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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

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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.

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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

1. Stool to lab:

for culture and examination for ova, cysts and parasites and Clostridium difficile toxin assay

2. 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

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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

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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

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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

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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

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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

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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

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Anaemia of chronic disease

Some endocrine disorders (e.g. hypopituitarism, hypothyroidism, hypoadrenalism

Some haematological disorders (e.g. aplastic anaemia, some haemolytic anaemias)

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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

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Physiological cause

Pathological cause

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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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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

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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.

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Treatment & investigation acute diarrhoea

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Treatment & investigation acute diarrhoea