Problem 6: Diarrhoea and Anaemia by Mateo Claude

Definitions

mateoaclaude — 2022-03-06 17:08:42 UTC

Definition
- 3 or more unformed stools/day
- Liquid volume over 200g/day
- Over less than 14 days
Types of causes
- Organic
  - Stool weight >250 g/day
  - Nocturnal bowel frequency and urgency
- Functional
  - Passage of frequent small-volume stools (often formed)
- Infective
  - Sudden onset of bowel frequency associated with cramp abdominal pains and fever
- Inflammatory
  - Bowel frequency with loose blood-stained stools
- Steatorrhea
  - Passage of pale offensive stools that float, often accompanied by loss of appetite and weight loss

mateoaclaude — 2022-03-06 17:08:54 UTC

Acute Diarrhoea

mateoaclaude — 2022-03-06 17:09:04 UTC

Definition: Sudden onset, short-lived and requires no investigation or treatment.

Aetiology
- Acute non-inflammatory diarrhoea
  - Watery without blood
  - Periumbilical cramps, bloating, nausea, or vomiting
  - Usually mild and self-limited
  - Caused by a virus or noninvasive bacteria
    - i.e --> food poisoning
  - Typically mild but can be voluminous and result in
    - dehydration with hypokalemia and metabolic acidosis
  - Diagnostic evaluation is limited to patients with diarrhoea that is severe or persists beyond 7 days
  - Faecal leukocytes are not present
- Acute inflammatory diarrhoea
  - Blood or pus with fever
  - Usually caused by an invasive or toxin-producing bacterium
  - Involves the colon: therefore small in volume
  - Associated with left lower quadrant cramps, urgency, and tenesmus
  - Diagnostic requires bacterial testing of stool
  - Faecal leukocytes or lactoferrin are usually present

Symptoms and Clinical features
- Fever
- Abdominal pain
- Vomiting
- Dehydration of severe

Investigations
- Done it has lasted for > 1 week

Stool to lab:
- for culture and examination for ova, cysts and parasites and Clostridium difficile toxin assay
No diagnosis yet:
- sigmoidoscopy and rectal biopsy should be performed and imaging should be considered

Treatment
- Oral fluid and electrolyte replacement often necessary
- Special oral rehydration solutions are available for use in severe episodes
- Antidiarrheal agents: impair clearance of any pathogen from the bowel but may be necessary for short-term relief; improve comfort
- Antibiotics: necessary depending on organism

mateoaclaude — 2022-03-06 17:09:23 UTC

Chronic Diarrhoea

mateoaclaude — 2022-03-06 17:09:38 UTC

Definition:
- Lasting for < 4 weeks or more

Aetiology
- Medications
  - Cholinesterase inhibitors, SSRIs, angiotensin II receptor blockers, proton pump inhibitors, NSAIDs, metformin, allopurinol, orlistat
- Osmotic diarrhoea
  - As stool leaves the colon, faecal osmolality is equal to the serum osmolality (major osmoles: Na+, K+, Cl-, HCO3-)
  - Osmotic gap: difference between measured osmolality of the stool and the estimated stool osmolality (should be less than 50 mOsm/kg)
  - Increased osmotic gap → diarrhoea is caused by ingestion or malabsorption of an osmotically active substance
  - The gut acts as a semipermeable membrane and fluid enters the bowel if there are large quantities of non-absorbed hypertonic substances in the lumen, because:
    - Ingestion of a non-absorbable substance
    - Generalised malabsorption so that high concentration of solute (e.g. glucose) remain in the lumen
    - Specific absorption defect (e.g. lactose malabsorption)
  - Most common causes: carbohydrate malabsorption, laxative abuse, and malabsorption syndromes
  - Resolves during fasting
  - CF malabsorbed carbohydrates: abdominal distension, bloating, flatulence due to increased gas production
  - Diagnosis: hydrogen breath test
- Secretory conditions
  - Increased intestinal secretion of fluid and electrolytes or decreased absorption results in a high-volume watery diarrhoea with a normal osmotic gap
  - There is little change in stool output during fasting state
  - Dehydration and electrolyte imbalance may develop

- Inflammatory conditions
  - IBD: ulcerative colitis and Crohn disease / Infective conditions
  - Damage to intestinal mucosal cells → loss of fluid and blood
  - Defective absorption of fluid and electrolytes
- Conditions of Malabsorption
  - Major causes:
    - Small mucosal intestinal diseases
    - Intestinal resections
    - Lymphatic obstruction
    - Small intestinal bacterial overgrowth
    - Pancreatic insufficiency
  - Weight loss
- Motility disorders
  - IBS
  - Lower abdominal pain and altered bowel habits without any evidence of serious organic disease (--> weight loss, nocturnal diarrhoea, anaemia, GI bleeding)
  - Abnormal intestinal motility secondary to systemic disorders, radiation enteritis, or surgery may result in diarrhoea due to rapid transit or to stasis of intestinal contents with bacterial overgrowth, resulting in malabsorption
- Chronic infections
  - Most common pathogen: protozoans Giarda, entamoeba histolytica, and Cyclospora and intestinal nematodes
  - Immunocompromised patients are more susceptible
- Systemic conditions
  - Thyroid disease, diabetes, collagen vascular disorders

Investigations
- CD Always requires investigation unlike AD
- Clinical history determines small or large bowel investigation
- Colonoscopy necessary if stool cultures are negative and small bowel disease is not suspected

mateoaclaude — 2022-03-06 17:09:54 UTC

mateoaclaude — 2022-03-06 17:16:07 UTC

Definition:
- A decrease in haemoglobin in the blood
  - below reference levels according to patient age and sex.
- Anaemia not a final diagnosis without the cause behind it.
Clinical Features:
- sometimes asymptomatic
- Increase O2 carrying blood capacity due to falling haemoglobin levels.
- Rise in 2,3-BPG causes shift of O2 dissociation curve to the right,
- Rapid blood loss with more severe symptoms in elderly

Sings and Symptoms
- Fatigue, headaches, faintness
- Breathlessness
- Angina
- Intermittent claudication
- Palpitations
- Pallor
- Tachycardia
- Systolic flow murmur
- Cardiac failure
- Specific signs include: (spoon-shaped nails, jaundice, bone deformities, leg ulcers).

Investigations:
- Peripheral blood tests:
  - Low Haemoglobin
  - Red cell indices
  - WBC count
  - Platelet count
  - Reticulocyte count
  - Blood film (for RBC morphology)
- Bone Marrow
  - Done following peripheral blood tests.
  - aspiration film for morphology of developing haemopoietic cells.
  - Trephine biopsy for histological examination
  - Other investigations: cytogenic, immunological, cytochemical markers, biochemical analyses, microbiological culture.

Normal values of peripheral blood

mateoaclaude — 2022-03-06 17:16:27 UTC

Alterations of Haemoglobin

mateoaclaude — 2022-03-06 17:16:48 UTC

Classification

mateoaclaude — 2022-03-06 17:17:08 UTC

mateoaclaude — 2022-03-06 17:20:27 UTC

Definition
- the presence of small, often hypochromic, red blood cells in a peripheral blood smear and is usually characterized by a low MCV (less than 83 micron 3)
Causes
- Fe deficiency most common cause (30%)
  - limited Fe absorption and frequent loss due to bleeding
  - Insoluble ferric form (Fe3+) is most abundant, poor bioavailability
    - Ferrous (Fe2+) is more readily absorbed
  - Defect in haem synthesis
- Anaemia of chronic disease: defect in haem synthesis
- Sideroblastic anaemia: defect in haem synthesis
- Thalassemia: defect in globin synthesis

Iron

mateoaclaude — 2022-03-06 17:24:42 UTC

Dietary Intake
- Average: 15-20 of iron daily
- 10% is absorbed
- Absorption may be increased to 20-30% in iron deficiency and pregnancy
- Non-haem iron: cereals
- Haem iron: better absorbed
Absorption
- Factors influencing Fe absorption
  - Haem Fe better absorbed than non-haem Fe
  - Gastric acidity keeps Fe in ferrous state and soluble in the upper gut
  - Formation of insoluble complexes decrease Fe absorption
  - Fe absorption is increased with low Fe stores and increased erythropoietic activity
  - Decreased absorption in Fe overload
  - Fe absorption mechanisms
    - Dietary haem Fe
    - Non-haem Fe Absorption
Transport in Blood
- Normal serum iron level: 13-32 μmol/L
- Higher in the morning
- Fe transported bound to transferrin (𝛽-globulin)
- Each transferrin molecule binds 2 atoms of ferric iron and is normally ⅓ saturated
- Most of iron bound to transferrin comes from macrophages in the reticuloendothelial system
- Transferrin-bound iron becomes attached to specific receptors to erythroblasts and reticulocytes in the marrow and the iron is removed
Iron stores
- Ferritin = water-soluble complex of iron and protein. It is more easily mobilised than hemosiderin for Hb formation. It is present in plasma
- Haemosiderin = insoluble iron-protein complex found in macrophages of bone marrow, liver and spleen.
- ⅔ of total body iron is in circulation as haemoglobin (2.5-3.0 in adult man)
- Also stored in reticuloendothelial cells, hepatocytes and skeletal cells: 0.5-1.5 g
- ⅔ is stored as ferritin, ⅓ as haemosiderin
- Small amount of iron in plasma, with some in myoglobin and enzymes
Iron requirements
- Each day 0.5-1.0 mg of iron is lost in faces, urine and sweat
- Loss due to menstruation: 30-40 mL blood/month, 0.5-0.7 mg iron/day
  - Blood loss through menstruation in excess of 100 mL will usually result in iron deficiency as increased iron absorption from the gut cannot compensate for such losses of iron
- Iron demand increases during growth (0.6 mg/day) and pregnancy (1-2 mg/day)
- Normal adult: iron content of the body remains relatively fixed
- Haemochromatosis (= increased in body iron content) is classified into:
  - Hereditary haemochromatosis: mutation in the HFE gene causes increased iron absorption
  - Secondary haemochromatosis : iron overload in condition treated by regular blood transfusion
Iron Deficiency Anaemia
Causes:
- Blood loss (most cases, usually from uterus or GI tract)
- Increased demands (e.g. growth and pregnancy)
- Decreased absorption
- Poor intake (e.g.little vegetables)
Clinical features
- Symptoms of anaemia
- Brittle nails
- Spoon-shaped nails
- Atrophy of the papillae of the tongue
- Angular stomatitis
- Brittle hair
- Syndrome of dysphagia and glossitis
Investigations
- Blood count and film
- Serum iron and iron-binding capacity
- Serum ferritin
- Serum soluble transferrin receptors
- Other investigations
  - Indicated by clinical history and examination.
  - Investigations of GI tract are often required to determine the cause of the iron deficiency

mateoaclaude — 2022-03-06 17:26:10 UTC

Caused by chronic infection and Chronic Inflammatory disease.
What chronic disease?
Pathophysiology
- decreased release of Fe from bone marrow to developing erythroblasts, inadequate erythropoietin response and decreased RBC survival.
- Mechanisms not know well (likely that hepcidin regulation and expression plays a major role).
Investigations
- Blood values
  - Serum iron and TIBS are low
  - Serum ferritin is normal or raised (inflammatory process)
  - Serum soluble transferrin receptor level is normal
- Stainable Fe present in marrow but not seen in erythroblasts.
Treatment
- Treatment of underlying disorder
- Patients unresponsive to Fe therapy

mateoaclaude — 2022-03-06 17:27:24 UTC

Definition: Inherited or acquired disorders characterised by a refractory anaemia, a variable number of hypochromic cells in the peripheral blood, and excess iron and ring sideroblasts in the bone marrow.

Causes
- Can be inherited as an X-linked disease transmitted by females
- Acquired causes:
  - Myelodysplasia
  - Myeloproliferative disorders
  - Myeloid leukaemia
  - Drugs (e.g. isoniazid)
  - Alcohol misuse
  - Lead toxicity

Diagnosis
- Presence of ring sideroblasts
- Perl’s reaction: you can see accumulation or iron in the mitochondria of erythroblasts due to disordered haem synthesis of haem synthesis forming a ring of iron granules around the nucleus
- Blood fil: dimorphic; ineffective haem synthesis is responsible for the microcytic hypochromic cells

Treatment
- Stop drugs or alcohol that might cause it
- In some cases, pyridoxine works
- Folic acid may be required to treat accompanying folate deficiency

When is it seen?

mateoaclaude — 2022-03-06 17:29:19 UTC

Anaemia of chronic disease
Some endocrine disorders (e.g. hypopituitarism, hypothyroidism, hypoadrenalism
Some haematological disorders (e.g. aplastic anaemia, some haemolytic anaemias)

mateoaclaude — 2022-03-06 17:34:43 UTC

Megaloblastic Anaemia
- definition: characterised by the presence in the bone marrow of erythroblasts with delayed nuclear maturation because of defective DNA synthesis (megaloblasts).
- Large megaloblasts with large, immature nuclei (image below).
- haematological findings
- biochemical basis
Treatment & Prevention
Vitamin B12
- function
  - methylation of homocysteine to methionine through demethylation of methyl THF polyglutamate to THF.
    - THF is a substrate for folate polygluta- mate synthesis.
  - Deoxyadenosylcobalamin is a coenzyme for the conver- sion of methylmalonyl CoA to succinyl CoA
- Absorption and transport
  - Vitamin B12 is liberated from protein complexes in food by gastric enzymes
    - then binds to a vitamin B12-binding protein (‘R’ binder from saliva)
  - Vitamin B12 is released from the ‘R’ binder by pancreatic enzymes and then becomes bound to an intrinsic factor.
  - It combines with vitamin B12 and carries it to specific receptors on the surface of the mucosa of the ileum.
  - Vitamin B12 enters the ileal cells and is transported from the enterocytes to the bone marrow and other tissues by TCII (carrier) or mainly bound TCI in plasma
- deficiency causes in table 8.4 below
- treatment (p. 384)
Pernicious Anaemia
- Definition
  - Pernicious anaemia (PA) is an autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in the gastric mucosa with consequent failure of intrinsic factor production and vitamin B12 malabsorption.
- Risk group and Epidemiology
  - Common in the elderly, with 1 in 8000 of the population aged over 60 years being affected in the UK. It can be seen in all races, but occurs more frequently in fair-haired and blue-eyed individuals, and those who have the blood group A. It is more common in females than males.
  - There is an association with other autoimmune diseases, particularly thyroid disease, Addison’s disease and vitiligo. Approximately one-half of all patients with PA have thyroid antibodies. There is a higher incidence of gastric carcinoma with PA (1–3%) than in the general population.
- Pathogenesis
  - Parietal cell antibodies are present in the serum in 90% of patients with PA – and also in many older patients with gastric atrophy. Conversely, intrinsic factor antibodies, although found in only 50% of patients with PA, are specific for this diagnosis. Two types of intrinsic factor antibodies are found: a blocking antibody, which inhibits binding of intrinsic factor to B12, and a precipitating antibody, which inhibits the binding of the B12-intrinsic factor complex to its receptor site in the ileum.
  - B12 deficiency may rarely occur in children from a congeni- tal deficiency or abnormality of intrinsic factor, or as a result of early onset of the adult autoimmune type.
- Pathology
  - Autoimmune gastritis affecting the fundus is present with plasma cell and lymphoid infiltration.
  - The parietal and chief cells are replaced by mucin-secreting cells. There is achlorhydria and absent secretion of intrinsic factors.
  - The histological abnormality can be improved by corticosteroid therapy, which supports an autoimmune basis for the disease.
Clinical features
- The onset of PA is insidious, with progressively increasing symptoms of anaemia.
- combination of pallor and mild jaundice caused by excess breakdown of haemoglobin. A red sore tongue (glossitis) and angular stomatitis are sometimes present
- Long untreated anaemia → neurological abnormalities with very low levels of serum B12 in patients who are not clinically anaemic.
- Dementia, psychiatric problems, hallucinations, delusions, and optic atrophy may occur from vitamin B12 deficiency.
Investigations
Haematological findings
Bone marrow
- shows the typical features of megaloblastic erythropoiesis,
Serum bilirubin
- may be raised as a result of ineffective erythropoiesis.
LDH
- raised due to haemolysis.
MMA and HC
- re raised in B12 deficiency. Useful in cases where the B12 and folate levels are not conclusive with only HC raised in folate deficiency.
Serum vitamine B12
- usually well below 160 ng/L, which is the lower end of the normal range. Serum
  vitamin B12 can be assayed using radioisotope dilution or immunological assays.
Serum folate
- normal or high
Red cell folate
- normal or reduced owing to inhibition of normal folate synthesis.
Absorption tests
- Vitamin B12 absorption tests are performed only occasionally when the underlying cause of the B12 deficiency is not obvious.
Schilling test
- Radioactive B12 is given orally followed by an i.m. injection of non-radioactive B12 to saturate B12 binding proteins and to flush out 58Co-B12.
- The urine is collected for 24 h and >10% of the oral dose would be excreted in a normal person.
GI test
- In PA there is achlorhydria. Intubation studies can be performed to confirm this but are rarely carried out in routine practice.
- Endoscopy or barium meal examination of the stomach is performed only if gastric symptoms are present.

Folic Acid
- Function
  - Intracellular polyglutamates are the active forms of folate and act as coenzymes in the transfer of single carbon units in amino acid metabolism and DNA synthesis
- Dietary intake
  - Folate is found in green vegetables, such as spinach and broccoli, and offal, such as liver and kidney. Cooking causes a loss of 60–90% of the folate. The minimal daily requirement is about 100 μg.

Folate deficiency
- Causes in Table 8.5 below.
- Clinical features
  - Patients with folate deficiency may be asymptomatic or present with symptoms of anaemia or of the underlying cause. Glossitis can occur. Unlike with B12 deficiency, neuropathy does not occur.
- Investigations
  - Blood measurements
    - Serum and red cell folate are assayed by radioisotope dilu- tion or immunological methods. Normal levels of serum folate are 4–18 μg/L (5–63 nmol/L). The amount of folate in the red cells is a better measure of tissue folate
    - Normal 160-640μg/L.
  - Further investigations
    - In many cases of folate deficiency, the cause is not obvious from the clinical picture or dietary history.
    - Occult gastro- intestinal disease should then be suspected and appropriate investigations, such as small bowel biopsy, should be performed.
- Treatment
  - 5 mg of folic acid daily; the same haematological response occurs as seen after treatment of vitamin B12 deficiency. Treatment should be given for about 4 months to replace body stores. Any underlying cause, e.g. coeliac disease, should be treated

mateoaclaude — 2022-03-06 17:35:35 UTC

Physiological cause
Pathological cause

mateoaclaude — 2022-03-06 17:36:18 UTC

Features
- Enhanced red cell breakdown and catabolism of heme:
- Result in an increase in the level of unconjugated or “indirect” bilirubin in the plasma/serum
  - can lead to jaundice
- Chronic hemolysis
  - risk of developing bilirubin gallstones.
Red Cell Breakdown
- RBCs at the end of their lifespan are engulfed by macrophages.
- RBC haemoglobin is catabolized.
- The heme is broken down into bilirubin, which is exported into the plasma where it binds to albumin.
- This complex is taken up by the liver, where bilirubin is conjugated with glucuronide and excreted in the bilem, enters the duodenum, and traverses the intestines

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mateoaclaude — 2022-03-07 06:32:08 UTC

mateoaclaude — 2022-03-07 06:40:56 UTC

C. difficile-associated diarrhoea/pseudomembranous colitis
- can be caused by antibiotics
- Occurs in the first few days after taking antibiotic up to 6 weeks after stopping the drug
- Caused by Clostridium difficile pathogen
Bile acid malabsorption
- Underdiagnosed cause of diarrhoea
- Occurs when the terminal ileum does not reabsorb bile acids
- Bile acids when present in increased concentrations in the colon lead to diarrhoea
  - Reduced water/electrolyte absorption
  - induce secretion and motility at higher concentrations
- Causes
  - Ileal resection and Ileal disease
  - Primary bile acid diarrhoea
  - Post Infective gastroenteritis
- SeHCAT test (diagnosis)→ radiolabelled bile acid analogue is administered and retention at 7 days is calculated.
- Treatment: bile salt sequestrants
  - inactivate bile acid (and effects) in the colon

Factitious diarrhoea:
- accounts for 4% of diarrhoea patients
- Purgative abuse
  - Commonly seen in females who take high-dose purgatives
    - Often extensively investigated for chronic diarrhoea
  - High volume and low serum potassium
  - Biochemical analysis of the stool may help diagnose laxative abuse

Dilution diarrhoea
- Raised stool weight due to dilution of stool with urine or tap water.
- Diagnosis: measure stool osmolality and electrolyte concentrations to calculate the faecal osmolar gap
HIV infection
- Most common pathogen: Cryptosporidium
- Cause is often not found → symptomatic treatment

mateoaclaude — 2022-03-07 07:14:25 UTC

mateoaclaude — 2022-03-07 07:46:18 UTC

mateoaclaude — 2022-03-07 07:51:20 UTC

Definition
- A raised MCV with macrocytosis on the peripheral blood film with a normoblastic rather than a megaloblastic bone marrow

Causes
- physiological cause: Pregnancy.
  - Macrocytosis may also occur in the newborn.
- pathological causes:
  - Alcohol
  - Liver disease
  - Reticulocytosis
  - Hypothyroidism
  - Some haematological disorders
  - Drugs (e.g. hydroxycarbamide, azathioprine)
  - Cold agglutinins

Mechanisms of diarrhoea

mmtzclaros1 — 2022-03-07 11:56:27 UTC

Mechanisms
Osmotic diarrhoea
The gut mucosa acts as a semipermeable membrane and
fluid enters the bowel if there are large quantities of non-
absorbed hypertonic substances in the lumen. This occurs
because:
! The patient has ingested a non-absorbable substance
(e.g. a purgative such as magnesium sulphate or
magnesium-containing antacid)
! The patient has generalized malabsorption so that high
concentrations of solute (e.g. glucose) remain in the
lumen
! The patient has a specific absorptive defect (e.g.
disaccharidase deficiency or glucose-galactose
malabsorption).
The volume of diarrhoea produced by these mechanisms
is reduced by the absorption of fluid by the ileum and colon.
The diarrhoea stops when the patient stops eating or the
malabsorptive substance is discontinued.

Secretory diarrhoea
In this disorder, there is both active intestinal secretion of
fluid and electrolytes as well as decreased absorption. The
mechanism of intestinal secretion is shown in Figure 6.45a.
Common causes of secretory diarrhoea are:
! Enterotoxins (e.g. cholera, E. coli thermolabile or
thermostable toxin, C. difficile)
! Hormones (e.g. vasoactive intestinal peptide in the
Verner–Morrison syndrome, p. 370)
! Bile salts (in the colon) following ileal resection
! Fatty acids (in the colon) following ileal resection
! Some laxatives (e.g. docusate sodium).
Inflammatory diarrhoea (mucosal destruction)
Diarrhoea occurs because of damage to the intestinal
mucosal cell so that there is a loss of fluid and blood (Fig.
6.45b). In addition, there is defective absorption of fluid and
electrolytes. Common causes are infective conditions (e.g.
dysentery due to Shigella) and inflammatory conditions (e.g.
ulcerative colitis and Crohn’s disease).
Abnormal motility
Diabetic, post-vagotomy and hyperthyroid diarrhoea are all
due to abnormal motility of the upper gut. Symptoms may
be exacerbated by small bowel bacterial overgrowth.
Causes of diarrhoea are shown in Table 6.21. It should be
noted that the irritable bowel syndrome, colorectal cancer,diverticular disease and faecal impaction with overflow in the
elderly do not cause ‘true’ organic diarrhoea (i.e. >250 g/
day), even though the patients may complain of diarrhoea.

Treatment & investigation acute diarrhoea

615230al — 2024-03-04 11:32:25 UTC