis (PD) because of the ARF. The prognosis is dependent upon the aetiology and renal function; there is a poor prognosis if patient requires HD or PD more than 7 days, but good prognosis is conceivable with total recovery of renal function with no arterial hypertension, and no proteinuria. Children with intra-cerebral involvement may be treated with plasma exchange, but efficacy and long-term use is not advisable [13-15].

Major neurological dysfunction occurs in a third of patients in atypical HUS and less than 10% in typical HUS; is associated with a poor prognosis [7]. There should be supportive information made available for the patient and parent or career/guardian. Eculizumab is a monoclonal antibody that binds to C5 to prevent the formation of C5a and the membrane attack complex [7,8]. This treatment has become popular and can be helpful for patients who may have extra renal involvement such as that seen in typical HUS. Its efficacy and safety in the treatment of aHUS has been highlighted recently [7,8].

Management

Either HD or PD treatments is essential when renal function is altered. It is crucial to control hypertension, thus preventing any longer term complications (Figures 2 and 3). RBC transfusion in children is common owing to anaemia [13-15]. Fraction Frozen Plasma (FFP) has been administered in adults [8].

Figure 2: Histological Stains of a Kidney Biopsy Specimen – Day 37 following Eculizumab Treatment characteristic of a HUS. (A) Almost all glomeruli give evidence of global sclerosis or collapse (Periodic Acid Schiff stain [PAS]; ×100). (B) Endothelial swelling is conspicuous and glomerular basement membranes are focally duplicated (Periodic Acid Methenamine silver stain [PAM]; ×1000). (C) Interstitial fibroedematous change and tubular atrophy are marked (Haematoxylin and Eosin stain [H&E]; ×200). (D, E) Arterial and arteriolar lumina stenosed or obstructed with intimal thickening (Elastica van Gieson stain [EVG]; ×1000). (F) Mononuclear cells infiltrated into intima of arteries (PASX1000). These findings are helpful demonstrating the diagnosis of TMA diagnosis (Slide stain taken from Okuda et al. 2015).

    
    
    Figure 2: Histological Stains of a Kidney Biopsy Specimen – Day 37 following
Eculizumab Treatment characteristic of a HUS. (A) Almost all glomeruli give
evidence of global sclerosis or collapse (Periodic Acid Schiff stain [PAS];
×100). (B) Endothelial swelling is conspicuous and glomerular basement
membranes are focally duplicated (Periodic Acid Methenamine silver stain
[PAM]; ×1000). (C) Interstitial fibroedematous change and tubular atrophy
are marked (Haematoxylin and Eosin stain [H&E]; ×200). (D, E) Arterial and
arteriolar lumina stenosed or obstructed with intimal thickening (Elastica van
Gieson stain [EVG]; ×1000). (F) Mononuclear cells infiltrated into intima of
arteries (PASX1000). These findings are helpful demonstrating the diagnosis
of TMA diagnosis (Slide stain taken from Okuda et al. 2015).

Figure 3: HUS - fibrin histological stain. Fibrin histological stain highlighting platelet-fibrin thrombi (red) in the glomerular capillaries, characteristic of HUS/microangiopathic disorder, (taken from https://slideplayer.com/ slide/11018533/) (accessed December 2016).

    
    
    Figure 3: HUS - fibrin histological stain. Fibrin histological stain highlighting
platelet-fibrin thrombi (red) in the glomerular capillaries, characteristic
of HUS/microangiopathic disorder, (taken from https://slideplayer.com/
slide/11018533/) (accessed December 2016).

Research perspectives

Haemoglobin (Hb) is the most direct indicator of clinical severity in haemolytic diseases. Its level may be close to normal values in mild forms (Hb >10 g/dL) or reduced in moderate (Hb 8–10 g/dL), severe (Hb 6–8 g/dL), and very severe (Hb 6 g/dL) forms (WHO 1989). In a differential diagnosis, an acute onset is more frequently observed in RBC enzymopathies involving the Pentose Phosphate (PP) shunt (e.g. glucose-6-phosphate-dehydrogenase, G6PD deficit) and in autoimmune haemolytic forms involving complement activation Autoimmune Haemolytic Anaemia (AIHA) caused by warm IgM, warm IgG + C, mixed, and Cold Agglutin Disease (CAD) (with thermal range close to physiological temperatures) and in Paroxysmal Nocturnal Haemoglobinuria (PNH) (Tables 6,7 and 8).

Table 6: HUS key haematology morphological features.




  
    HUS – Key Morphological Features
  
  
    Peripheral blood smear depicts striking red cell fragmentation 
  
  
    Findings of    microangiopathic haemolytic anaemia 
  
  
    Deformed,    irregular or helmet-shaped RBCs – schistocytes 
  
  
    Thrombocytopenia    (counts of 50 x 109/l) or less 
  
  
    Neutrophil    may be quite marked – it is a marker of adverse prognosis 
  
  
    Polychromasia    (greyish tinge) may be marked 
  
  
    Bone Marrow    is cellular – response to haemolysis/ red cell breakdown 
  
  
    (Table adapted from Taylor et al.,    1999; Taylor 2001a; Taylor 2001b; Taylor et al., 2004)



Table 6:  HUS key haematology morphological features.

Table 7: HUS– chemistry/ microbiology.




  
    HUS - Chemistry 
  
  
    Urea, Creatinine and Electrolytes demonstrate    abnormally high results 
  
  
    Urine, if present, may contain protein and RBCs 
  
  
    Liver Function Test (LFTS) can be normal 
  
  
    Urine dipstick can show some protein leaking    (24hr urine collection needed to quantify) 
  
  
    Electrophoresis can be helpful and important    to establish extent of protein leaking 
  
  
    Blood Urea Nitrogen (BUN) is markedly elevated 
  
  
    HUS - Microbiology 
  
  
    Cultured species of E-coli is performed 
  
  
    Mainly looking for group Enterohaemarrohagic E-Coli (EHEC) 
  
  
    (Table adapted from Taylor et al.,    1999; Taylor 2001a; Taylor 2001b; Taylor et al., 2004)



Table 7:  HUS– chemistry/ microbiology.

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Citation: Muhammad SN, Abdel Meguid E and Novo’s R. Haemolytic Uraemic Syndrome (HUS): Clinical Medicine Versus Clinical Anatomy. Austin J Anat. 2017; 4(1): 1064. ISSN:2381-8921

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